Mari Aksnes

• Aksnes, Mari (2025). Sex Differences in Biofluid Biomarkers for Alzheimer’s Disease. Neurodegenerative Diseases. ISSN 1660-2854. 25(3), p. 134–144. doi: 10.1159/000545717. Full text in Research Archive Show summary

  Background: Alzheimer’s disease (AD), the most common cause of dementia, affects twice as many women as men. Moreover, sex is increasingly recognised as an important factor for AD, influencing symptom presentation, progression, disease biology, and treatment responses. In parallel, AD biomarkers are becoming more accessible with the discovery of specific and accurate blood-based biomarkers and their incorporation in AD diagnostic frameworks. This narrative review aimed to summarise sex differences in the concentration and interpretation of biofluid biomarkers for AD. Summary: Biological sex may influence both the concentration and interpretation of biofluid biomarkers for AD pathology such as amyloid-β aggregation, tau neurofibrillary tangles, neurodegeneration, or neuroinflammation. While some biofluid biomarkers display consistent sex differences in absolute levels, most biomarker levels have not been found to differ consistently by sex. Nonetheless, even biomarkers that do not differ in absolute levels display sex-specific associations with clinically relevant variables such as brain atrophy, cognitive impairment, and disease progression. Key Message: Sex may influence the interpretation of AD biomarkers depending on their context of use, and more research is required to develop sex-specific guidelines. Future research should aim to study sex differences and sex-specific associations with variables of interest, as well as the underlying factors driving sex differences in AD.

• Knapskog, Anne-Brita; Edwin, Trine Holt; Ueland, Per Magne; Ulvik, Arve; Fang, Fei & Eldholm, Rannveig Sakshaug [Show all 11 contributors for this article] (2024). Sex-specific associations of kynurenic acid with neopterin in Alzheimer’s disease. Alzheimer's Research & Therapy. 16(1). doi: 10.1186/s13195-024-01531-7. Full text in Research Archive Show summary

  Background: Sex differences in neuroinflammation could contribute to women’s increased risk of Alzheimer’s disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, dysregulation of the kynurenine pathway (KP) contributes to neuroinflammation and there is some evidence of sex differences in KP metabolism. However, the sex-specific associations between KP metabolism and biomarkers of AD and neuroinflammation need to be explored further. Methods: Here we investigate sex differences in cerebrospinal fluid concentrations of seven KP metabolites and sex-specific associations with established AD biomarkers and neopterin, an indicator of neuroinflammation. This study included 311 patients with symptomatic AD and 105 age-matched cognitively unimpaired (CU) controls, followed for up to 5 years. Results: We found sex differences in KP metabolites in the AD group, with higher levels of most metabolites in men, while there were no sex differences in the CU group. In line with this, more KP metabolites were significantly altered in AD men compared to CU men, and there was a trend in the same direction in AD women. Furthermore, we found sex-specific associations between kynurenic acid and the kynurenic acid/quinolinic acid ratio with neopterin, but no sex differences in the associations between KP metabolites and clinical progression. Discussion: In our cohort, sex differences in KP metabolites were restricted to AD patients. Our results suggest that dysregulation of the KP due to increased inflammation could contribute to higher AD risk in women.

• Aksnes, Mari; Schibstad, Mari Haavig; Chaudhry, Farrukh Abbas; Neerland, Bjørn Erik; Caplan, Gideon A. & Saltvedt, Ingvild Tina [Show all 17 contributors for this article] (2024). Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium. Communications Medicine. 4(1). doi: 10.1038/s43856-024-00558-z. Full text in Research Archive Show summary

  Background The aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration. Methods Using a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer’s disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium. Results Here we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status. Conclusions Several CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.

• Aksnes, Mari; Edwin, Trine Holt; Saltvedt, Ingvild Tina; Eldholm, Rannveig Sakshaug; Chaudhry, Farrukh Abbas & Halaas, Nathalie Bodd [Show all 9 contributors for this article] (2023). Sex-specific associations of matrix metalloproteinases in Alzheimer’s disease. Biology of Sex Differences. 14(1). doi: 10.1186/s13293-023-00514-x. Full text in Research Archive Show summary

