Tormod Fladby

• Jarholm, Jonas Alexander; Teceläo, Sandra Raquel Ramos; Kirsebom, Bjørn-Eivind; Ghazi, Mostafa Mehdipour; Pålhaugen, Lene & Gisladottir, Berglind [Show all 17 contributors for this article] (2026). Independent prognostic value of peak width of skeletonized mean diffusivity on clinical progression in Alzheimer's disease. Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. 18(3). doi: 10.1002/dad2.70416. Full text in Research Archive Show summary

  INTRODUCTION Peak width of skeletonized mean diffusivity (PSMD) is a candidate magnetic resonance imaging marker for global white matter integrity. We investigated the value of PSMD in predicting clinical progression in amyloid-positive and amyloid-negative individuals. METHODS PSMD, cognition, and amyloid status were measured in 254 subjects from the Dementia Disease Initiation (DDI) cohort and 211 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Survival analysis was conducted on 166 DDI subjects and validated in 178 ADNI subjects using Clinical Dementia Rating scale. RESULTS High PSMD amyloid-positive individuals had an increased risk of clinical progression relative to those with low PSMD, driven by independent additive effects of amyloid pathology and PSMD. Higher PSMD was predominantly associated with slower processing speed and reduced executive function, but not with memory performance. DISCUSSION Combining PSMD with amyloid status may improve the prediction of clinical progression in Alzheimer's disease, particularly in relation to executive and processing speed domains.

• Dai, Linbin; Kirsebom, Bjørn-Eivind; Wang, Chenxi; Zhang, Mengguo; Wang, Qiong & Ni, Ming [Show all 12 contributors for this article] (2026). Cerebrospinal fluid NPTX1 and NPTXR predict neurodegeneration and clinical progression in Alzheimer’s disease. Nature Communications. 17(1). doi: 10.1038/s41467-026-70472-6. Full text in Research Archive
• Knudtzon, Stephanie; Kirsebom, Bjørn-Eivind; Pålhaugen, Lene; Bettella, Francesco; Gisladottir, Berglind & Bahrami, Shahram [Show all 19 contributors for this article] (2026). Genotype–phenotype interaction in Alzheimer's disease immune activation. Alzheimer's & Dementia. ISSN 1552-5260. 22(1). doi: 10.1002/alz.70978. Full text in Research Archive Show summary

  Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder influenced by genetic factors, particularly related to immune activation. This study examines genotype-phenotype interactions affecting immune responses in AD as a reaction to neurodegeneration. Methods: We computed AD polygenic risk scores (PRSs) informed by shared AD-autoimmunity genetics (AD PRSINFL), AD-independent immune activation score from 10 autoimmune diseases (sum PRSIMMUNE), and standard AD PRSs for 294 individuals. Cerebrospinal fluid (CSF) immune markers (sTREM2, clusterin, fractalkine, and chitinase 3 like protein (YKL-40)) were regressed on PRSs, and their interaction with neurodegeneration markers (total tau [t-tau] or neurofilament light chain [NfL]). Results: High AD PRSINFL scores correlated with lower sTREM2 (β = −0.18, p < 0.01), clusterin (β = −0.12, p < 0.05), and fractalkine (β = −0.13, p < 0.05) levels in cases with elevated t-tau. High sum PRSIMMUNE score correlated with lower clusterin in cases with elevated NfL (β = −0.12, p < 0.05). Discussion: Genetic predisposition for immune activation might cause unfavorable immune response in early AD.

• Akdeniz, Bayram Cevdet; Bahrami, Shahram; Hagen, Espen; Fuhrer, Julian; Fominykh, Vera & Shadrin, Alexey [Show all 108 contributors for this article] (2026). Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer’s Disease in European Populations: Development and Validation. medRxiv. doi: 10.1101/2025.07.28.25332293. Full text in Research Archive Show summary

  Abstract Objectives Polygenic hazard score (PHS) models can be used to predict the age-associated risk for complex diseases, including Alzheimer’s disease (AD). In this study, we present an improved PHS model for AD that incorporates a large number of genetic variants and demonstrates enhanced predictive accuracy for age of onset in European populations compared to alternative models. Methods We used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model. We developed a PHS model building on 720 genetic variants, including Apolipoprotein E ( APOE ) ε2 and ε4 alleles. We used Elastic Net-regularized Cox regression approach to develop the PHS model. Results The new PHS model (EADB720) improved prediction accuracy compared to alternative models in European populations, with the Odds Ratio OR80/20 from the highest quintile of risk (80th risk percentile and above) to the lowest quintile of risk (20th risk percentile and below) varying between 5.10 and 13.15 within the range of age of onset from 65 – 85 years. Our model also improved risk stratification across ε3/3 individuals of European ancestry (OR80/20 ranges from 1.95 to 3.52). It was also successfully validated in independent datasets (HUSK, DemGene and ADNI) by achieving OR80/20 up to 10.00 in each independent dataset. Conclusion Our EADB720 model significantly improves the accuracy of age-associated risk of AD across European populations (pval<0.03). Accurately predicting the age of onset of AD is of large clinical importance to implementing new AD medication and early intervention in clinical settings.

• Eliassen, Ingvild Vøllo; Kirsebom, Bjørn-Eivind; Waterloo, Knut; Skogseth, Ragnhild Eide; Grøntvedt, Gøril Rolfseng & Hemminghyth, Mathilde Suhr [Show all 11 contributors for this article] (2025). Pathological biomarkers for Alzheimer’s disease in cognitively unimpaired individuals are not associated with cognitive decline at two-year follow-up. Applied neuropsychology: Adult. ISSN 2327-9095. doi: 10.1080/23279095.2025.2518566. Full text in Research Archive Show summary

  Background Alzheimer’s disease (AD) pathology may be present in cognitively unimpaired individuals, but the clinical implications of this are unclear. Subtle cognitive decline is a potential marker of preclinical AD. Objective To investigate whether two-year cognitive change scores are influenced by AD-linked cerebrospinal fluid (Aβ42/40, p-tau, t-tau, NfL) or plasma (p217, BD-tau, NfL) biomarker pathology in individuals who are cognitively unimpaired at baseline. Methods Participants were 148 cognitively unimpaired older adults (mean age = 68.11). Mean cognitive change over two years was compared between participants with normal and pathological biomarker status, for each biomarker separately. Results We found no significant difference between mean change scores in people with abnormal biomarker values compared to normal biomarker groups. Conclusion Regardless of baseline CSF biomarker positivity, no significant cognitive change was observed in this group.

• Arslan, Burak; Andreasson, Ulf; Rembeza, Elzbieta; Axelsson, Markus; Novakova, Lenka & Kirsebom, Bjørn-Eivind [Show all 13 contributors for this article] (2025). Validation of a plasma GFAP immunoassay and establishment of age-related reference values: bridging analytical performance and routine implementation. Clinical Chemistry and Laboratory Medicine. ISSN 1434-6621. 63(12), p. 2522–2535. doi: 10.1515/cclm-2025-0870. Full text in Research Archive Show summary

  Abstract Objectives Glial fibrillary acidic protein (GFAP) is a well-established biomarker of astrocytic activation associated with neurodegenerative diseases, neuroinflammatory disorders, and traumatic brain injury. With increasing interest in blood-based biomarkers, the need for analytically validated assays and reliable reference intervals is critical for routine clinical implementation. This study aimed to analytically validate the MSD S-Plex ® GFAP immunoassay for plasma and to establish age-stratified reference intervals in an apparently healthy population. Methods This study was conducted in two phases. First, key analytical validation parameters – including repeatability, intermediate precision, measurement range, interferences, and sample stability – were evaluated following Clinical and Laboratory Standards Institute (CLSI) and published protocol guidelines. Second, reference intervals were derived from 579 apparently healthy individuals aged 17–91 years using a right-sided non-parametric percentile method. Age-specific upper reference limits were calculated for three predefined age groups, and a continuous age-dependent centile model was applied. Results MSD S-Plex ® GFAP assay demonstrated strong analytical performance, with coefficients of variation for repeatability and intermediate precision below 12 %. After accounting for the 1:2 dilution ratio, the validated measurement range was 0.425–1760 ng/L, with all calibration residuals remaining within ±15 %. GFAP concentrations were unaffected by hemolysis (p=0.85) and remained stable for up to 7 days at 4 °C and under frozen storage conditions. Age-stratified upper reference limits for plasma GFAP were established as 38 pg/mL (18–<50 years), 73 pg/mL (≥50–<70 years), and 156 pg/mL (≥70 years). Additionally, sex-related differences were observed after age 50, with females showing higher absolute GFAP levels than males. A strong positive correlation between age and plasma GFAP levels was observed (Spearman’s r=0.832, p<0.0001). Conclusions This study demonstrates the robust analytical performance of the MSD S-Plex ® GFAP assay and establishes age-related reference values for plasma GFAP. These findings support its suitability for routine clinical use and enhance its applicability in the diagnosis and monitoring of central nervous system (CNS) pathologies, such as neurodegenerative diseases, neuroinflammatory disorders, and acute brain injuries, within biomarker-supported clinical algorithms.

• Jaramillo-Jiménez, Alberto; Mantilla-Ramos, Yorguin-Jose; Tovar-Rios, Diego Alejandro; Lopera, Francisco; Aguillón, David & Ochoa-Gomez, John Fredy [Show all 15 contributors for this article] (2025). Characterizing resting-state EEG oscillatory and aperiodic activity in neurodegenerative diseases: A multicentric study. Computers in Biology and Medicine. ISSN 0010-4825. 197(Part B). doi: 10.1016/j.compbiomed.2025.111080. Full text in Research Archive
• Kirsebom, Bjørn-Eivind; Nilsson, Johanna; Vromen, Ellen; Arnesen, Peter Mikael; Bjørnerud, Atle & Brinkmalm, Ann [Show all 23 contributors for this article] (2025). Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer’s disease genetic pathways. Molecular Neurodegeneration. 20(1), p. 1–21. doi: 10.1186/s13024-025-00899-w. Full text in Research Archive Show summary

  Abstract Background Synapse loss is linked to cognitive symptoms in Alzheimer’s Disease (AD) and Cerebrospinal fluid (CSF) synaptic biomarkers may clarify disease heterogeneity and disease mechanisms for progression beyond amyloid (Aβ) and tau pathologies, potentially revealing new drug targets. Methods We used a mass-spectrometry panel of 17 synaptic biomarkers including neuronal pentraxins (NPTXs) linked to glutamatergic signaling, and 14-3-3 proteins linked to tau-pathology and synaptic plasticity. Synapse markers were evaluated in two independent cohorts: Dementia Disease Initiation (DDI) ( n  = 346) and Amsterdam Dementia Cohort (n =  397 ), both with cognitive assessments up to 10 years. We used linear regression to compare synapse marker differences between CSF-determined Aβ + cognitively normal (CN) and Mild Cognitive Impairment (MCI) groups, with or without CSF tau pathology (Tau+/-), relative to CN Aβ-/Tau- controls; and associations between synapse markers and medial temporal lobe (MTL) MRI volumetrics in the DDI cohort and with verbal memory in both cohorts. A funneling procedure identified proteins related to Aβ/Tau pathology and memory impairment in both cohorts, which were used to evaluate relations to Aβ/Tau biological progression in the DDI cohort and memory decline in both cohorts. Finally, we explored genetic pathways associated with these synaptic proteins. Results In both cohorts, most markers were elevated in Aβ+/Tau + cases compared to controls, particularly 14-3-3ζ/δ. Several proteins were reduced in Aβ+/Tau- cases, especially NPTX-2, while 14-3-3ζ/δ remained elevated. However, the increase in e.g. 14-3-3ζ/δ and reduction in e.g. NPTX2 were more pronounced in patients with MCI than CN cases regardless of tau-pathology, corresponding to verbal memory impairment and MTL atrophy. Elevated baseline 14-3-3ζ/δ and rab GDP Dissociation Inhibitor Alpha (GDI-1) associated with future progression from Aβ+/Tau- to Aβ+/Tau+. Significant associations (all p  < 0.001) were found between 14-3-3 protein genes ( YWHAZ , YWHAE ) and pathways linked to AD, including the p38 MAPK, IGF, PIK3/AKT and between GDI1 and p38 MAPK upstream pathway ( p  < 0.05) all connected to synaptic plasticity. Correspondingly, a robust 14-3-3ζ/δ association with future memory decline was observed in both cohorts. Conclusions Reduced markers for excitatory signaling in Aβ+/Tau- and increased synaptic plasticity markers in Aβ+/Tau + cases suggest differential but linked processes underlying disease progression and resilience in the groups.

• Oomens, Julie E; Vos, Stephanie JB; Maserejian, Nancy N; Boada, Mercè; Didic, Mira & Engelborghs, Sebastiaan [Show all 106 contributors for this article] (2025). Associations of lifestyle factors with amyloid pathology in persons without dementia. Journal of Alzheimer's Disease. ISSN 1387-2877. 108(3), p. 1043–1059. doi: 10.1177/13872877251379083. Full text in Research Archive Show summary

  Background The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood. Objective The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology. Methods For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology. Results We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004). Conclusions In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.

• Padrela, Beatriz E.; Teceläo, Sandra Raquel Ramos; Kirsebom, Bjørn-Eivind; Geier, Oliver Marcel; Tranfa, Mario & Masserini, Federico [Show all 22 contributors for this article] (2025). Blood-brain barrier water exchange in relation to amyloid, cognition and cerebrovascular burden. NeuroImage: Clinical. 49. doi: 10.1016/j.nicl.2025.103926. Full text in Research Archive Show summary

  Blood-brain barrier (BBB) water exchange may serve as a sensitive early biomarker for Alzheimer’s disease and age-related cognitive decline. This study applied a non-invasive multi-echo arterial spin labeling (ASL) technique to measure BBB water exchange time (Tex), cerebral blood flow (CBF), and arterial transit time (ATT) in 160 adults aged 50 years and older. Participants were classified as cognitively normal (CN), having subjective cognitive decline (SCD), or mild cognitive impairment (MCI). They were assessed for amyloid status and cerebrovascular burden. Compared to CN participants, Tex was significantly lower in both SCD (−9.5 %) and MCI (−14.5 %) groups, suggesting that reductions in BBB water exchange emerge early in the course of cognitive decline. In contrast, CBF was reduced only in MCI participants (−20.8 % compared to CN), and ATT was significantly increased only in individuals with severe cerebrovascular burden (Fazekas score 3). Notably, Tex showed a stepwise decrease with increasing Fazekas scores (1–2), supporting its sensitivity to moderate small vessel disease. No associations were found between Tex and amyloid positivity after adjusting for age and sex. These findings indicate that Tex alterations may precede changes in traditional perfusion markers and are more closely related to vascular and early cognitive changes than to amyloid pathology. BBB water exchange mapping may therefore provide a promising, non-invasive tool to detect early neurovascular dysfunction that contributes to cognitive decline in aging populations, potentially offering a useful biomarker for early intervention trials targeting vascular contributions to dementia.

• Chong, Joyce Ruifen; Hye, Abdul; Boada, Mercè; Svenningsson, Per; Fladby, Tormod & Årsland, Dag (2025). Cerebrospinal fluid biomarkers of Alzheimer's disease in Lewy body diseases: The performance of fully automated immunoassays. Journal of Alzheimer's Disease. ISSN 1387-2877. 108(1 suppl.), p. S8–S19. doi: 10.1177/13872877251360404. Full text in Research Archive
• Gonzalez-Ortiz, Fernando; Vávra, Jakub; Payne, Emma; Kirsebom, Bjørn-Eivind; Sjöbom, Ulrika & Santos, Cristiano [Show all 18 contributors for this article] (2025). The potential dual role of tau phosphorylation: Plasma phosphorylated-tau217 in newborns and Alzheimer's disease. Brain Communications. 7(3). doi: 10.1093/braincomms/fcaf221. Full text in Research Archive
• Richter, Grit; Kirsebom, Bjørn-Eivind; Jarholm, Jonas Alexander; Pålhaugen, Lene; Gisladottir, Berglind & Aarsland, Dag [Show all 11 contributors for this article] (2025). Comparison of CSF neurofilament light chain and total tau as neurodegeneration markers: Associations with synaptic markers and cognitive outcomes. Neurobiology of Aging. ISSN 0197-4580. 155, p. 13–23. doi: 10.1016/j.neurobiolaging.2025.07.005. Full text in Research Archive Show summary

  Clinically, Alzheimer's disease (AD) is characterized by progressive cognitive decline due to neuronal and synaptic degeneration. Neurofilament light chain (NfL) and total tau (T-tau) reflect neurodegeneration, NfL putatively more related to white and T-tau to grey matter. This study examines how cerebrospinal fluid (CSF) neurodegeneration markers (T-tau, NfL or both) are correlated with synaptic markers and clinical progression. We included 331 individuals with (n = 212) and without (n = 119) pathological CSF Aβ42/40 ratios. Associations between CSF NfL, T-tau, and the synaptic biomarkers neurogranin and BACE1 were assessed using Pearson’s correlation. Group differences in synaptic marker levels were evaluated using linear regression comparing individuals with isolated pathological T-tau, NfL, or both, versus biomarker-negative individuals. Clinical progression to MCI or dementia was assessed using a Cox proportional hazards model (n = 257; mean follow-up = 3.75 years). Linear regression and Cox proportional hazards models included age, sex, and dichotomized APOE-ε4 carriership as covariates. T-tau had a stronger correlation with neurogranin(r = 0.84) and BACE1(r = 0.73) than NfL(r = 0.51 and 0.48; p < 0.001). Group-wise comparisons confirmed this, showing that only individuals with pathological T-tau—alone or with NfL—had significantly higher synaptic marker levels (p < 0.001). Only the combination of pathological T-tau and NfL was associated with a significantly increased risk of clinical progression(HR=6.79; p < 0.001). These findings suggest that T-tau is more closely related to early synaptic dysfunction in AD than NfL. The combined elevation of both biomarkers, linked to greater clinical decline, supports a dual contribution of grey- and white matter degeneration to disease progression.

• Aarsland, Dag; Sunde, Anita Lenora; Tovar-Rios, Diego Alejandro; Leuzy, Antoine; Fladby, Tormod & Zetterberg, Henrik [Show all 18 contributors for this article] (2025). Prevalence of Alzheimer’s disease pathology in the community. Nature. ISSN 0028-0836. doi: 10.1038/s41586-025-09841-y. Full text in Research Archive Show summary

  The prevalence of Alzheimer’s disease neuropathological changes (ADNCs), the leading cause of cognitive impairment, remains uncertain. Recent blood-based biomarkers enable scalable assessment of ADNCs 1 . Here we measured phosphorylated tau at threonine 217 in 11,486 plasma samples from a Norwegian population-based cohort of individuals over 57 years of age as a surrogate marker for ADNCs. The estimated prevalence of ADNCs increased with age, from less than 8% in people 58–69.9 years of age to 65.2% in those over 90 years of age. Among participants aged 70 years or older, 10% had preclinical Alzheimer’s disease, 10.4% had prodromal Alzheimer’s disease and 9.8% had Alzheimer’s disease dementia. Furthermore, among those 70 years of age or older, ADNCs were present in 60% of people with dementia, in 32.6% of those with mild cognitive impairment and in 23.5% of the cognitively unimpaired group. Our findings suggest a higher prevalence of Alzheimer’s disease dementia in older individuals and a lower prevalence of preclinical Alzheimer’s disease in younger groups than previously estimated.

• Wimo, Anders; Handels, Ron; Blennow, Kaj; Kirsebom, Bjørn-Eivind; Selnes, Per & Bon, Jaka [Show all 16 contributors for this article] (2025). Cost-effectiveness of diagnosing and treating patients with early Alzheimer's disease with anti-amyloid treatment in a clinical setting. Journal of Alzheimer's Disease. ISSN 1387-2877. 104(4), p. 1167–1184. doi: 10.1177/13872877251323231. Full text in Research Archive
• Etesami, Maede Sadat; Benth, Jurate Saltyte; Kliem, Elisabeth; Weider, Siri; Thommessen, Bente & Fladby, Tormod [Show all 8 contributors for this article] (2025). Cognitive Improvement After Stroke: Prevalence and Pattern During the First 3 Months. Neuropsychology. ISSN 0894-4105. 39(3), p. 235–247. doi: 10.1037/neu0000986. Full text in Research Archive
• Gonzalez-Ortiz, Fernando; Kirsebom, Bjørn-Eivind; Yakoub, Yara; Gundersen, Julia Kristine; Pålhaugen, Lene & Waterloo, Knut [Show all 19 contributors for this article] (2025). Associations Between Changes in Levels of Phosphorylated Tau and Severity of Cognitive Impairment in Early Alzheimer Disease. Neurology. ISSN 0028-3878. 104(11). doi: 10.1212/WNL.0000000000213676. Full text in Research Archive Show summary

  Background and Objectives: Aligning biomarker evidence with clinical presentation in early Alzheimer disease (AD) is essential for improving diagnosis, prognosis, and interventions. This study evaluates the relationship between cognitive impairment, future decline, and phosphorylated tau levels in plasma and CSF in predementia AD. Methods: This longitudinal observational study included predementia cases and controls from 2 independent cohorts: the Norwegian Dementia Disease Initiation (DDI) and Canadian Pre-Symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD). In DDI, cognitively normal (CN) and mild cognitive impairment (MCI) cases were classified using CSF Aβ42/40 ratio (A) and p-tau181 (T), whereas classification in PREVENT-AD (A) was based on amyloid PET scans. In DDI, we assessed CSF-plasma correlations for p-tau181, p-tau217, and p-tau231. Diagnostic accuracies were evaluated through receiver operating characteristic analyses. Linear mixed models evaluated p-tau associations with future memory decline. Between-group differences in plasma p-tau217 were assessed in both cohorts. Results: In DDI (n = 431), participants were classified as CN A−/T− (n = 169), A+/T− (CN = 26, MCI = 24), A+/T+ (CN = 40, MCI = 105), and A−/T+ (CN = 34, MCI = 33), with a mean age of 64.1 years and 55.9% female. In PREVENT-AD (n = 190), participants were categorized as CN A− (n = 118), CN A+ (n = 49), and MCI A+ (n = 21), with a mean age of 67.8 years and 72.6% female. In DDI, plasma p-tau217 showed high accuracy in identifying A+ participants (areas under the curve [AUC]: 0.85) and a moderate correlation with CSF p-tau217 (rho = 0.65, p < 0.001). Diagnostic accuracy of plasma p-tau217 was greater in MCI A+ (AUC: 0.89) than in CN A+ (AUC: 0.79, p < 0.05) and in A+/T+ (AUC: 0.88) vs A+/T− (AUC: 0.78, p < 0.05). p-Tau181 and p-tau231 had weaker CSF-plasma correlations (rho = 0.47 and rho = 0.32, p < 0.001) and were less associated with cognitive status in A+ individuals. Higher plasma p-tau217 in A+ MCI vs A+ CN individuals (p < 0.001) was confirmed in PREVENT-AD. All CSF p-tau markers, but only plasma p-tau217, were associated with future memory decline (β = 0.05, p < 0.05). Discussion: Our findings suggest that, unlike p-tau181 and p-tau231, plasma p-tau217 consistently aligns with cognitive status in A+ individuals and better reflects CSF biomarker abnormalities, reducing discrepancies between clinical and biochemical findings. Its association with baseline and future memory decline highlights its diagnostic and prognostic value, particularly when CSF analysis or PET is unavailable.

• Lorentzen, Ingrid Myrvoll; Espenes, Johan Jacob; Eliassen, Ingvild Vøllo; Hessen, Erik; Waterloo, Knut & Timón-Reina, Santiago [Show all 10 contributors for this article] (2025). Norwegian normative data for regression-based D-KEFS color-word interference test derived measures and comparison to conventional contrast measures. Applied neuropsychology: Adult. ISSN 2327-9095. doi: 10.1080/23279095.2025.2462605. Full text in Research Archive
• Knudtzon, Stephanie; Nordengen, Kaja; Pålhaugen, Lene; Gisladottir, Berglind; Jarholm, Jonas Alexander & Bråthen, Geir [Show all 11 contributors for this article] (2025). Sexual dimorphisms in innate immune activation markers in predementia Alzheimer’s disease. Brain Communications. 7(3). doi: 10.1093/braincomms/fcaf161. Full text in Research Archive Show summary

  Visual impairment due to stroke is common. However, controversy exists on how best to screen for visual impairment, the timing at which to screen, and on the optimal management of the varying types of visual impairment. This European Stroke Organisation (ESO) guideline provides evidence-based recommendations to assist clinicians in decision-making on screening methods, timing of screening and assessment and management options in adult stroke survivors. The target audience for this guideline is health care providers involved in stroke care from prehospital screening, in stroke units and rehabilitation centres, ophthalmological departments and community stroke care, and for stroke survivors and care givers. The guideline was developed according to the ESO standard operating procedure and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews and, where possible, meta-analyses of the literature, assessed the quality of the available evidence and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available to provide recommendations based on the GRADE approach. We found evidence of acceptability and feasibility of early visual screening within 1 week of stroke onset. We describe the accuracy of various vision screening tools at pre-hospital and hyper/acute stages as well as specialist vision assessment. We suggest vision screening in all patients with stroke to improve detection of their visual problems We describe a range of treatment options for visual impairment post-stroke across the typical categories of impaired central vision, ocular stroke (central retinal artery occlusion), eye movements, visual fields, visual neglect and visual perception. This guideline highlights specific areas where robust evidence is lacking and where further definitive randomised controlled trials and diagnostic accuracy studies are required.

• Wiels, Wietse A.; Oomens, Julie E.; Engelborghs, Sebastiaan; Baeken, Chris; Arnim, Christine A.F. Von & Boada, Mercè [Show all 119 contributors for this article] (2025). Depressive Symptoms and Amyloid Pathology. JAMA psychiatry. ISSN 2168-6238. 82(3), p. 296–310. doi: 10.1001/jamapsychiatry.2024.4305. Full text in Research Archive
• Kirsebom, Bjørn-Eivind; Gonzalez-Ortiz, Fernando; Vigneswaran, Sinthujah; Bråthen, Geir; Skogseth, Ragnhild Eide & Gisladottir, Berglind [Show all 18 contributors for this article] (2025). Repeated plasma p-tau217 measurements to monitor clinical progression heterogeneity. Alzheimer's & Dementia. ISSN 1552-5260. 21(5). doi: 10.1002/alz.70319. Full text in Research Archive
• Hemminghyth, Mathilde Suhr; Breitve, Monica Haraldseid; Chwiszczuk, Luiza; Gisladottir, Berglind; Hessen, Erik & Siafarikas, Nikias Ioannis [Show all 12 contributors for this article] (2025). Demographically unadjusted cognitive test scores may enhance the validity of mild cognitive impairment as a dementia prodrome. Applied neuropsychology: Adult. ISSN 2327-9095. doi: 10.1080/23279095.2025.2518576. Full text in Research Archive
• Nicolas, Aude; Sherva, Richard; Grenier-Boley, Benjamin; Kim, Yoontae; Kikuchi, Masataka & Timsina, Jigyasha [Show all 52 contributors for this article] (2025). Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations. Nature Genetics. ISSN 1061-4036. 57(7), p. 1598–1610. doi: 10.1038/s41588-025-02227-w. Full text in Research Archive
• Zhou, Robin Ziyue; Gaunitz, Stefan; Kirsebom, Bjørn-Eivind; Lundin, Britt; Hellström, Marie & Jejcic, Alenka [Show all 12 contributors for this article] (2025). Blood N-glycomics reveals individuals at risk for cognitive decline and Alzheimer's disease. EBioMedicine. 113. doi: 10.1016/j.ebiom.2025.105598. Full text in Research Archive
• Wang, Heling; Duque, Gustavo; Siow, Richard; Medina, Tomás Alejandro Schmauck; Zhang, Jianying & Sandset, Per Morten [Show all 39 contributors for this article] (2024). Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway–UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies. The journals of gerontology. Series A, Biological sciences and medical sciences. ISSN 1079-5006. 79(4). doi: 10.1093/gerona/glae029. Full text in Research Archive Show summary

  Abstract Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a “Money Follows Cooperation agreement” between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

• Hemminghyth, Mathilde Suhr; Chwiszczuk, Luiza; Breitve, Monica Haraldseid; Gisladottir, Berglind; Grøntvedt, Gøril Rolfseng & Nakling, Arne Exner [Show all 9 contributors for this article] (2024). Cerebrospinal fluid neurofilament light chain mediates age-associated lower learning and memory in healthy adults. Neurobiology of Aging. ISSN 0197-4580. 135, p. 39–47. doi: 10.1016/j.neurobiolaging.2023.12.005. Full text in Research Archive Show summary

  Multiple cognitive domains, including learning, memory, and psychomotor speed, show significant reductions with age. Likewise, several cerebrospinal fluid (CSF) neurodegenerative biomarkers, including total tau (t-tau, a marker of neuronal body injury) and neurofilament light chain (NfL, a marker of axonal injury) show age-related increases in normal aging. In the current study, we aimed to investigate whether the age-effect within different cognitive domains was mediated by age-associated CSF markers for neurodegenerative changes. We fitted 10 mediation models using structural equation modeling to investigate this in a cohort of 137 healthy adults, aged 40–80 years, from the Norwegian Dementia Disease Initiation (DDI) study. Here, t-tau and NfL were defined as mediators between age and different cognitive tests. The models showed that NfL mediated the age-effect for CERAD learning and memory recall (learning: β = −0.395, p < 0.05; recall: β = −0.261, p < 0.01). No such effect was found in the other models. Our findings suggest that the age-related lower performance in verbal learning and memory may be linked to NfL-associated neurodegenerative changes in cognitively healthy adults.

• Ghazi, Mostafa Mehdipour; Selnes, Per; Reina, Santiago Timon; Teceläo, Sandra Raquel Ramos; Ingala, Silvia & Bjørnerud, Atle [Show all 9 contributors for this article] (2024). Comparative analysis of multimodal biomarkers for amyloid-beta positivity detection in Alzheimer's disease cohorts. Frontiers in Aging Neuroscience. 16. doi: 10.3389/fnagi.2024.1345417. Full text in Research Archive Show summary

  Introduction: Efforts to develop cost-effective approaches for detecting amyloid pathology in Alzheimer’s disease (AD) have gained significant momentum with a focus on biomarker classification. Recent research has explored non-invasive and readily accessible biomarkers, including magnetic resonance imaging (MRI) biomarkers and some AD risk factors.<p> <p>Methods: In this comprehensive study, we leveraged a diverse dataset, encompassing participants with varying cognitive statuses from multiple sources, including cohorts from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and our in-house Dementia Disease Initiation (DDI) cohort. As brain amyloid plaques have been proposed as sufficient for AD diagnosis, our primary aim was to assess the effectiveness of multimodal biomarkers in identifying amyloid plaques, using deep machine learning methodologies. <p>Results: Our findings underscore the robustness of the utilized methods in detecting amyloid beta positivity across multiple cohorts. Additionally, we investigated the potential of demographic data to enhance MRI-based amyloid detection. Notably, the inclusion of demographic risk factors significantly improved our models’ ability to detect amyloid-beta positivity, particularly in early-stage cases, exemplified by an average area under the ROC curve of 0.836 in the unimpaired DDI cohort. <p>Discussion: These promising, non-invasive, and cost-effective predictors of MRI biomarkers and demographic variables hold the potential for further refinement through considerations like APOE genotype and plasma markers.