  Introduction Alzheimer’s disease (AD) can be characterised in vivo by biomarkers reflecting amyloid-β (Aβ) and tau pathology. However, there is a need for biomarkers reflecting additional pathological pathways. Matrix metalloproteinases (MMPs) have recently been highlighted as candidate biomarkers for sex-specific mechanisms and progression in AD. Methods In this cross-sectional study, we investigated nine MMPs and four tissue inhibitors of metalloproteinases (TIMPs) in the cerebrospinal fluid of 256 memory clinic patients with mild cognitive impairment or dementia due to AD and 100 cognitively unimpaired age-matched controls. We studied group differences in MMP/TIMP levels and examined the associations with established markers of Aβ and tau pathology as well as disease progression. Further, we studied sex-specific interactions. Results MMP-10 and TIMP-2 levels differed significantly between the memory clinic patients and the cognitively unimpaired controls. Furthermore, MMP- and TIMP-levels were generally strongly associated with tau biomarkers, whereas only MMP-3 and TIMP-4 were associated with Aβ biomarkers; these associations were sex-specific. In terms of progression, we found a trend towards higher MMP-10 at baseline predicting more cognitive and functional decline over time exclusively in women. Conclusion Our results support the use of MMPs/TIMPs as markers of sex differences and progression in AD. Our findings show sex-specific effects of MMP-3 and TIMP-4 on amyloid pathology. Further, this study highlights that the sex-specific effects of MMP-10 on cognitive and functional decline should be studied further if MMP-10 is to be used as a prognostic biomarker for AD.

• Knapskog, Anne Brita; Aksnes, Mari; Edwin, Trine Holt; Ueland, Per Magne; Ulvik, Arve & Fang, Fei [Show all 11 contributors for this article] (2023). Higher concentrations of kynurenic acid in CSF are associated with the slower clinical progression of Alzheimer's disease. Alzheimer's & Dementia. ISSN 1552-5260. 19(12), p. 5573–5582. doi: 10.1002/alz.13162. Full text in Research Archive Show summary

  INTRODUCTION The kynurenine pathway's (KP) malfunction is closely related to Alzheimer's disease (AD), for antagonistic kynurenic acid (KA) and agonistic quinolinic acid act on the N-methyl-D-aspartate receptor, a possible therapeutic target in treating AD. METHODS In our longitudinal case–control study, KP metabolites in the cerebrospinal fluid were analyzed in 311 patients with AD and 105 cognitively unimpaired controls. RESULTS Patients with AD exhibited higher concentrations of KA (β = 0.18, P < 0.01) and picolinic acid (β = 0.20, P < 0.01) than the controls. KA was positively associated with tau pathology (β = 0.29, P < 0.01), and a higher concentration of KA was associated with the slower progression of dementia. DISCUSSION The higher concentrations of neuroprotective metabolites KA and picolinic acid suggest that the activation of the KP's neuroprotective branch is an adaptive response in AD and may be a promising target for intervention and treatment. Highlights Patients with Alzheimer's disease (AD) exhibited higher concentrations of kynurenic acid and picolinic acid than controls. Higher concentrations of kynurenic acid were associated with slower progression of AD. Potential neurotoxic kynurenines were not increased among patients with AD. Activation of the kynurenine pathway's neuroprotective branch may be an adaptive response in AD.

• Aksnes, Mari; Capogna, Elettra; Vidal-Piñeiro, Didac; Chaudhry, Farrukh Abbas; Myrstad, Marius & Idland, Ane-Victoria [Show all 13 contributors for this article] (2023). Matrix metalloproteinases are associated with brain atrophy in cognitively unimpaired individuals. Neurobiology of Aging. ISSN 0197-4580. 131, p. 11–23. doi: 10.1016/j.neurobiolaging.2023.05.012. Full text in Research Archive Show summary

  Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been linked to age-related neurodegeneration and Alzheimer’s disease (AD), but their role in normal aging is poorly understood. We used linear mixed models to determine if baseline or rate of yearly change in cerebrospinal fluid (CSF) levels of MMP-2; MMP-3; MMP-10; TIMP-123 (composite of TIMP-1, TIMP-2, and TIMP-3); or TIMP-4 predicted changes in bilateral entorhinal cortex thickness, hippocampal volume, or lateral ventricle volume in cognitively unimpaired individuals. We also assessed effects on the CSF AD biomarkers amyloid-β42 and phosphorylated tau181. Low baseline levels of MMP-3 predicted larger ventricle volumes and more entorhinal cortex thinning. Increased CSF MMP-2 levels over time predicted more entorhinal thinning, hippocampal atrophy, and ventricular expansion, while increased TIMP-123 over time predicted ventricular expansion. No MMP/TIMPs predicted changes in CSF AD biomarkers. Notably, we show for the first time that longitudinal increases in MMP-2 and TIMP-123 levels may predict age-associated brain atrophy. In conclusion, MMPs and TIMPs may play a role in brain atrophy in cognitively unimpaired aging.