• Gundersen, Julia Kristine; Gonzalez-Ortiz, Fernando; Karikari, Thomas; Kirsebom, Bjørn-Eivind Seljelid; Mertes, Katrin & Zetterberg, Henrik [Show all 11 contributors for this article] (2024). Neuronal plasma biomarkers in acute ischemic stroke. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. doi: 10.1177/0271678X241293537. Full text in Research Archive Show summary

  Early imaging-based detection of acute ischemic stroke (AIS) has improved in the era of reperfusion therapy. Despite of this, prognosis of outcome after AIS remains a challenge. Therefore, parameters that support clinical decision making are sought. Blood-based biomarkers have the potential to provide valuable information in addition to the established prognostic factors. Neuronal biomarkers of acute or degenerative neuronal injury have shown to be reliably detected in plasma. These biomarkers are well-established in neurodegenerative pathology, such as Alzheimer’s disease. In this study, we explored the association between stroke diameter and plasma biomarkers for neuronal injury and tau pathophysiology (brain-derived tau [BD-tau], phosphorylated-tau-217 [p-tau21] and neurofilament light [NfL]) in patients (n = 193) admitted to the acute ward, Akershus University Hospital. All patients received a final diagnosis of AIS, transient ischemic attack or stroke mimics. Blood samples were obtained the day after admission. We find that levels of BD-tau (p = .004) and NfL (p = .011) were higher after AIS than in patients with stroke mimics. The cortical stroke diameter correlated with BD-tau (tau-b = 0.64, p < .001) and p-tau217 (tau-b = 0.36, p = .003). Linear regression confirmed BD-tau to be the strongest variable associated with stroke diameter, pointing to the potential clinical value of plasma BD-tau in outcome prediction after AIS.

• Wimo, Anders; Kirsebom, Bjørn-Eivind Seljelid; Reina, Santiago Timon; Vromen, Ellen; Selnes, Per & Bon, Jaka [Show all 12 contributors for this article] (2024). Costs of diagnosing early Alzheimer's disease in three European memory clinic settings: Results from the precision medicine in Alzheimer's disease project. International Journal of Geriatric Psychiatry. ISSN 0885-6230. 39(7). doi: 10.1002/gps.6126. Full text in Research Archive Show summary

  Objectives - The implementation of disease-modifying treatments for Alzheimer's Disease (AD) will require cost-effective diagnostic processes. As part of The Precision Medicine In AD consortium (PMI-AD) project, the aim is to analyze the baseline costs of diagnosing early AD at memory clinics in Norway, Slovenia, and the Netherlands.<p> <p>Methods - The costs of cognitive testing and a clinical examination, apolipoprotein E, magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), positron emission tomography and blood-based biomarkers (BBM), which are used in different combinations in the three countries, were analyzed. Standardized unit costs, adjusted for GDP per capita and based on Swedish conditions were applied. The costs were expressed in euros (€) as of 2019. A diagnostic set comprising clinical examination, cognitive testing, MRI and CSF was defined as the gold standard, with MRI mainly used as an exclusion filter.<p> <p>Results - Cost data were available for 994 persons in Norway, 169 in Slovenia and 1015 in the Netherlands. The mean diagnostic costs were 1478 (95% confidence interval 1433–1523) € in Norway, 851 (731–970) € in Slovenia and 1184 (1135–1232) € in the Netherlands. Norway had the highest unit costs but also the greatest use of tests. With a uniform diagnostic test set applied, the diagnostic costs were 1264 (1238–1291) €, in Norway, 843 (771–914) € in Slovenia and 1184 (1156–1213) € in the Netherlands. There were no major cost differences between the final set of diagnoses.<p> <p>Conclusions - The total costs for setting a diagnosis of AD varied somewhat in the three countries, depending on unit costs and use of tests. These costs are relatively low in comparison to the societal costs of AD.

• Eriksson, Cecilia Magdalena; Kirsebom, Bjørn-Eivind Seljelid; Espenes, Ragna; Siafarikas, Nikias Ioannis; Waterloo, Knut & Rongve, Arvid [Show all 10 contributors for this article] (2024). Depressive Symptoms Are Not Associated with Predementia Cerebrospinal Fluid Amyloid Pathology. Dementia and Geriatric Cognitive Disorders Extra. 14(1), p. 40–48. doi: 10.1159/000539284. Full text in Research Archive Show summary

  Introduction: Depressive symptoms are associated with Alzheimer’s disease (AD), but their neurobiological and neuropsychological correlates remain poorly understood. We investigate if depressive symptoms are associated with amyloid (Aβ) pathology and cognition in predementia AD. Methods: We included subjective cognitive decline (SCD, n = 160) and mild cognitive impairment (MCI, n = 192) from the dementia disease initiation cohort. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS-15). Aβ pathology was determined using cerebrospinal fluid (CSF) Aβ42/40 ratio. Associations between depressive symptoms and cognition were assessed with logistic regression. Results: Only the Aβ negative MCI group (MCI-Aβ−) was associated with depressive symptoms (odds ratio [OR] = 2.65, p = 0.005). Depressive symptoms were associated with worse memory in MCI-Aβ− (OR = 0.94, p = 0.039), but with better performance in MCI-Aβ+ (OR = 1.103, p = 0.001). Conclusion: Our results suggest that depressive symptoms in MCI are neither associated with Aβ pathology, nor AD-associated memory impairment. However, memory impairment in non-AD MCI may relate to depressive symptoms.

• Arulf, Sofia Egebäck; Zhou, Robin Ziyue; Kirsebom, Bjørn-Eivind Seljelid; Jejcic, Alenka; Fladby, Tormod & Winblad, Bengt [Show all 8 contributors for this article] (2024). Bisecting N-Acetylglucosamine Correlates with Phospho-Tau181 in Subjective Cognitive Decline but not in Control Cases. Journal of Alzheimer's Disease. ISSN 1387-2877. 100(1), p. S93–S101. doi: 10.3233/JAD-240628. Full text in Research Archive
• Gonzalez-Ortiz, Fernando; Karikari, Thomas K.; Vruchte, Danielle Taylor-Te; Shepherd, Dawn; Kirsebom, Bjørn-Eivind Seljelid & Fladby, Tormod [Show all 8 contributors for this article] (2024). Plasma phosphorylated-tau217 is increased in Niemann–Pick disease type C. Brain Communications. 6(6). doi: 10.1093/braincomms/fcae375. Full text in Research Archive Show summary

  Niemann–Pick disease type C and Alzheimer’s disease are distinct neurodegenerative disorders that share the presence of neurofibrillary tangle pathology. In this multicentre study, we measured plasma phosphorylated-tau217 in controls (n = 60), Niemann–Pick disease type C (n = 71) and Alzheimer’s disease (n = 30 positive for amyloid and negative for tau in CSF [A+ T−] and n = 30 positive for both [A+ T+ ]). Annual Severity Increment Score and Lysotracker measurements were evaluated in the Niemann–Pick disease type C group to estimate the rate of progression and lysosomal enlargement, respectively. In the cross-sectional analysis, plasma phosphory lated-tau217 was increased in Niemann–Pick disease type C compared with controls (2.52 ± 1.93 versus 1.02 ± 0.34 pg/mL, respectively, P < 0.001) and inversely correlated with age at disease onset (R = −0.54, P < 0.001). In the longitudinal analysis, plasma phosphorylated-tau217 was associated with disease progression determined by Annual Severity Increment Score (R = 0.48, P < 0.001) and lysosomal enlargement (R = 0.26, P = 0.004). We found no differences between A+ T− Alzheimer’s disease and Niemann–Pick disease type C (2.67 ± 1.18 versus 2.52 ± 1. 93 pg/mL, P = 0.31); however, A+ T+ Alzheimer’s disease had significantly higher levels than Niemann–Pick disease type C (3.26 ± 1.36 versus 2.52 ± 1.93 pg/mL, P = 0.001). Our findings suggest that plasma p-tau217 can increase in brain disorders with isolated tau pathology. Plasma p-tau217 associations with disease progression and severity make it a potential marker in Niemann–Pick disease type C.

• Gonzalez-Ortiz, Fernando; Kirsebom, Bjørn-Eivind Seljelid; Contador, José; Tanley, Jordan E.; Selnes, Per & Gisladottir, Berglind [Show all 33 contributors for this article] (2024). Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer’s disease. Nature Communications. 15(1). doi: 10.1038/s41467-024-47286-5. Full text in Research Archive Show summary

  Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer’s disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ (“A”) and neurodegeneration (“N”) abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.

• Knudtzon, Stephanie; Nordengen, Kaja; Grøntvedt, Gøril Rolfseng; Jarholm, Jonas Alexander; Eliassen, Ingvild Vøllo & Selnes, Per [Show all 12 contributors for this article] (2024). Age-adjusted CSF t-tau and NfL do not improve diagnostic accuracy for prodromal Alzheimer’s Disease. Neurobiology of Aging. ISSN 0197-4580. 141, p. 74–84. doi: 10.1016/j.neurobiolaging.2024.05.016. Full text in Research Archive Show summary

  Cerebrospinal fluid total-tau (t-tau) and neurofilament light chain (NfL) are biomarkers of neurodegeneration and are increased in Alzheimer’s disease (AD). In order to adjust for age-related increases in t-tau and NfL, cross-sectional age-adjusted norms were developed based on amyloid negative cognitively normal (CN) adults aged 41–78 years (CN, n = 137). The age-adjusted norms for t-tau and NfL did not improve receiver operating curve based diagnostic accuracies in individuals with mild cognitive impairment (MCI) due to AD (AD-MCI, n = 144). Furthermore, while NfL was correlated with higher age in AD-MCI, no significant correlation was found for t-tau. The cox proportional hazard models, applied in 429 participants with baseline t-tau and NfL, showed higher hazard ratio of progression to MCI or dementia without age-adjustments (HR = 3.39 for t-tau and HR = 3.17 for NfL), as compared to using our norms (HR = 2.29 for t-tau and HR = 1.89 for NfL). Our results indicate that utilizing normative reference data could obscure significant age-related increases in these markers associated with neurodegeneration and AD leading to a potential loss of overall diagnostic accuracy.

• Bentivenga, Giuseppe Mario; Gonzalez-Ortiz, Fernando; Baiardi, Simone; Kirsebom, Bjørn-Eivind Seljelid; Mastrangelo, Andrea & Mammana, Angela [Show all 11 contributors for this article] (2024). Clinical value of novel blood-based tau biomarkers in Creutzfeldt–Jakob disease. Alzheimer's & Dementia. ISSN 1552-5260. doi: 10.1002/alz.14422. Full text in Research Archive Show summary

  BACKGROUND The diagnostic and prognostic performance of the novel fluid biomarkers brain-derived tau (BD-tau) and phospho-tau217 (p-tau217) in Creutzfeldt–Jakob disease (CJD) is not defined.<p> <p>METHODS We measured cerebrospinal fluid (CSF) and plasma BD-tau, p-tau217, p-tau181, total tau (t-tau), neurofilament light (NfL), and 14-3-3 in 100 CJD patients, 100 with non-prion rapidly progressive dementia (np-RPD), 92 with mild cognitive impairment due to Alzheimer's disease (AD-MCI), and 55 healthy controls (HC). <p>RESULTS Plasma BD-tau performed comparably to plasma t-tau but had lower performance than CSF t-tau (p < 0.001) and 14-3-3 (p = 0.014) in CJD versus np-RPD differential diagnosis. Plasma BD-tau diagnostic accuracy increased when ratioed to plasma p-tau217, matching CSF 14-3-3. Plasma BD-tau levels were associated with survival (p < 0.001), outperforming t-tau and NfL. <p>DISCUSSION Plasma BD-tau is a valuable marker for CJD prognostication. In the clinical setting, the plasma BD-tau/p-tau217 ratio provides an accurate, fast marker supporting the clinical diagnosis of CJD.

• Nordengen, Kaja; Kirsebom, Bjørn-Eivind Seljelid; Richter, Grit; Pålhaugen, Lene; Gisladottir, Berglind & Siafarikas, Nikias Ioannis [Show all 22 contributors for this article] (2023). Longitudinal cerebrospinal fluid measurements show glial hypo- and hyperactivation in predementia Alzheimer’s disease. Journal of Neuroinflammation. 20(1). doi: 10.1186/s12974-023-02973-w. Full text in Research Archive Show summary

  Background Brain innate immune activation is associated with Alzheimer’s disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles. Methods We included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline (n = 535) and follow-up (n = 213), between 1 and 6 years from baseline (mean 2.8 years). We measured Aβ42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A−/T−/N−, A+/T−/N−, A+/T+ or N+, or A−/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group. Results Cross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis (p < 0.001, A+/T+ or N+ and A−/T+ or N+, compared to A−/T−/N−). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T−/N− cases (all p < 0.05). CSF sTREM2, YKL-40, clusterin, fractalkine (p < 0.001) and MCP-1 (p < 0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile (p < 0.01). Conclusions Immune hypoactivation and reduced neuron–microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns.

• Öhman, Fredrik; Eckerström, Marie; Hessen, Erik; Espenes, Johan Jacob; Eliassen, Ingvild Vøllo & Lorentzen, Ingrid Myrvoll [Show all 12 contributors for this article] (2023). Demographically adjusted Rey–Osterrieth Complex Figure Test norms in a Swedish and Norwegian cohort aged 49–77 years and comparison with North American norms. Scandinavian Journal of Psychology. ISSN 0036-5564. doi: 10.1111/sjop.12966. Full text in Research Archive Show summary

  Introduction The Rey–Osterrieth Complex Figure Test (RCFT) is one of the most commonly used neuropsychological tests in Sweden and Norway. However, no publications provide normative data for this population. The objective of this study was to present demographically adjusted norms for a Swedish and Norwegian population and to evaluate these in an independent comparison group.<p> <p>Methods The RCFT was administrated to 344 healthy controls recruited from the Swedish Gothenburg MCI study, the Norwegian Dementia Disease Initiation study, and the Swedish Cardiopulmonary Bioimage Study. Age ranged from 49 to 77 years (mean = 62.4 years, SD = 5.0 years), and education ranged from 6 to 24 years (mean = 13.3 years, SD = 3.0 years). Using a regression-based procedure, we investigated the effects of age, sex, and years of education on test performance. We compared and evaluated our Swedish and Norwegian norms with North American norms in an independent comparison group of 145 individuals. <p>Results In healthy controls, age and education were associated with performance on the RCFT. When comparing normative RCFT performance in an independent comparison group, North American norms generally overestimated immediate and delayed recall performance. In contrast, our Swedish and Norwegian norms appear to better take into account factors of age and education. <p>Conclusions We presented demographically adjusted norms for the RCFT in a Swedish and Norwegian sample. This is the first normative study of the RCFT that presents normative data for this population. In addition, we showed that North American norms might produce inaccurate normative estimations in an independent comparison group.

• Espenes, Johan Jacob; Lorentzen, Ingrid Myrvoll; Eliassen, Ingvild Vøllo; Hessen, Erik; Waterloo, Knut K & Timón, Santiago [Show all 10 contributors for this article] (2023). Regression-based normative data for the D-KEFS Color-Word Interference Test in Norwegian adults ages 20–85. The Clinical Neuropsychologist. ISSN 1385-4046. doi: 10.1080/13854046.2023.2276967. Full text in Research Archive Show summary

  <p><i>Objective:</i> The Delis-Kaplan Executive Function System (D-KEFS) Color-Word-Interference Test (CWIT; AKA Stroop test) is a widely used measure of processing speed and executive function. While test materials and instructions have been translated to Norwegian, only American age-adjusted norms from D-KEFS are available in Norway. We here develop norms in a sample of 1011 Norwegians between 20 and 85 years. We provide indexes for stability over time and assess demographic adjustments applying the D-KEFS norms. <p><i>Method:</i> Participants were healthy Norwegian adults from Center for Lifespan Changes in Brain and Cognition (LCBC) (n = 899), the Dementia Disease Initiation (n = 77), and Oslo MCI (n = 35). Using regression-based norming, we estimated linear and non-linear effects of age, education, and sex on the CWIT 1-4 subtests. Stability over time was assessed with intraclass correlation coefficients (ICC). The normative adjustment of the D-KEFS norms was assessed with linear regression models. <p><i>Results:</i> Increasing age was associated with slower completion on all CWIT subtests in a non-linear fashion (accelerated lowering of performance with older age). Women performed better on CWIT-1&3. Higher education predicted faster completion time on CWIT-3&4. The original age-adjusted norms from D-KEFS did not adjust for sex or education. Furthermore, we observed significant, albeit small effects of age on all CWIT subtests. ICC analyses indicated moderate to good stability over time. <p><i>Conclusion:</i> We present demographically adjusted regression-based norms and stability indexes for the D-KEFS CWIT subtests. US D-KEFS norms may be inaccurate for Norwegians with high or low educational attainment, especially women.

• Waggestad, Therese Händel; Kirsebom, Bjørn-Eivind; Strobel, Carsten; Wallin, Anders; Eckerström, Marie & Fladby, Tormod [Show all 7 contributors for this article] (2023). Improving validity of the trail making test with alphabet support. Frontiers in Psychology. 14. doi: 10.3389/fpsyg.2023.1227578. Full text in Research Archive Show summary

  Objective: The Trail Making Test (TMT) is commonly used worldwide to evaluate cognitive decline and car driving ability. However, it has received critique for its dependence on the Latin alphabet and thus, the risk of misclassifying some participants. Alphabet support potentially increases test validity by avoiding misclassification of executive dysfunction in participants with dyslexia and those with insufficient automatization of the Latin alphabet. However, Alphabet support might render the test less sensitive to set-shifting, thus compromising the validity of the test. This study compares two versions of the TMT: with and without alphabet support. Methods: We compared the TMT-A, TMT-B, and TMT-B:A ratios in two independent normative samples with (n = 220) and without (n = 64) alphabet support using multiple regression analysis adjusted for age and education. The sample comprised Scandinavians aged 70–84 years. Alphabet support was included by adding the Latin alphabet A–L on top of the page on the TMT-B. We hypothesized that alphabet support would not change the TMT-B:A ratio. Results: After adjusting for age and years of education, there were no significant differences between the two samples in the TMT-A, TMT-B, or the ratio score (TMT-B:A). Conclusion: Our results suggest that the inclusion of alphabet support does not alter TMT’s ability to measure set-shifting in a sample of older Scandinavian adults.

• Røvang, Martin Soria; Selnes, Per; MacIntosh, Bradley; Groote, Inge Rasmus; Pålhaugen, Lene & Sudre, Carole H [Show all 8 contributors for this article] (2023). Segmenting white matter hyperintensities on isotropic three-dimensional Fluid Attenuated Inversion Recovery magnetic resonance images: Assessing deep learning tools on a Norwegian imaging database. PLOS ONE. 18(8). doi: 10.1371/journal.pone.0285683. Full text in Research Archive Show summary

  An important step in the analysis of magnetic resonance imaging (MRI) data for neuroimaging is the automated segmentation of white matter hyperintensities (WMHs). Fluid Attenuated Inversion Recovery (FLAIR-weighted) is an MRI contrast that is particularly useful to visualize and quantify WMHs, a hallmark of cerebral small vessel disease and Alzheimer’s disease (AD). In order to achieve high spatial resolution in each of the three voxel dimensions, clinical MRI protocols are evolving to a three-dimensional (3D) FLAIR-weighted acquisition. The current study details the deployment of deep learning tools to enable automated WMH segmentation and characterization from 3D FLAIR-weighted images acquired as part of a national AD imaging initiative. Based on data from the ongoing Norwegian Disease Dementia Initiation (DDI) multicenter study, two 3D models—one off-the-shelf from the NVIDIA nnU-Net framework and the other internally developed—were trained, validated, and tested. A third cutting-edge Deep Bayesian network model (HyperMapp3r) was implemented without any de-novo tuning to serve as a comparison architecture. The 2.5D in-house developed and 3D nnU-Net models were trained and validated in-house across five national collection sites among 441 participants from the DDI study, of whom 194 were men and whose average age was (64.91 +/- 9.32) years. Both an external dataset with 29 cases from a global collaborator and a held-out subset of the internal data from the 441 participants were used to test all three models. These test sets were evaluated independently. The ground truth human-in-the-loop segmentation was compared against five established WMH performance metrics. The 3D nnU-Net had the highest performance out of the three tested networks, outperforming both the internally developed 2.5D model and the SOTA Deep Bayesian network with an average dice similarity coefficient score of 0.76 +/- 0.16. Our findings demonstrate that WMH segmentation models can achieve high performance when trained exclusively on FLAIR input volumes that are 3D volumetric acquisitions. Single image input models are desirable for ease of deployment, as reflected in the current embedded clinical research project. The 3D nnU-Net had the highest performance, which suggests a way forward for our need to automate WMH segmentation while also evaluating performance metrics during on-going data collection and model retraining.

• Jarholm, Jonas Alexander; Bjørnerud, Atle; Dalaker, Turi Olene; Akhavi, Mehdi Sadat; Kirsebom, Bjørn-Eivind & Pålhaugen, Lene [Show all 14 contributors for this article] (2023). Medial Temporal Lobe Atrophy in Predementia Alzheimer's Disease: A Longitudinal Multi-Site Study Comparing Staging and A/T/N in a Clinical Research Cohort. Journal of Alzheimer's Disease. ISSN 1387-2877. 94(1), p. 259–279. doi: 10.3233/JAD-221274. Full text in Research Archive Show summary

  Background: Atrophy of the medial temporal lobe (MTL) is a biological characteristic of Alzheimer’s disease (AD) and can be measured by segmentation of magnetic resonance images (MRI). Objective: To assess the clinical utility of automated volumetry in a cognitively well-defined and biomarker-classified multi-center longitudinal predementia cohort. Methods: We used Automatic Segmentation of Hippocampal Subfields (ASHS) to determine MTL morphometry from MRI. We harmonized scanner effects using the recently developed longitudinal ComBat. Subjects were classified according to the A/T/N system, and as normal controls (NC), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). Positive or negative values of A, T, and N were determined by cerebrospinal fluid measurements of the Aβ42/40 ratio, phosphorylated and total tau. From 406 included subjects, longitudinal data was available for 206 subjects by stage, and 212 subjects by A/T/N. Results: Compared to A–/T–/N– at baseline, the entorhinal cortex, anterior and posterior hippocampus were smaller in A+/T+orN+. Compared to NC A– at baseline, these subregions were also smaller in MCI A+. Longitudinally, SCD A+ and MCI A+, and A+/T–/N– and A+/T+orN+, had significantly greater atrophy compared to controls in both anterior and posterior hippocampus. In the entorhinal and parahippocampal cortices, longitudinal atrophy was observed only in MCI A+ compared to NC A–, and in A+/T–/N– and A+/T+orN+ compared to A–/T–/N–. Conclusion: We found MTL neurodegeneration largely consistent with existing models, suggesting that harmonized MRI volumetry may be used under conditions that are common in clinical multi-center cohorts.

• Lorentzen, Ingrid Myrvoll; Espenes, Johan Jacob; Eliassen, Ingvild Vøllo; Hessen, Erik; Waterloo, Knut K & Nakling, Arne Exner [Show all 10 contributors for this article] (2023). Investigating the relationship between allocentric spatial working memory and biomarker status in preclinical and prodromal Alzheimer’s disease. Applied neuropsychology: Adult. ISSN 2327-9095. doi: 10.1080/23279095.2023.2236262. Full text in Research Archive Show summary

  The 4 Mountain Test (4MT) is a test of allocentric spatial working memory and has been proposed as an earlier marker of predementia Alzheimer’s disease (AD) than episodic verbal memory. We here compare the 4MT to the CERAD word list memory recall in both cognitively normal (CN) and mild cognitive impairment (MCI) cases with or without cerebrospinal fluid markers (CSF) of Alzheimer’s disease pathology. Linear regression was used to assess the influence of CSF determined Aβ-plaque (Aβ-/+) or neurofibrillary tau tangles (Tau-/+) on 4MT and CERAD recall performance. Analyses were performed in the full sample and the CN and MCI sub-samples. Pearson correlations were calculated to examine the relationship between 4MT and tests of psychomotor speed, verbal memory, cognitive flexibility, verbal fluency, and visuo-spatial perception. Analyses showed no significant differences in 4MT scores between Aβ-/Aβ+, nor Tau-/Tau + participants, irrespective of cognitive status. In contrast, CERAD recall scores were lower in both Aβ+ compared to Aβ- (p<.01), and Tau + compared to Tau- participants (p<.01) in the full sample analyses. There were no significant differences in CERAD recall performance between Aβ- vs. Aβ+ and Tau- vs. to Tau + in the in CN/MCI sub-samples. 4MT scores were significantly correlated with tests of psychomotor speed, cognitive flexibility, and visuo-spatial perception in the full sample analyses. In conclusion, the CERAD recall outperformed the 4MT as a cognitive marker of CSF determined AD pathology. This suggests that allocentric working memory, as measured by the 4MT, may not be used as an early marker of predementia AD.

• Aspli, Klaus Thanke; Aaseth, Jan; Holmøy, Trygve; Blennow, Kaj; Zetterberg, Henrik & Kirsebom, Bjørn-Eivind Seljelid [Show all 8 contributors for this article] (2023). CSF, Blood, and MRI Biomarkers in Skogholt’s Disease—A Rare Neurodegenerative Disease in a Norwegian Kindred. Brain Sciences. 13(11). doi: 10.3390/brainsci13111511. Full text in Research Archive Show summary

  Skogholt’s disease is a rare neurological disorder that is only observed in a small Norwegian kindred. It typically manifests in adulthood with uncharacteristic neurological symptoms from both the peripheral and central nervous systems. The etiology of the observed cerebral white matter lesions and peripheral myelin pathology is unclear. Increased cerebrospinal fluid (CSF) concentrations of protein have been confirmed, and recently, very high concentrations of CSF total and phosphorylated tau have been detected in Skogholt patients. The symptoms and observed biomarker changes in Skogholt’s disease are largely nonspecific, and further studies are necessary to elucidate the disease mechanisms. Here, we report the results of neurochemical analyses of plasma and CSF, as well as results from the morphometric segmentation of cerebral magnetic resonance imaging. We analyzed the biomarkers Aβ_1––42, Aβ_1–40, Aβ_x–38, Aβ_x–40, Aβ_x–42, total and phosphorylated tau, glial fibrillary acidic protein, neurofilament light chain, platelet-derived growth factor receptor beta, and beta-trace protein. All analyzed CSF biomarkers, except neurofilament light chain and Aβ1/_x–42, were increased several-fold. In blood, none of these biomarkers were significantly different between the Skogholt and control groups. MRI volumetric segmentation revealed decreases in the ventricular, white matter, and choroid plexus volumes in the Skogholt group, with an accompanying increase in white matter lesions. The cortical thickness and subcortical gray matter volumes were increased in the Skogholt group. Pathophysiological changes resulting from choroidal dysfunction and/or abnormal CSF turnover, which may cause the increases in CSF protein and brain biomarker levels, are discussed.

• Timón, Santiago; Rincón, Mariano; Martínez-Tomás, Rafael; Kirsebom, Bjørn-Eivind Seljelid & Fladby, Tormod (2023). A Knowledge Graph Framework for Dementia Research Data. Applied Sciences. 13(18), p. 1–23. doi: 10.3390/app131810497. Full text in Research Archive Show summary

  Dementia disease research encompasses diverse data modalities, including advanced imaging, deep phenotyping, and multi-omics analysis. However, integrating these disparate data sources has historically posed a significant challenge, obstructing the unification and comprehensive analysis of collected information. In recent years, knowledge graphs have emerged as a powerful tool to address such integration issues by enabling the consolidation of heterogeneous data sources into a structured, interconnected network of knowledge. In this context, we introduce DemKG, an open-source framework designed to facilitate the construction of a knowledge graph integrating dementia research data, comprising three core components: a KG-builder that integrates diverse domain ontologies and data annotations, an extensions ontology providing necessary terms tailored for dementia research, and a versatile transformation module for incorporating study data. In contrast with other current solutions, our framework provides a stable foundation by leveraging established ontologies and community standards and simplifies study data integration while delivering solid ontology design patterns, broadening its usability. Furthermore, the modular approach of its components enhances flexibility and scalability. We showcase how DemKG might aid and improve multi-modal data investigations through a series of proof-of-concept scenarios focused on relevant Alzheimer’s disease biomarkers.

• Kirsebom, Bjørn-Eivind; Richter, Grit; Nordengen, Kaja; Aarsland, Dag; Bråthen, Geir & Tijms, Betty M [Show all 15 contributors for this article] (2022). Stable cerebrospinal fluid neurogranin and β-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer's disease patients. Brain Communications. 4(5), p. 1–16. doi: 10.1093/braincomms/fcac244. Full text in Research Archive Show summary

  Cerebrospinal fluid (CSF) β-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer’s disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T−/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer’s disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T−/N−, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer’s disease continuum and controlled with normal markers (A−/T−/N−, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T−/N− and A+/T+/N+ as compared to A−/T−/N− healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A−/T−/N− to A+/T−/N− (n = 12), from A+/T−/N− to A+/T or N+ (n = 12), remained stable A+/T−/N− (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A−/T−/N− (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A−/T−/N− healthy controls, neurogranin was unaltered in A+/T−/N− (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T−/N− (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T−/N− (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = −0.29, P = 0.0006) than neurogranin (b = −0.20, P = 0.002) and BACE1 (b = −0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T−/N− to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer’s disease subgroups, putatively with different options for treatment.

• Aarsland, Dag; Khalifa, Khadija; Bergland, Anne Katrine; Sønnesyn, Hogne; Oppedal, Ketil & Holteng, Lise Birgitte Austbø [Show all 14 contributors for this article] (2022). A Randomised Placebo-Controlled Study of Purified Anthocyanins on Cognition in Individuals at Increased Risk for Dementia. The American journal of geriatric psychiatry. ISSN 1064-7481. 31(2), p. 141–151. doi: 10.1016/j.jagp.2022.10.002. Full text in Research Archive Show summary

  Importance Identifying nutritional compounds which can reduce cognitive decline in older people is a hugely important topic. Objective To study the safety and effect of anthocyanins in maintaining cognitive functioning in people at increased risk for dementia. Design, setting, and participants Participants (206 individuals, aged 60–80 years) diagnosed with either mild cognitive impairment (MCI) or two or more cardiometabolic disorders (i.e., diabetes, hypertension, obesity) were enrolled at three different centres in Norway. Intervention Participants were randomly assigned to four capsules with a total of 320 mg/d of naturally purified anthocyanins or placebo 1:1 for 24 weeks. Main outcomes and measures The primary outcome was the Quality of Episodic Memory composite measure (0–100) from an online cognitive test battery CogTrack, which was administered at baseline and monthly for the next 24 weeks. Secondary outcomes included other cognitive scores from the CogTrack battery. We applied mixed effects models with a baseline test score, group, time and their interaction as fixed effects, as well as other predefined baseline covariates. The primary comparison was the group difference at week 24 based on a modified intention-to-treat principle. Results : The primary analysis did not show a significant group difference at 24 weeks (78.2 versus 76.8; adjusted mean difference 1.4 (95% confidence interval -0.9–3.7); effect size 0.15; p = 0.23). However, there was a significant difference in slopes during weeks 8–24 (p = 0.007); the anthocyanin group improved while the placebo group worsened. No differences were found for the secondary cognitive outcomes. Anthocyanin capsules were well-tolerated and safe to use. Conclusion Anthocyanin supplementation for 24 weeks was safe and well tolerated in people with MCI or cardiometabolic disorders. We found no significant group difference in episodic memory at the end of the study but statistically significant differences in slopes. Further studies are warranted to explore whether anthocyanins supplementation can reduce cognitive decline in people at increased risk of dementia.