• Aksnes, Mari; Aass, Hans Christian Dalsbotten; Tiiman, Ann; Terenius, Lars; Bogdanovic, Nenad & Vukojević, Vladana [Show all 7 contributors for this article] (2022). Serum Amyloidogenic Nanoplaques and Cytokines in Alzheimer's Disease: Pilot Study in a Small Naturalistic Memory Clinic Cohort. Journal of Alzheimer's Disease. ISSN 1387-2877. 86(3), p. 1459–1470. doi: 10.3233/JAD-215504. Full text in Research Archive Show summary

  Background: Neuroinflammation is a central component of Alzheimer’s disease (AD) and correlates closely with amyloid pathology. Markers of inflammation such as cytokines, and amyloidogenic aggregates, so-called nanoplaques, are both promising biomarker candidates for AD. We have previously shown that there is a relationship between the levels of nanoplaques and cytokines in cerebrospinal fluid, but it is unknown whether this association extends to serum. Objective: Investigate in a naturalistic memory clinic cohort whether the associations between nanoplaques and cytokines in the cerebrospinal fluid extends to serum. Methods: We collected serum from 49 patients assessed for cognitive complaints at the Oslo University Hospital Memory Clinic (15 with clinical AD). We assessed the levels of serum nanoplaques with the novel Thioflavin-T fluorescence correlation spectroscopy (ThT-FCS) assay. Serum levels of nine cytokines (eotaxin-1, granulocyte colony-stimulating factor [G-CSF], interleukin [IL]-6, IL-7, IL-8, monocyte chemoattractant protein-1 (MCP-1), gamma induced protein 10 (IP-10), macrophage inflammatory protein [MIP]-1α, and MIP-1β) were quantified with a multiplex assay and read on a Luminex IS 200 instrument. Results: Serum nanoplaques were not increased in clinical AD patients compared to non-AD memory clinic patients and nanoplaques were not associated with any cytokines. The cytokines IL-8 and G-CSF were increased in patients with clinical AD compared to non-AD patients. Conclusion: In this small pilot study, serum nanoplaques were not associated with serum cytokines. Nanoplaque levels could not be used to separate clinical AD patients from non-AD patients in this unselected memory clinic cohort.

• Aksnes, Mari; Tiiman, Ann; Edwin, Trine Holt; Terenius, Lars; Bogdanovic, Nenad & Vukojevic, Vladana [Show all 7 contributors for this article] (2021). Comparison of cerebrospinal fluid amyloidogenic nanoplaques with core biomarkers of Alzheimer's disease. Frontiers in Aging Neuroscience. 12:608628, p. 1–11. doi: 10.3389/fnagi.2020.608628. Full text in Research Archive Show summary

  Accurate biomarkers of Alzheimer’s disease (AD) are essential for early diagnosis and intervention. Available biomarkers are not sufficient to permit the monitoring of AD progression over time, and additional biomarkers are required. Measures of aggregated amyloid-β (Aβ) could be useful biomarkers for AD. Here, we investigate whether levels of Thioflavin-T (ThT) positive amyloid aggregates, i.e., nanoplaques, in cerebrospinal fluid (CSF) could serve as useful biomarkers for AD. One-hundred and eighteen memory clinic patients were AT(N) classified, and CSF nanoplaque concentrations were compared between patients on the “Alzheimer’s continuum” (A+ patients) and patients with “Normal AD biomarkers” or “Non-AD pathologic change” (A− patients). CSF nanoplaque concentrations and sizes were quantified using the novel ThT-Fluorescence Correlation Spectroscopy (ThT-FCS) assay, and core biomarkers (Aβ42, total tau and phosphorylated tau) were determined by enzyme-linked immunosorbent assays. We investigated the association between nanoplaque concentrations and core biomarkers, and the diagnostic value of nanoplaque levels. Nanoplaque levels were increased in A+ patients compared to A− patients. Nanoplaque concentrations were negatively associated with Aβ42, but not related to total tau or phosphorylated tau measures. Quantification of nanoplaques did not improve the classification of patients on the Alzheimer’s continuum compared to the core biomarkers alone. Dynamic changes in nanoplaques concentration and size throughout AD stages should be explored in longitudinal studies.