• Bellenguez, Céline; Küçükali, Fahri; Jansen, Iris E.; Kleineidam, Luca; Moreno-Grau, Sonia & Amin, Najaf [Show all 407 contributors for this article] (2022). New insights into the genetic etiology of Alzheimer's disease and related dementias. Nature Genetics. ISSN 1061-4036. 54(4), p. 412–436. doi: 10.1038/s41588-022-01024-z. Full text in Research Archive Show summary

  Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

• Jansen, Iris E.; Lee, Sven J. van der; Gomez-Fonseca, Duber; Rojas, Itziar de; Dalmasso, Maria Carolina & Grenier-Boley, Benjamin [Show all 50 contributors for this article] (2022). Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers. Acta Neuropathologica. ISSN 0001-6322. 144(5), p. 821–842. doi: 10.1007/s00401-022-02454-z. Full text in Research Archive Show summary

  Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

• Grambaite, Ramune; Arnesen, Marie; Hjemdal, Odin; Fladby, Tormod & Thommessen, Bente (2022). Hukommelse etter iskemisk hjerneslag. Nevropsykologi : Medlemsblad for Norsk Nevropsykologisk Forening. ISSN 1500-8347. 24(1), p. 4–11. Full text in Research Archive
• Motazedi, Ehsan; Cheng, Weiqiu; Thomassen, Jesper Qvist; Frei, Oleksandr; Rongve, Arvid & Athanasiu, Lavinia [Show all 30 contributors for this article] (2022). Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer's Disease in Nordic Populations. Journal of Alzheimer's Disease. ISSN 1387-2877. 88(4), p. 1533–1544. doi: 10.3233/JAD-220174. Full text in Research Archive Show summary

  Background: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer’s disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. Objective: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. Methods: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian DemGene cohort (n = 2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (n = 7,643) and The Copenhagen General Population Study (CGPS) cohort (n = 10,886). Results: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. Conclusion: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations.

• Eliassen, Ingvild Vøllo; Kirsebom, Bjørn-Eivind; Fladby, Tormod; Waterloo, Knut; Sando, Sigrid Botne & Hemminghyth, Mathilde Suhr [Show all 12 contributors for this article] (2022). Regression-Based Cognitive Change Norms Applied in Biochemically Defined Predementia Alzheimer’s Disease. Neuropsychology. ISSN 0894-4105. 37(1), p. 32–43. doi: 10.1037/neu0000853. Full text in Research Archive Show summary

  Objective: We aim to develop 2-year cognitive change norms for adults ages 41–84 for six cognitive tests, and to evaluate these norms in groups with AD biomarkers. Background: Practice effects are common in repeated neuropsychological testing. Not accounting for practice effects may obscure cognitive decline in early Alzheimer’s disease (AD). Method: We developed standardized regression-based change norms from normative samples consisting of healthy controls from the Dementia Disease Initiation study (n = 125), the Trønderbrain study (n = 57), and the Gothenburg mild cognitive impairment (MCI) study (n = 65). Norms were applied in a sample with cognitive symptoms (subjective cognitive decline or MCI) and AD cerebrospinal fluid (CSF) biomarkers (n = 246), classified according to the A/T/N system. Results: The change norms adjusted for pertinent demographics and practice effects. The group with cognitive complaints displayed a trend toward cognitive decline compared to the normative group, with the A+T/N+ subgroup showing the most marked decline. This was observed in tests of episodic memory and cognitive flexibility/divided attention. Conclusions: We present 2-year cognitive change norms for adults between 41 and 84 years, adjusted for practice and demographics. A web-based change norm calculator is provided.

• Espenes, Jacob; Eliassen, Ingvild Vøllo; Öhman, Fredrik; Hessen, Erik; Waterloo, Knut K & Eckerström, Marie [Show all 13 contributors for this article] (2022). Regression‐based normative data for the Rey Auditory Verbal Learning Test in Norwegian and Swedish adults aged 49–79 and comparison with published norms. The Clinical Neuropsychologist. ISSN 1385-4046. doi: 10.1080/13854046.2022.2106890. Full text in Research Archive Show summary

  The Rey Auditory Verbal Learning Test (RAVLT) is a widely used measure of episodic verbal memory. To our knowledge, culturally adapted and demographically adjusted norms for the RAVLT are currently not available for Norwegian and Swedish adults, and imported North American norms are often used. We here develop regression-based norms for Norwegian and Swedish adults and compare our norms to North American norms in an independent sample of cognitively healthy adults. Method: Participants were 244 healthy adults from Norway and Sweden between the aged 49 and 79 years, with between 6 and 24 years of education. Using a multiple multivariate regression-based norming procedure, we estimated effects of age, sex, and years of education on basic and derived RAVLT test scores. The newly developed norms were assessed in an independent comparison group of cognitively healthy adults (n = 145) and compared to recently published North American regression-based norms. Results: Lower age, female sex and more years of education predicted higher performance on the RAVLT. The new norms adequately adjusted for age, education, and sex in the independent comparison group. The American norms corrected for demographics on all RAVLT trials except trials 4, 7, list B, and trials 1–5 total. Test-retest (M = 2.55 years) reliability varied from poor to good. Conclusion: We propose regression-based norms for the RAVLT adjusting for pertinent demographics. The norms may be used for assessment of Norwegian and Swedish adults between the aged of 49 and 79 years, with between 6 and 24 years of education.

• Nordengen, Kaja; Pålhaugen, Lene; Bettella, Francesco; Bahrami, Shahram; Selnes, Per & Jarholm, Jonas Alexander [Show all 10 contributors for this article] (2022). Phenotype-informed polygenic risk scores are associated with worse outcome in individuals at risk of Alzheimer's disease. Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. 14(1), p. 1–13. doi: 10.1002/dad2.12350. Full text in Research Archive Show summary

  Introduction Patients with predementia Alzheimer's disease (AD) and at-risk subjects are targets for promising disease-modifying treatments, and improved polygenic risk scores (PRSs) could improve early-stage case selection. Methods Phenotype-informed PRSs were developed by selecting AD-associated variants conditional on relevant inflammatory or cardiovascular traits. The primary outcome was longitudinal changes in measures of AD pathology, namely development of pathological amyloid deposition, medial temporal lobe atrophy, and cognitive decline in a prospective cohort study including 394 adults without AD dementia. Results High-risk groups defined by phenotype-informed AD PRSs had significantly steeper volume decline in medial temporal cortices, and the high-risk group defined by the cardiovascular-informed AD PRS had significantly increased hazard ratio of pathological amyloid deposition, compared to low-risk groups. Discussion AD PRSs informed by inflammatory disorders or cardiovascular risk factors and diseases are associated with development of AD pathology markers and may improve identification of subjects at risk for progression of AD.

• Borda, Miguel Germán; Ferreira, Daniel; Selnes, Per; Tovar-Rios, Diego Alejandro; Jaramillo-Jiménez, Alberto & Kirsebom, Bjørn-Eivind [Show all 12 contributors for this article] (2022). Timed Up and Go in People with Subjective Cognitive Decline Is Associated with Faster Cognitive Deterioration and Cortical Thickness. Dementia and Geriatric Cognitive Disorders. ISSN 1420-8008. 51(1), p. 63–72. doi: 10.1159/000522094. Full text in Research Archive Show summary

  <p><i>Introduction:</i> Early markers of neurodegeneration provide an opportunity to detect, monitor, and initiate interventions in individuals who have an increased risk of developing dementia. Here, we investigated whether the Timed Up and Go (TUG) test is associated with early brain neurodegeneration and whether the TUG test could be a marker of cognitive decline in people with subjective cognitive decline (SCD). <p><i>Methods:</i> This is a longitudinal analysis of the Dementia Disease Initiation Study, a prospective, community-based, cohort study from Norway, designed to investigate early markers of cognitive impairment and dementia. Participants were classified as SCD and healthy controls (HC). The main studied variables were the TUG test and cognition as measured by the Mini-Mental State Examination and the Consortium to Establish a Registry for Alzheimer’s Disease memory composite score. Additionally, we investigated the cross-sectional association of brain morphology with the TUG using 1.5T-MRI. <p><i>Results:</i> The sample included 45 participants (SCD = 21, HC = 24) followed during a mean time of 1.50 ± 0.70 years. At baseline, the cognitive performance did not differ between the groups, but TUG was longer in SCD. Slower baseline TUG was associated with a faster cognitive decline in both groups and it was also associated with reduced cortical thickness especially in motor, executive, associative, and somatosensory cortical regions in people with SCD. <p><i>Discussion/Conclusion:</i> TUG predicted cognitive change in individuals with SCD, and there was a negative association between TUG and cortical thickness. TUG is a promising cheap and noninvasive marker of early cognitive decline and may help initiate interventions in individuals who have an increased risk of dementia.

• Jansen, Willemijn J.; Janssen, Olin; Tijms, Betty M.; Vos, Stephanie J. B.; Ossenkoppele, Rik & Visser, Pieter Jelle [Show all 182 contributors for this article] (2022). Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum. JAMA Neurology. ISSN 2168-6149. 79(3), p. 228–243. doi: 10.1001/jamaneurol.2021.5216. Full text in Research Archive Show summary

  Importance One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. Objective To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. Design, Setting, and Participants This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. Exposures Alzheimer disease biomarkers detected on PET or in CSF. Main Outcomes and Measures Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. Results Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling–based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, −2% to 9%; P = .18). Conclusions and Relevance This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

• Grøntvedt, Gøril Rolfseng; Sando, Sigrid Botne; Lauridsen, Camilla; Bråthen, Geir; White, Linda Rosemary & Salvesen, Øyvind [Show all 11 contributors for this article] (2022). Association of Klotho protein levels and KL-VS heterozygosity with Alzheimer disease and amyloid and tau burden. JAMA Network Open. 5(11), p. 1–13. doi: 10.1001/jamanetworkopen.2022.43232. Full text in Research Archive Show summary

  Importance Identification of proteins and genetic factors that reduce Alzheimer disease (AD) pathology is of importance when searching for novel AD treatments. Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden. Whether this association is mediated by the Klotho protein remains unclear. Objectives To assess concentrations of Klotho in cerebrospinal fluid (CSF) and plasma among cognitively healthy controls and patients with AD and to correlate these findings with KL-VS heterozygosity status and amyloid and tau burden.<p> <p>Design, Setting, and Participants This case-control study combined 2 independent case-control AD cohorts consisting of 243 referred patients with AD and volunteer controls recruited from January 1, 2009, to December 31, 2018. Klotho levels were measured in CSF and plasma and correlated with KL-VS heterozygosity status and levels of CSF amyloid-β 42 (Aβ42), total tau, and phosphorylated tau. Statistical analysis was performed from January 1, 2021, to March 1, 2022. <p>Main Outcomes and Measures Associations of Klotho levels in CSF and plasma with levels of CSF biomarkers were analyzed using linear regression. Association analyses were stratified separately by clinical groups, APOE4 status, and KL-VS heterozygosity. Pearson correlation was used to assess the correlation between CSF and plasma Klotho levels. <p>Results A total of 243 participants were included: 117 controls (45 men [38.5%]; median age, 65 years [range, 41-84 years]), 102 patients with mild cognitive impairment due to AD (AD-MCI; 59 men [57.8%]; median age, 66 years [range, 46-80 years]), and 24 patients with dementia due to AD (AD-dementia; 12 men [50.0%]; median age, 64.5 years [range, 54-75 years]). Median CSF Klotho levels were higher in controls (1236.4 pg/mL [range, 20.4-1726.3 pg/mL]; β = 0.103; 95% CI, 0.023-0.183; P = .01) and patients with AD-MCI (1188.1 pg/mL [range, 756.3-1810.3 pg/mL]; β = 0.095; 95% CI, 0.018-0.172; P = .02) compared with patients with AD-dementia (1073.3 pg/mL [range, 698.2-1661.4 pg/mL]). Higher levels of CSF Klotho were associated with lower CSF Aβ42 burden (β = 0.519; 95% CI, 0.201-0.836; P < .001) and tau burden (CSF total tau levels: β = −0.884; 95% CI, 0.223 to −0.395; P < .001; CSF phosphorylated tau levels: β = −0.672; 95% CI, −1.022 to −0.321; P < .001) independent of clinical, KL-VS heterozygosity, or APOE4 status. There was a weak correlation between Klotho CSF and plasma levels among the entire cohort (Pearson correlation r = 0.377; P < .001). <p>Conclusions and Relevance The findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant. When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered.

• Janssen, Olin; Jansen, Willemijn J.; Vos, Stephanie J.B.; Boada, Mercè; Parnetti, Lucilla & Gabryelewicz, Tomasz [Show all 61 contributors for this article] (2021). Characteristics of subjective cognitive decline associated with amyloid positivity. Alzheimer's & Dementia. ISSN 1552-5260. doi: 10.1002/alz.12512. Full text in Research Archive
• Siafarikas, Nikias Ioannis; Alnæs, Dag; Sanchez, Jennifer Monereo; Lund, Martina J.; Selbæk, Geir & Korsnes, Maria Stylianou [Show all 13 contributors for this article] (2021). Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment and Alzheimer's disease with dementia. International Psychogeriatrics. ISSN 1041-6102. 33(11), p. 1217–1228. doi: 10.1017/S1041610221000934. Full text in Research Archive Show summary

  We present associations between neuropsychiatric symptoms (NPS) and brain morphology in a large sample of patients with mild cognitive impairment (MCI) and Alzheimer’s disease with dementia (AD dementia). Several studies assessed NPS factor structure in MCI and AD dementia, but we know of no study that tested for associations between NPS factors and brain morphology. The use of factor scores increases parsimony and power. For transparency, we performed an additional analysis with selected Neuropsychiatric Inventory – Questionnaire (NPI-Q) items. Including regional cortical thickness, cortical and subcortical volumes, we examined associations between NPS and brain morphology across the whole brain in an unbiased fashion. We reported both statistical significance and effect sizes, using linear models adjusted for multiple comparisons by false discovery rate (FDR). Moreover, we included an interaction term for diagnosis and could thereby compare associations of NPS and brain morphology between MCI and AD dementia. We found an association between the factor elation and thicker right anterior cingulate cortex across MCI and AD dementia. Associations between the factors depression to thickness of the banks of the left superior temporal sulcus and psychosis to the left post-central volume depended on diagnosis: in MCI these associations were positive, in AD dementia negative. Our findings indicate that NPS in MCI and AD dementia are not exclusively associated with atrophy and support previous findings of associations between NPS and mainly frontotemporal brain structures.

• Lorentzen, Ingrid Myrvoll; Espenes, Johan Jacob; Hessen, Erik; Waterloo, Knut; Bråthen, Geir & Timón, Santiago [Show all 9 contributors for this article] (2021). Regression-based norms for the FAS phonemic fluency test for ages 40–84 based on a Norwegian sample. Applied neuropsychology: Adult. ISSN 2327-9095. doi: 10.1080/23279095.2021.1918128. Full text in Research Archive Show summary

  The FAS phonemic fluency test is a commonly used neuropsychological test of executive function and processing speed. Although Norwegian discrete norms have been developed for the FAS test, American regression-based norms are frequently used by clinicians in Norway. However, language and cultural differences impact performance on the FAS test, and using foreign norms may not be appropriate. Moreover, while discrete norming relies on stratified subgroups of demographics, regression-based norming uses the entire sample to estimate the influence of demographics on performance and may thus improve normative estimates. Here we develop regression-based norms for the FAS phonemic fluency test based on n = 204 healthy Norwegian controls between the ages 40−84 from the Norwegian Dementia Disease Initiation cohort (DDI). We compare the proposed regression norms to published Norwegian discrete norms and American regression-based norms in an independent sample of n = 182 cognitively healthy adults reporting subjective cognitive decline (SCD). We found that years of education was the only significant predictor of FAS performance in our normative sample, accounting for 14.9% of the variance. Both the proposed regression-based norms and previously published discrete norms adequately adjusted for demographics in the independent sample. In contrast, the American norms underestimated the effect of education and overestimated the effect of age. While both the proposed Norwegian regression norms and the previously published discrete norms are suitable for use in Norway, the proposed regression norms may be less vulnerable to sub-stratification sample characteristics posed by discrete norming procedures, and thereby improve normative estimation.

• Sønderby, Ida Elken; Meer, Dennis van der; Moreau, Clara; Kaufmann, Tobias; Walters, G. Bragi & Ellegaard, Maria [Show all 76 contributors for this article] (2021). 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans. Translational Psychiatry. 11. doi: 10.1038/s41398-021-01213-0. Full text in Research Archive Show summary

  Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

• Wightman, Douglas P.; Jansen, Iris E.; Savage, Jeanne E.; Shadrin, Alexey; Bahrami, Shahram & Holland, Dominic [Show all 59 contributors for this article] (2021). A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease. Nature Genetics. ISSN 1061-4036. 53, p. 1276–1282. doi: 10.1038/s41588-021-00921-z. Full text in Research Archive Show summary

  Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.

• Kliem, Elisabeth; Gjestad, Elise Ødegård; Ryum, Truls; Olsen, Alexander; Thommessen, Bente & Indredavik, Bent [Show all 10 contributors for this article] (2021). The Relationship of Psychiatric Symptoms with Performance-Based and Self-Reported Cognitive Function After Ischemic Stroke. Journal of the International Neuropsychological Society. ISSN 1355-6177. 28(1), p. 35–47. doi: 10.1017/S1355617721000187. Full text in Research Archive Show summary

  Objective: Findings on the relationship of psychiatric symptoms with performance-based and self-reported cognitive function post-stroke are inconclusive. We aimed to (1) study the relation of depression and anxiety to performance-based cognitive function and (2) explore a broader spectrum of psychiatric symptoms and their association with performance-based versus self-reported cognitive function. Method: Individuals with supratentorial ischemic stroke performed neuropsychological examination 3 months after stroke. For primary analyses, composite scores for memory and attention/executive function were calculated based on selected neuropsychological tests, and the Hospital Anxiety and Depression Scale (HADS) was used. Psychiatric symptoms and self-reported cognitive function for secondary aims were assessed using the Symptom-Checklist-90 – Revised (SCL-90-R). Results: In a sample of 86 patients [mean (M) age: 64.6 ± 9.2; Mini-Mental State Examination (MMSE), 3–7 days post-stroke: M = 28.4 ± 1.7; National Institutes of Health Stroke Scale (NIHSS) after 3 months: M = 0.7 ± 1.6] depressive symptoms (HADS) were associated with poorer memory performance after controlling for age, sex, and education (p ≤ .01). In a subsample (n = 41; Age: M = 65.7 ± 8.1; MMSE: M = 28.4 ± 1.8; NIHSS: M = 1.0 ± 1.9), symptoms of phobic anxiety (SCL-90-R) were associated with poorer performance-based memory and attention/executive function, and symptoms of anxiety (SCL-90-R) with lower attention/executive function. Higher levels of self-reported cognitive difficulties were associated with higher scores in all psychiatric domains (p ≤ .05). Conclusion: Even in relatively well-functioning stroke patients, depressive symptoms are associated with poorer memory. The results also suggest that various psychiatric symptoms are more related to self-reported rather than to performance-based cognitive function. Screening for self-reported cognitive difficulties may not only help to identify patients with cognitive impairment, but also those who need psychological treatment.

• Siafarikas, Nikias Ioannis; Kirsebom, Bjørn-Eivind; Srivastava, Deepak P; Eriksson, Cecilia Magdalena; Auning, Eirik & Hessen, Erik [Show all 10 contributors for this article] (2021). Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression. Scientific Reports. 11. doi: 10.1038/s41598-021-99794-9. Full text in Research Archive Show summary

  To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-β 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (pADJ < 0.05) and predementia AD (pADJ < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (pADJ < 0.001), BACE1 (pADJ < 0.05) and Ng/BACE1 ratio (pADJ < 0.01). All groups had significantly lower Aβ 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as “predementia AD with depression”.

• Rajkumar, Anto P.; Hye, Abdul; Lange, Johannes; Manesh, Yazmin Rashid; Ballard, Clive & Fladby, Tormod [Show all 7 contributors for this article] (2020). Next-generation RNA-sequencing of serum small extracellular vesicles discovers potential diagnostic biomarkers for dementia with Lewy bodies. The American journal of geriatric psychiatry. ISSN 1064-7481. p. 1–12. doi: 10.1016/j.jagp.2020.10.012. Full text in Research Archive
• Espenes, Johan Jacob; Hessen, Erik; Eliassen, Ingvild Vøllo; Waterloo, Knut; Eckerström, Marie & Sando, Sigrid Botne [Show all 10 contributors for this article] (2020). Demographically adjusted trail making test norms in a Scandinavian sample from 41 to 84 years. The Clinical Neuropsychologist. ISSN 1385-4046. 34, p. 1–18. doi: 10.1080/13854046.2020.1829068. Full text in Research Archive Show summary

  Objective: The trail making test (TMT) is one of the most widely used neuropsychological tests. TMT-A provides measures of visual scanning/visuomotor speed and TMT-B involves additional demands on executive functions. Derived scores TMT B-A and TMT B/A enhance measures of executive functioning. However, simple B-A subtraction may lead to false estimates of executive dysfunction in clinical samples. Norms for TMT have been published in several countries but are currently lacking for Scandinavia. Methods: A total of 292 healthy controls between age 41 and 84 years were included from the Norwegian “Dementia Disease Initiation” (DDI) study (n ¼ 170) and the Gothenburg Mild Cognitive Impairment (MCI) study (n ¼ 122). We used a regression-based procedure to develop demographically adjusted norms for basic (TMT-A and TMT-B) and derived measures (TMT B-A and B/A). We also propose a regression-based alternative to the TMT B-A measure named “TMT-b”. The proposed norms were compared to norms from Heaton et al. and Tombaugh. Results: Due to differences in the estimated normative effects of demographics on performance, the proposed norms for TMT were better suited in the Scandinavian sample compared with published non-Scandinavian norms. The proposed TMT-b measure was highly correlated to TMT B-A (r ¼ 0.969, p < 0.001). Conclusion: We here propose demographically adjusted norms for the TMT for ages 41 through 84 years based on a Scandinavian

• Brooker, Helen; Williams, Gareth; Hampshire, Adam; Corbett, Anne; Aarsland, Dag & Cummings, Jeffrey [Show all 14 contributors for this article] (2020). FLAME: A computerized neuropsychological composite for trials in early dementia. Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. 12(e12098). doi: 10.1002/dad2.12098. Full text in Research Archive Show summary

  Introduction Sensitive neuropsychological tests are needed to improve power for clinical trials in early Alzheimer's disease (AD). Methods To develop a neuropsychological composite (FLAME – Factors of Longitudinal Attention, Memory and Executive Function), we assessed, 10,714 participants over the age of 50 from PROTECT with validated computerized assessments for 2 years. A factorial analysis was completed to identify the key cognitive factors in all participants, and further analyses examined sensitivity to change in people with stage 2/3 early Alzheimer's disease (AD) according to the US Food and Drug Administration (FDA) framework. Results The FLAME composite score (speed of attention, accuracy of attention, memory, and executive function) distinguished between normal cognition and stage 2/3 early AD at baseline, and was sensitive to cognitive and global/functional decline over 2 years, with the potential to improve power for clinical trials. Discussion FLAME is sensitive to change, providing a straightforward approach to reduce sample size for RCTs in early AD. Conclusion FLAME is a useful computerized neuropsychology composite with utility for clinical trials focusing on cognition.

• Eliassen, Ingvild Vøllo; Fladby, Tormod; Kirsebom, Bjørn-Eivind; Waterloo, Knut; Eckerström, Marie & Wallin, Anders [Show all 9 contributors for this article] (2020). Predictive and diagnostic utility of brief neuropsychological assessment in detecting Alzheimer's pathology and progression to dementia. Neuropsychology. ISSN 0894-4105. 34(8), p. 851–861. doi: 10.1037/neu0000698. Full text in Research Archive Show summary

  Objective: To assess the role of brief neuropsychological assessments in prediction and identification of Alzheimer’s disease (AD) pathology and progression to AD dementia. Method: Adults (N = 255; range = 40–81 years) with self-reported cognitive decline underwent baseline and 2-year follow-up clinical assessment, including a brief neuropsychological screening and lumbar puncture. Five different mild cognitive impairment (MCI) algorithms were applied on baseline cognitive test results: one conventional, three amnestic (lenient, stringent, multidomain), and one comprehensive criterion. We compared predictive and diagnostic accuracy of these MCI criteria by performing logistic regression analyses and calculating diagnostic accuracy measures for 2-year outcomes of (1) clinical diagnosis of AD dementia and (2) cerebrospinal fluid biomarkers in the Alzheimer’s continuum. Results: The lenient amnestic MCI criterion showed the largest effect size for predicting progression to AD dementia (OR = 13.762, 99% CI = 1.969–96.194, p = .001) and AD biomarkers (OR = 4.855, 99% CI = 1.974–11.924, p < .001) after 2 years. This criterion was sensitive for progression to dementia (sensitivity = 92.0%, specificity = 54.8%, positive likelihood ratio [LR+] = 2.03, LR− = 0.15) and showed the highest overall diagnostic accuracy for AD biomarkers (sensitivity = 72.7%, specificity = 59.1%, LR+ = 1.78, negative likelihood ratio [LR−] = 0.46). The multidomain amnestic MCI criterion produced the highest specificity for dementia (sensitivity = 76.0%, specificity = 73.0%, LR+ = 2.82, LR− = 0.33) and AD biomarkers (sensitivity = 46.8% specificity = 70.9% LR+ = 1.61, LR− = 0.75). Conclusions: Defining MCI using a brief neuropsychological battery provided limited accuracy for progression to AD dementia and cerebrospinal fluid Aβ. The lenient amnestic MCI criterion identified the highest number of individuals who progressed to clinical AD or showed biomarker pathology, but this approach included a substantial number of false positives. (PsycInfo Database Record (c) 2020 APA, all rights reserved)

• Bergland, Anne Katrine; Proitsi, Petroula; Kirsebom, Bjørn-Eivind; Sønnesyn, Hogne; Hye, Abdul & Larsen, Alf Inge [Show all 11 contributors for this article] (2020). Exploration of plasma lipids in mild cognitive impairment due to Alzheimer's disease. Journal of Alzheimer's Disease. ISSN 1387-2877. 77(3), p. 1117–1127. doi: 10.3233/JAD-200441. Full text in Research Archive Show summary

  <p><i>Background: </i>Lipids have important structural roles in cell membranes and changes to these membrane lipids may influence β- and γ-secretase activities and thus contribute to Alzheimer’s disease (AD) pathology. <p><i>Objective:</i> To explore baseline plasma lipid profiling in participants with mild cognitive impairment (MCI) with and without AD pathology. <p><i>Methods: </i>We identified 261 plasma lipids using reversed-phase liquid chromatography/mass spectrometry in cerebrospinal fluid amyloid positive (Aβ+) or negative (Aβ–) participants with MCI as compared to controls. Additionally, we analyzed the potential associations of plasma lipid profiles with performance on neuropsychological tests at baseline and after two years. <p><i>Results: </i>Sphingomyelin (SM) concentrations, particularly, SM(d43:2), were lower in MCI Aβ+ individuals compared to controls. Further, SM(d43:2) was also nominally reduced in MCI Aβ+ individuals compared to MCI Aβ–. No plasma lipids were associated with performance on primary neuropsychological tests at baseline or between the two time points after correction for multiple testing. <p><i>Conclusion: </i>Reduced plasma concentrations of SM were associated with AD.

• Ballard, Clive; Aarsland, Dag; Cummings, Jeffrey; O'Brien, John; Mills, Roger & Molinuevo, Jose Luis [Show all 11 contributors for this article] (2020). Drug repositioning and repurposing for Alzheimer disease. Nature Reviews Neurology. ISSN 1759-4758. p. 1–13. doi: 10.1038/s41582-020-0397-4. Full text in Research Archive
• Espenes, Ragna; Kirsebom, Bjørn-Eivind; Eriksson, Cecilia Magdalena; Waterloo, Knut K; Hessen, Erik & Johnsen, Stein Harald [Show all 8 contributors for this article] (2020). Amyloid plaques and symptoms of depression links to medical help-seeking due to subjective cognitive decline. Journal of Alzheimer's Disease. ISSN 1387-2877. 75(3), p. 879–890. doi: 10.3233/JAD-190712. Full text in Research Archive Show summary

  <i>Background:</i> Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer’s disease (AD). However, patients reporting SCD to their general practitioner are not always referred to a memory clinic.<p> <p><i>Objective:</i> To investigate whether prior history of medical help-seeking is associated with AD biomarker abnormality, worse cognitive performance, and/or depressive symptoms in SCD.<p> <p><i>Methods</i>: We compared levels of cerebrospinal fluid (CSF) A<i>β</i>_{1 - 42}, cognitive performance, and depressive symptoms (15-item Geriatric Depression Scale, GDS-15) between healthy controls (<i>n</i> = 88), SCD with a history of medical help seeking (SCD-HS, <i>n</i> = 67), and SCD non help-seekers (SCD-NHS, <i>n</i> = 44). Cases with evidence of amyloid plaques (CSF A<i>β</i>_{1 - 42} ≤708 ng/l) and symptoms of depression (GDS-15≥6) were determined in both SCD groups.<p> <p><i>Results</i>: The SCD-HS group had lower CSF A<i>β</i>_{1 - 42} (<i>p</i> < 0.01), lower word list learning and memory recall (p < 0.0001), and an increased level of depressive symptoms (<i>p</i> < 0.0001) compared to controls and SCD-NHS cases. The SCD-HS group had more cases with symptoms of depression (<i>n</i> = 12, 18%) and amyloid plaques (<i>n</i> = 18, 27%) compared to SCD-NHS (<i>n</i> = 1, 2% and <i>n</i> = 7, 16%, respectively). None of the SCD-HS cases and only one SCD-NHS case had concurrent symptoms of depression and amyloid plaques. The SCD-HS cases showed equal word list learning and memory performance regardless of amyloid status or symptoms of depression.<p> <p><i>Conclusion</i>: Medical help-seeking in SCD is associated with an increased risk of AD pathology or symptoms of depression. However, subtle memory deficits are seen in SCD help-seekers, also without amyloid plaques or symptoms of depression.

• Pålhaugen, Lene; Sudre, Carole H; Teceläo, Sandra Raquel Ramos; Nakling, Arne; Almdahl, Ina Selseth & Kalheim, Lisa Flem [Show all 13 contributors for this article] (2020). Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. 41(5), p. 1–13. doi: 10.1177/0271678X20957604. Full text in Research Archive Show summary

  White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer’s disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aβ1-42 pathology (Aβ+/−) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH (p = 0.001) and occipital DWMH (p = 0.003) loads were increased in SCD-Aβ+ compared with Aβ− controls. In MCI-Aβ+ compared with Aβ− controls, there were differences in global WMH (p = 0.003), as well as occipital DWMH (p = 0.001) and temporal DWMH (p = 0.002) loads. FRS-CVD was associated with frontal PWMHs (p = 0.003) and frontal DWMHs (p = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aβ+ and MCI-Aβ+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology.