• Aksnes, Mari; Aass, Hans Christian Dalsbotten; Tiiman, Ann; Edwin, Trine Holt; Terenius, Lars & Bogdanovic, Nenad [Show all 8 contributors for this article] (2021). Associations of cerebrospinal fluid amyloidogenic nanoplaques with cytokines in Alzheimer's disease. Translational Neurodegeneration. ISSN 2096-6466. 10(1). doi: 10.1186/s40035-021-00244-3. Full text in Research Archive Show summary

  Background: The aggregation of amyloid β (Aβ) is central in the pathogenesis of Alzheimer's disease (AD). Recently it has been shown that specifically, larger, Thioflavin T-binding Aβ aggregates are associated with increased neuroinflammation and cytokine release. This study was aimed to quantify fibrillary amyloid aggregates, so-called nanoplaques, and investigate their relationship with cytokines in the cerebrospinal fluid (CSF). Methods: CSF was collected from 111 patients assessed for cognitive complaints at the Oslo University Hospital Memory Clinic. The patients were grouped based on their amyloid status. The CSF nanoplaque concentration was quantified with the Thioflavin T-fluorescence correlation spectroscopy (ThT-FCS) assay. The levels of nine cytokines (eotaxin-1, granulocyte stimulating factor, interleukin [IL]-6, IL-7, IL-8, monocyte chemoattractant protein-1, gamma-induced protein 10, macrophage inflammatory protein [MIP]-1α, and MIP-1β) were quantified with a magnetic bead-based multiplex assay and read on a Luminex IS 200 instrument. Results: There were 49 amyloid-negative and 62 amyloid-positive patients in the cohort; none of the cytokines differed significantly between the amyloid groups. The increased nanoplaque levels were associated with levels of MIP-1β below the lower limit of quantification, and with decreased levels of MIP-1α and IL-8. The associations remained significant when adjusted for age, sex, cognitive function, apolipoprotein ε4 status and CSF core biomarker levels. Conclusion: The cytokine levels were not associated with amyloid status in this cohort. The nanoplaque levels were negatively associated with MIP-1β, MIP-1α and IL-8, which is in line with recent findings suggesting that the upregulation of some cytokine markers has a protective role and is negatively associated with AD progression.

• Aksnes, Mari; Müller, Ebba Gløersen; Tiiman, Ann; Edwin, Trine Holt; Terenius, Lars & Rootwelt-Revheim, Mona-Elisabeth [Show all 9 contributors for this article] (2020). Amyloidogenic nanoplaques in cerebrospinal fluid: Relationship to amyloid brain uptake and clinical Alzheimer's disease in a memory clinic cohort. Journal of Alzheimer's Disease. ISSN 1387-2877. 77(2), p. 831–842. doi: 10.3233/JAD-200237. Full text in Research Archive Show summary

  Background: Aggregation of amyloid-β (Aβ) is an early pathological event in Alzheimer’s disease (AD). Consequently, measures of pathogenic aggregated Aβ are attractive biomarkers for AD. Here, we use a recently developed Thioflavin-T-Fluorescence Correlation Spectroscopy (ThT-FCS) assay to quantify structured ThT-responsive protein aggregates, so-called nanoplaques, in the cerebrospinal fluid (CSF). Objective: The overall aim of this work was to assess whether ThT-FCS determined CSF nanoplaque levels could predict amyloid brain uptake as determined by 18F-Flutemetamol PET analysis. Further, we assess whether nanoplaque levels could predict clinical AD. Methods: Nanoplaque levels in the CSF from 54 memory clinic patients were compared between sub-groups classified by 18F-Flutemetamol PET as amyloid-positive or amyloid-negative, and by clinical assessment as AD or non-AD. Results: Nanoplaque levels did not differ between amyloid groups and could not predict brain amyloid uptake. However, nanoplaque levels were significantly increased in patients with clinical AD, and were significant predictors for AD when adjusting for age, sex, cognitive function, and apolipoprotein E (APOE) genotype. Conclusion: The concentration of nanoplaques in the CSF differentiates patients with clinical AD from non-AD patients.

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