• Khalifa, Khadija; Bergland, Anne Katrine; Sønnesyn, Hogne; Oppedal, Ketil; Oesterhus, Ragnhild & Dalen, Ingvild [Show all 12 contributors for this article] (2020). Effects of purified anthocyanins in people at risk for dementia: Study protocol for a phase II randomized controlled trial. Frontiers in Neurology. 11:916, p. 1–10. doi: 10.3389/fneur.2020.00916. Full text in Research Archive Show summary

  Background: The number of people with dementia is increasing, with huge challenges for society and health-care systems. There are no disease-modifying therapies available. There is, therefore, an urgent need to identify strategies to reduce the risk of developing dementia. Anthocyanins are a class of compounds found in dark berries and fruits with some effects that might reduce the risk for cognitive decline and the development of dementia in older people. Aim: This phase II three-center, randomized, 24-week, placebo-controlled study, ongoing in Norway, aims to evaluate the safety, and efficacy of anthocyanins in modifying key dementia-related mechanisms and maintain cognitive functioning in older people at risk for dementia. Methods: Participants (220 individuals aged 60–80 years) who meet the inclusion criteria (either mild cognitive impairment or two or more cardiometabolic disorders) are being enrolled in this study at three different centers in Norway. Participants are block randomized to identically appearing capsules containing 80 mg of naturally purified anthocyanins or placebo 1:1. Dosage is 2 + 2 capsules per day for 24 weeks. The primary outcome will be the quality of episodic memory score, a composite measure from the extensively validated online cognitive test battery CogTrack®, which is administered at baseline and monthly for the next 6 months. Secondary outcomes include other major scores from CogTrack, as well as a range of neuroimaging and other biomarkers. Anthocyanin metabolites will be measured in blood and cerebrospinal fluid. The change from baseline scores will be subject to a mixed model for repeated measures analysis of covariance. The primary comparison will be the contrast (difference in the least-square means) between active and placebo at the end of the study (week 24). The primary study population will be a modified intention-to-treat population (ClinicalTrials.gov, NCT03419039). Discussion: This study aims to demonstrate whether there are beneficial effects of purified anthocyanins on cognition and relevant biological functions in people at increased risk for dementia. Forthcoming results may contribute to further improvement of intervention strategies to prevent or delay the onset of dementia, including a potential decision to take anthocyanins toward phase III trials.

• Henjum, Kristi; Årskog, Vibeke Helen; Jendresen, Charlotte Bille; Fladby, Tormod; Torp, Reidun & Nilsson, Lars (2020). Analyzing microglial-associated Aβ in Alzheimer’s disease transgenic mice with a novel mid-domain Aβ-antibody. Scientific Reports. 10(10590). doi: 10.1038/s41598-020-67419-2. Full text in Research Archive Show summary

  The mechanisms of amyloid-β (Aβ)-degradation and clearance in Alzheimer’s disease (AD) pathogenesis have been relatively little studied. Short Aβ-fragments form by enzymatic cleavage and alternate amyloid-beta precursor protein (APP)-processing. Here we characterized a novel polyclonal Aβ-antibody raised against an Aβ mid-domain and used it to investigate microglial Aβ-uptake in situ by microscopy at the light- and ultrastructural levels. The rabbit Aβ-mid-domain antibody (ab338), raised against the mid-domain amino acids 21–34 (Aβ21–34), was characterized with biochemical and histological techniques. To identify the epitope in Aβ recognized by ab338, solid phase and solution binding data were compared with peptide folding scores as calculated with the Tango software. The ab338 antibody displayed high average affinity (KD: 6.2 × 10−10 M) and showed preference for C-terminal truncated Aβ-peptides ending at amino acid 34 and Aβ-mid domain peptides with high scores of β-turn structure. In transgenic APP-mouse brain, ab338 labelled amyloid plaques and detected Aβ-fragments in microglia at the ultra- and light microscopic levels. This reinforces a role of microglia/macrophages in Aβ-clearance in vivo. The ab338 antibody might be a valuable tool to study Aβ-clearance by microglial uptake and Aβ-mid-domain peptides generated by enzymatic degradation and alternate production.

• Hessen, Erik; Kirsebom, Bjørn-Eivind; Eriksson, Cecilia Magdalena; Eliassen, Carl Fredrik Andestad; Nakling, Arne & Bråthen, Geir [Show all 9 contributors for this article] (2019). In Brief Neuropsychological Assessment, Amnestic Mild Cognitive Impairment (MCI) Is associated with Cerebrospinal Fluid Biomarkers for Cognitive Decline in Contrast to the Prevailing NIA-AA MCI Criterion. Journal of Alzheimer's Disease. ISSN 1387-2877. 67(2), p. 715–723. doi: 10.3233/JAD-180964. Full text in Research Archive Show summary

  Background: In the care of persons with cognitive problems, it is important to use a valid mild cognitive impairment (MCI) criterion that discriminates well between normal and pathological aging. Objective: To find the brief neuropsychological screening criterion that best correlates with cerebrospinal fluid (CSF) biomarkers for cognitive decline and dementia in persons seeking help for cognitive problems. Methods: 452 consecutively recruited patients (age 40–80 years) from memory-clinics in the Norwegian national multicentre longitudinal study Dementia Disease Initiation were included. CSF data as well as full data from brief neuropsychological screening were available for all patients. Results: Amnestic MCI, including at least one memory test below T-score 40, outperformed the conventional US National Institute on Aging-Alzheimer’s Association (NIA-AA) MCI criterion. Only amnestic MCI was significantly associated with biomarker pattern of NIA-AA stage 2 (low CSF Aβ42 concentrations and elevated tau) in multivariate regression analysis. Conclusions: The finding that amnestic MCI based on brief neuropsychological assessment is significantly associated with CSF biomarkers for cognitive decline and Alzheimer’s disease is in accordance with longitudinal studies that find memory impairment; both in itself and especially in combination with other cognitive deficit to constitute a risk factor for subsequent cognitive decline and dementia. The prevalence of pathological biomarkers for Alzheimer’s disease is common in the elderly and the clinical significance of present findings depend on longitudinal validation.

• Fang, Evandro Fei; Hou, Yujun; Palikaras, Konstantinos; Adriaanse, Bryan A.; Kerr, Jesse S. & Yang, Beimeng [Show all 20 contributors for this article] (2019). Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nature Neuroscience. ISSN 1097-6256. 22(3), p. 401–412. doi: 10.1038/s41593-018-0332-9. Full text in Research Archive Show summary

  Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer’s disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models. In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD+ supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1 (PTEN-induced kinase-1)-, PDR-1 (Parkinson’s disease-related-1; parkin)-, or DCT-1 (DAF-16/FOXO-controlled germline-tumor affecting-1)-dependent pathways. Mitophagy diminishes insoluble Aβ1–42 and Aβ1–40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.

• Rongve, Arvid; Witoelar, Aree; Ruiz, Agustín; Athanasiu, Lavinia; Abdelnour, Carla & Clarimon, Jordi [Show all 40 contributors for this article] (2019). GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study. Scientific Reports. 9(7013). doi: 10.1038/s41598-019-43458-2. Full text in Research Archive Show summary

  Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10−8). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10−6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

• Hope, Tuva Roaldsdatter; Selnes, Per; Rektorová, Irena; Anderkova, Lubomira; Nemcova-Elfmarkova, Nela & Balážová, Zuzana [Show all 9 contributors for this article] (2019). Diffusion tensor and restriction spectrum imaging reflect different aspects of neurodegeneration in Parkinson's disease. PLOS ONE. 14(5), p. 1–13. doi: 10.1371/journal.pone.0217922. Full text in Research Archive Show summary

  To meet the need for Parkinson’s disease biomarkers and evidence for amount and distribution of pathological changes, MRI diffusion tensor imaging (DTI) has been explored in a number of previous studies. However, conflicting results warrant further investigations. As tissue microstructure, particularly of the grey matter, is heterogeneous, a more precise diffusion model may benefit tissue characterization. The purpose of this study was to analyze the diffusion-based imaging technique restriction spectrum imaging (RSI) and DTI, and their ability to detect microstructural changes within brain regions associated with motor function in Parkinson’s disease. Diffusion weighted (DW) MR images of a total of 100 individuals, (46 Parkinson’s disease patients and 54 healthy controls) were collected using b-values of 0–4000s/mm2. Output diffusion-based maps were estimated based on the RSI-model combining the full set of DW-images (Cellular Index (CI), Neurite Density (ND)) and DTI-model combining b = 0 and b = 1000 s/mm2 (fractional anisotropy (FA), Axial-, Mean- and Radial diffusivity (AD, MD, RD)). All parametric maps were analyzed in a voxel-wise group analysis, with focus on typical brain regions associated with Parkinson’s disease pathology. CI, ND and DTI diffusivity metrics (AD, MD, RD) demonstrated the ability to differentiate between groups, with strongest performance within the thalamus, prone to pathology in Parkinson’s disease. Our results indicate that RSI may improve the predictive power of diffusion-based MRI, and provide additional information when combined with the standard diffusivity measurements. In the absence of major atrophy, diffusion techniques may reveal microstructural pathology. Our results suggest that protocols for MRI diffusion imaging may be adapted to more sensitive detection of pathology at different sites of the central nervous system.

• Kirsebom, Bjørn-Eivind; Espenes, Ragna; Hessen, Erik; Waterloo, Knut; Johnsen, Stein Harald & Gundersen, Elisabeth [Show all 10 contributors for this article] (2019). Demographically adjusted CERAD wordlist test norms in a Norwegian sample from 40 to 80 years. The Clinical Neuropsychologist. ISSN 1385-4046. 33(13), p. 27–39. doi: 10.1080/13854046.2019.1574902. Full text in Research Archive Show summary

  Background/Objective: In recent years, several slightly younger cohorts have been established in order to study the preclinical and prodromal phases of dementia. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) wordlist memory test (WLT) is widely used in dementia research. However, culturally adapted and demographically adjusted test norms for younger ages are lacking. Method: This paper investigates effects of age, gender and years of education on test performance and offers demographically adjusted norms for the CERAD WLT using a regression-based norming procedure for the age span 40–80years based on healthy controls (n¼227) from the Norwegian “Dementia Disease Initiation” (DDI) (n¼168) and “Trønderbrain” (n¼59) cohorts. In order to evaluate normative performance, we apply the norms to an independent sample of persons diagnosed with mild cognitive impairment (MCI = 168) and perform multiple regression analyses to evaluate adjustment of pertinent demographics. Results: CERAD WLT norms adjusted for effects of age, gender and educational level are proposed. The norms successfully adjusted for effects of age, gender and education in an independent sample of Norwegians with MCI. Conclusion: Demographically adjusted norms for the CERAD WLT for ages 40–80years based on a Norwegian sample are proposed. To our knowledge, this is the first normative study of this test to offer demographically adjusted norms for this age span.

• Fang, Fei; Hou, Y; Palikaras, Konstantinos; Adriaanse, BA; Kerr, SJ & Yang, B [Show all 19 contributors for this article] (2019). Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nature Neuroscience. ISSN 1097-6256. 22(3), p. 401–412. doi: 10.1038/s41593-018-0332-9. Full text in Research Archive

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• Lambert, Jean Charles; Ramirez, Alfredo; Ruiz, Agustín; Andreassen, Ole; Sims, Rebecca & Hiltunen, Mikko [Show all 517 contributors for this article] (2026). Consensus meta-analysis of genome-wide association studies for Alzheimer’s disease and related dementias. Nature Genetics. ISSN 1061-4036. 58, p. 1214–1225. doi: 10.1038/s41588-026-02583-1. Full text in Research Archive Show summary

  To better characterize the genetic architecture underlying Alzheimer’s disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.

• Delvenne, Aurore; Rizzo, Marianna; Zhang, Bailin; Levit, Mikhail; Zetterberg, Henrik & Blennow, Kaj [Show all 31 contributors for this article] (2025). CSF proteomics reveals distinct choroid plexus-related protein signatures in AD, PD and DLB. Alzheimer's & Dementia. ISSN 1552-5260. 21(s1). doi: 10.1002/alz70855_102631. Full text in Research Archive Show summary

  Background The choroid plexus (ChP) plays a role in cerebrospinal fluid (CSF) production, protein transport and clearance, and central nervous system homeostasis. Emerging evidence suggests that ChP dysfunction is implicated in the pathogenesis of neurodegenerative diseases. We aim to investigate ChP involvement in the pathophysiology of Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) using CSF proteomics. Method We included individuals with AD (n = 150), PD (n = 75), DLB (n = 53), and controls (n = 47) from 6 centers of the European Platform for Neurodegenerative Diseases (EPND) project. AD was defined as abnormal CSF Aβ42/40 (Roche NeuroToolKit) without meeting clinical criteria of PD or DLB. Controls had normal cognition and CSF Aβ42/40. Using the Olink Explore 3072 assay, 2902 CSF proteins were quantified. Proteins were classified as highly expressed in the ChP using the Allen Brain Atlas. Pairwise comparisons of protein concentrations between disease and controls were conducted, adjusting for age and sex. Weighted Gene Co-expression Network Analysis (WGCNA) was performed on ChP-expressed proteins to identify co-expression modules, followed by Wilcoxon tests to compare module expression profiles across groups. Pathway enrichment analysis was conducted using Gene Ontology. Result Of the 2902 proteins quantified, 799 were highly expressed by the ChP. In PD versus controls, 37% of the dysregulated proteins were highly expressed in the ChP, compared to 30% in AD versus controls and 28% in DLB versus controls (Figure 1). The dysregulated ChP-expressed proteins in AD, PD and DLB were predominantly distinct and associated with different underlying pathways (Figure 2). WGCNA identified four co-expression modules related to the proteins with high ChP expression. Module 1, related to innate immunity (complement), was decreased in AD versus all other groups. Module 2, linked to transcriptional and translational processes, was increased in PD versus controls and AD. Module 3, related to the extracellular matrix, was increased in DLB versus AD. No significant differences were observed for module 4 (Figure 3). Conclusion Our findings highlight the distinct involvement of ChP-expressed proteins in the pathophysiology of AD, PD, and DLB, revealing disease-specific patterns. Further research is essential to elucidate mechanistic involvement of the ChP in disease progression across these disorders.

• Rizzo, Marianna; Teunissen, Charlotte E.; Brosseron, Frederic; Kuhs, Sandra; Kollmorgen, Gwendlyn & Zetterberg, Henrik [Show all 30 contributors for this article] (2025). Associations between CSF complement factors and biomarkers of amyloid, tau, neurofilament light chain, and α-synuclein in AD, DLB, and PD. doi: 10.1002/alz70856_104363. Full text in Research Archive Show summary

  Background While evidence suggests complement system involvement in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease (PD), its association with disease biomarkers remains unclear. We investigated the relationship of complement factors with amyloid, tau, NfL, and α-synuclein in CSF in AD, DLB, PD, and controls. Method We included 321 individuals with AD, DLB, PD, and controls from 6 centers of the EPND study. CSF Aβ42/40, p-tau181, NfL, and α-syn were centrally measured using NeuroToolKit (Roche Diagnostics), and 14 CSF complement factors using Milliplex (Merck KGaA). Controls were defined as normal cognition and normal Aβ42/40, whereas AD as abnormal Aβ42/40 without meeting clinical criteria of DLB or PD. Linear regression models adjusted for age and sex were used. Associations were post-hoc compared between individuals with low(≤23), intermediate(24-27), and high(≥28) MMSE scores. Result Sample characteristics are presented in Table 1. Lower Aβ42/40 levels were associated with lower levels of 7 complement factors in controls and with higher C1q and C2 levels specifically in AD (Figure 1, Figure 2). No associations of Aβ42/40 with complement were found in DLB and PD. Higher p-tau181 levels were associated with increased levels of 7 complement factors in controls and 6 in AD, and showed fewer associations in DLB and PD. The strength of p-tau181 associations with complement was similar across groups. Higher NfL levels were widely associated with higher complement factor levels in controls (13) and AD (12), and less in PD (6) and DLB (4). Higher α-syn levels were broadly associated with higher complement factor levels in AD (13), controls (12), and DLB (12), but only minimally in PD (1). The strength of these NfL and α-syn associations with complement was not disease-specific. Conversely, compared to all groups, in PD higher α-syn levels were associated with lower C5, C5a, C9, factor-I and properdin levels. Individuals with intermediate MMSE scores largely drove the associations of α-syn with complement in AD. MMSE level did not clearly impact other associations. Conclusion CSF complement factors were associated with amyloid, tau, NfL, and α-synuclein, suggesting complement system involvement in several neurodegenerative diseases. Complement showed disease-specific associations with amyloid in AD and α-synuclein in PD.

• Jaramillo-Jimenez, Alberto; Mantilla-Ramos, Yorguin Jose; Tovar-Rios, Diego Alejandro; Lopera, Francisco; Niño, David Fernando Aguillón & Gómez, John Fredy Ochoa [Show all 16 contributors for this article] (2025). Mega-Analysis of Oscillatory and Aperiodic Resting-State EEG Alterations in Neurodegenerative Diseases. Alzheimer's & Dementia. ISSN 1552-5260. 21, p. e103714–e103714. doi: 10.1002/alz70856_103714. Full text in Research Archive
• Gonzalez-Ortiz, Fernando; Turton, Michael K.; Gobom, Johan; Brinkmalm, Gunnar; Harrison, Peter & Simonsen, Anja Hviid [Show all 9 contributors for this article] (2025). Novel MTBR-specific immunoassays MTBR-1 and MTBR-pTau262 for assessment of tau pathology in Alzheimer's disease. Alzheimer's & Dementia. ISSN 1552-5260. 21(S7). doi: 10.1002/alz70861_108526. Full text in Research Archive
• Zhou, Robin Ziyue; Gaunitz, Stefan; Skoldunger, Anders; Wimo, Anders; Winblad, Bengt & Fladby, Tormod [Show all 8 contributors for this article] (2025). Blood N-glycomics reveals individuals at risk for cognitive decline and Alzheimer’s disease. Alzheimer's & Dementia. ISSN 1552-5260. 21(S7). doi: 10.1002/alz70861_108302. Full text in Research Archive Show summary

  Background It is increasingly clear that aberrant N-glycosylation of proteins is an early pathogenic trigger in Alzheimer’s disease (AD). Thus, we hypothesized that determination of the blood N-glycome could reveal AD-specific glycomic patterns, especially in early stages of the disease. Method For N-glycan quantification in blood, we developed a method based on porous graphite carbon liquid chromatography coupled to tandem mass spectrometry (PGC-LC-MS/MS). We simultaneously determined levels of 62 N-glycan structures in 100 individuals from two different cohorts. In the Swedish National Study on Aging and Care in Nordanstig (SNAC-N) cohort, we analyzed blood samples from 40 age- and sex-matched AD and control individuals. In the Norwegian Dementia Disease Initiation (DDI) cohort, we analyzed blood samples from 60 individuals from A-T-, A+T-, and A+T+ biomarker groups, matched by age, sex, and education. Result In the Swedish SNAC-N discovery cohort, a specific blood signature of low levels of a group of N-glycans was associated with AD dementia, lower cognitive function, as well as higher levels of AD biomarkers such as blood pTau217. In the Norwegian DDI cohort, a similar low N-glycosylation blood signature was associated with APOE4 genotype and future cognitive decline, but not with A/T status. In short, low levels of 14 N-glycan structures were associated with poor cognitive outcome in both cohorts. Conclusion Here, we provided an extensive characterization of the blood N-glycome in AD. We showed that the blood N-glycome could predict cognitive decline in an amyloid/tau independent manner. Blood N-glycomics should be further developed as a minimally invasive prognostic biomarker in early stages of dementia.

• Holmøy, Trygve; Hardang, Ingrid Marie; Fladby, Tormod; Kirsebom, Bjørn-Eivind & Røysland, Ragnhild (2025). Nevrofilament lettkjede – en markør for nevronskade. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 145(8). doi: 10.4045/tidsskr.25.0245. Full text in Research Archive
• Stefansson, Hreinn; Walters, G. Bragi; Sveinbjornsson, Gardar; Tragante, Vinicius; Einarsson, Gudmundur & Helgason, Hannes [Show all 67 contributors for this article] (2024). Homozygosity for R47H in TREM2 and the Risk of Alzheimer's Disease. New England Journal of Medicine. ISSN 0028-4793. 390(23), p. 2217–2219. doi: 10.1056/NEJMc2314334. Full text in Research Archive
• Wang, Heling; Siow, Richard; Schmauck-Medina, Tomás Alejandro; Zhang, Jianying; Sandset, Per Morten & Filshie, Clare [Show all 38 contributors for this article] (2024). Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies. The journals of gerontology. Series A, Biological sciences and medical sciences. ISSN 1079-5006. 79(4), p. 1–10. doi: 10.1093/gerona/glae029. Full text in Research Archive Show summary

  Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a “Money Follows Cooperation agreement” between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

• Padrela, Beatriz; Mahroo, Amnah; Tee, Mervin; Sneve, Markus Handal; Moyaert, Paulien & Geier, Oliver [Show all 43 contributors for this article] (2024). Developing blood-brain barrier arterial spin labelling as a non-invasive early biomarker of Alzheimer's disease (DEBBIE-AD): a prospective observational multicohort study protocol. BMJ Open. 14(3). doi: 10.1136/bmjopen-2023-081635. Full text in Research Archive Show summary

  Introduction Loss of blood-brain barrier (BBB) integrity is hypothesised to be one of the earliest microvascular signs of Alzheimer’s disease (AD). Existing BBB integrity imaging methods involve contrast agents or ionising radiation, and pose limitations in terms of cost and logistics. Arterial spin labelling (ASL) perfusion MRI has been recently adapted to map the BBB permeability non-invasively. The DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium aims to develop this modified ASL-MRI technique for patient-specific and robust BBB permeability assessments. This article outlines the study design of the DEBBIE cohorts focused on investigating the potential of BBB-ASL as an early biomarker for AD (DEBBIE-AD). Methods and analysis DEBBIE-AD consists of a multicohort study enrolling participants with subjective cognitive decline, mild cognitive impairment and AD, as well as age-matched healthy controls, from 13 cohorts. The precision and accuracy of BBB-ASL will be evaluated in healthy participants. The clinical value of BBB-ASL will be evaluated by comparing results with both established and novel AD biomarkers. The DEBBIE-AD study aims to provide evidence of the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD and AD-related pathologies. Ethics and dissemination Ethics approval was obtained for 10 cohorts, and is pending for 3 cohorts. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

• Rongve, Arvid; Aarsland, Dag; Fladby, Tormod; Øksengård, Anne Rita & Selbæk, Geir (2024). Ny tidsalder for behandling og diagnostikk av Alzheimers sykdom. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 145(1). doi: 10.4045/tidsskr.24.0604. Full text in Research Archive
• Hemminghyth, Mathilde Suhr; Breitve, Monica Haraldseid; Gisladottir, Berglind; Grøntvedt, Gøril Rolfseng; Nakling, Arne Exner & Fladby, Tormod [Show all 8 contributors for this article] (2023). Cerebrospinal fluid neurofilament light chain mediates age-related decline in learning and memory in healthy adults. Full text in Research Archive
• Siafarikas, Nikias Ioannis; Kirsebom, Bjørn-Eivind; Srivastava, Deepak P.; Eriksson, Cecilia Magdalena; Auning, Eirik & Hessen, Erik [Show all 10 contributors for this article] (2022). Author Correction: Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression (Scientific Reports, (2021), 11, 1, (20375), 10.1038/s41598-021-99794-9). Scientific Reports. 12(1). doi: 10.1038/s41598-022-22274-1. Full text in Research Archive
• Becu, Marcia Constance Noemi; Bonnevie, Tora; Polti, Ignacio; Jarholm, Jonas Alexander; Grøntvedt, Gøril Rolfseng & Bråthen, Geir [Show all 9 contributors for this article] (2022). Entorhinal grid-like representation in early Alzheimer's disease: association with biomarkers concentration and genetic risk. Full text in Research Archive
• Wightman, Douglas P.; Jansen, Iris E.; Savage, Jeanne E.; Shadrin, Alexey; Bahrami, Shahram & Holland, Dominic [Show all 114 contributors for this article] (2022). Author Correction: A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease (Nature Genetics, (2021), 53, 9, (1276-1282), 10.1038/s41588-021-00921-z). Nature Genetics. ISSN 1061-4036. 54(7), p. 1062–1062. doi: 10.1038/s41588-022-01126-8. Full text in Research Archive
• Wightman, Douglas P.; Jansen, Iris E.; Savage, Jeanne E.; Shadrin, Alexey A.; Bahrami, Shahram & Holland, Dominic [Show all 114 contributors for this article] (2021). Author Correction: A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease (Nature Genetics, (2021), 53, 9, (1276-1282), 10.1038/s41588-021-00921-z). Nature Genetics. ISSN 1061-4036. doi: 10.1038/s41588-021-00977-x. Full text in Research Archive
• Espenes, Johan Jacob; Eliassen, Ingvild Vøllo; Fladby, Tormod; Eckerström, Marie; Anders, Wallin & Waterloo, Knut [Show all 8 contributors for this article] (2020). Demographically adjusted test norms for the Rey Auditory Verbal Learning Test in Norwegian and Swedish adults from 41 to 79 years. Full text in Research Archive
• Kliem, Elisabeth; Gjestad, Elise Ødegård; Ryum, Truls; Olsen, Alexander; Thommessen, Bente & Indredavik, Bent [Show all 9 contributors for this article] (2020). Relations Between Psychiatric Symptoms, Performance-based and Self-Reported Cognitive Function After Stroke. Full text in Research Archive
• Espenes, Johan Jacob; Kirsebom, Bjørn-Eivind; Vøllo, Ingvild Eliassen; Espenes, Ragna; Waterloo, Knut & Hessen, Erik [Show all 7 contributors for this article] (2019). Demographically adjusted norms for basic and derived measures on the Trail Making Test A & B based on a Norwegian sample age 40 – 84 years. Full text in Research Archive
• Kirsebom, Bjørn-Eivind; Selnes, Per; Richter, Grit; Gisladottir, Berglind; Wettergreen, Marianne & Torsetnes, Silje Bøen [Show all 9 contributors for this article] (2019). Cerebrospinal fluid Neurogranin/BACE1 ratio differentiate normal controls, pre-dementia Alzheimer’s and Parkinson’s disease cases. Full text in Research Archive
• Skogseth, Ragnhild Eide; Aarsland, Dag; Gilhus, Nils Erik & Fladby, Tormod (2019). Biomarker and pathology studies in neurodegenerative cognitive impairment. Universitetet i Bergen. ISSN 9788230865682. Full text in Research Archive Show summary

  Background: Dementia is a major cause of functional impairment and early death in older age groups. Neurodegenerative disorders are the most common cause of dementia. The most frequent neuropathological lesions include neurofibrillary tangles and senile plaques, hallmark lesions for Alzheimer´s disease (AD), and Lewy body pathology, which characterize Lewy body disease (LBD). Clinically, the neuropathological entity LBD can present as either Parkinson´s disease (PD) or dementia with Lewy bodies (DLB), differentiated on the basis of the presenting symptoms being either motor or cognitive. While the majority of LBD patients develop both motor symptoms and cognitive impairment, some patients with clinical PD will never experience cognitive impairment and likewise some patients with DLB will never develop motor symptoms. Similarly the clinical presentation of AD is also heterogeneous, for instance, the highly variable occurrence of neuropsychiatric symptoms and rate of progression. These differences have a major impact on quality of life for patients and carers, as well as health care costs, but their mechanisms and neuropathological underpinnings are poorly understood. Furthermore the correlation between clinical diagnosis and neuropathological findings is relatively low, and LBD patients presenting with cognitive impairment particularly risk being misclassified as AD. This highlight the need for more precise biomarkers for these clinical syndromes that can be implemented at the start of and during the course of the disease. Biomarkers may inform about disease pathology, thus paving the way for new treatment, they increase diagnostic accuracy and aid in setting a prognosis. Biomarkers are needed in the selection of patients for treatment studies and to identify which patients should benefit from new treatment when available. The cerebrospinal fluid (CSF) biomarkers beta-amyloid 42 (abeta42), total tau (t-tau) and tau protein phosphorylated at amino acid 181 (p-tau181) reflect key AD pathologies. The Lewy bodies found in LBD are composed mainly of the protein !-synuclein. !-synuclein is reduced in CSF in LBD, but with considerable overlap between LBD, controls and other disease groups. Aim: The main aim of this thesis was to increase understanding of pathological mechanisms underlying important clinical features in neurodegenerative cognitive impairment, by exploring the associations between clinical presentation and biomarkers and pathology. The first objective was to explore the association between AD pathology CSF markers and neuropsychiatric symptoms in newly diagnosed AD patients; secondly to assess the association between CSF markers of AD and LBD pathology and early cognitive impairment in PD; thirdly to examine the correlation between clinical diagnosis of DLB and Lewy body pathology at autopsy. Methods: This is a clinical translational neuroscience project based on two clinical cohort studies. The dementia Study of Western Norway (Demvest) included newly diagnosed dementia patients from specialist clinics in geriatric medicine and old age psychiatry in Western Norway. The Parkinson´s Progression Markers Initiative (PPMI) is an international multicentre study, including newly diagnosed PD patients and healthy controls. A comprehensive battery of neuropsychological tests, a structured neuropsychiatric evaluation, clinical examination, and imaging were part of both studies. CSF sampling was done according to standardized protocols and CSF was analysed using commercially available immunoassays. In the Demvest study, participants were recruited for brain donation, and autopsy results were obtained applying commonly used neuropathological protocols and diagnostic criteria. Results: We undertook three specific studies to investigate objective I, II and III. In study I, apathy in patients with early Alzheimer´s disease correlated with t-tau and ptau181 concentrations in CSF, higher values being associated with more severe apathy. There were no associations between depression or psychosis and agitation and CSF markers. In study II, decreased CSF !-synuclein in newly diagnosed PD-patients without dementia correlated with impaired global cognition and impairment of executive functions and attention. CSF abeta42 was decreased in PD with mild cognitive impairment compared with controls after adjusting for covariates. No correlations were found between memory or visuospatial functions and CSF markers. Study III examined autopsy results of 56 patients followed from dementia diagnosis to death. 20 patients received a pathological diagnosis of LBD; the corresponding clinical diagnosis were probable DLB (n=11), Parkinson´s disease with dementia (PDD) (n=5) and probable or possible AD (n=4). Of the 56, 14 patients received a clinical diagnosis of probable DLB, 11 of these had pathological LBD and three AD. Sensitivity, specificity, positive and negative predictive values of a clinical DLB diagnosis were 73%, 93%, 70%, and 90% respectively. Conclusions and implications: We have reported a novel association between neuropsychiatric symptoms and CSF biomarkers reflecting core AD pathology. The relationship between t-tau and p-tau181 and apathy may reflect an association between neurofibrillary tangle pathology and apathy in early AD. Cognitive impairment in early PD was associated with biomarkers of both Lewy body and AD pathology. 18 of 20 LBD patients in the Demvest study had Braak neurofibrillary tangle stage IV or higher, representing severe AD pathology at autopsy. Thus our findings suggest a role for AD pathology in both early and established LBD. Accurate diagnosis is crucial for clinical practice and research. With a sensitivity of 73%, the clinical 2005 DLB criteria are not sensitive enough. More than one in four DLB patients were not identified even when structured rating scales for core DLB symptoms were applied. We regard a specificity of 93% as satisfactory. Our results illustrate that not all DLB patients fulfil the 2005 DLB criteria at disease presentation, highlighting the need for re-evaluation of the diagnosis if new symptoms appear. Studies applying the most recent 2017 DLB criteria will show if this revision has increased sensitivity without decreasing specificity.

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