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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Docent Maria Swanberg, Lund University,
- Second opponent: Researcher Kristoffer Haugarvoll, University of Bergen,
- Third member and chair of the evaluation committee: Professor Morten Ingvar Lossius, University of Oslo
Chair of the Defence
Professor Bjørnar Hassel, University of Oslo
Principal Supervisor
Senior Researcher Lasse Pihlstrøm, OUS - Oslo University Hospital
Summary
Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by motor and non-motors symptoms. Cognitive decline and dementia are among the most debilitating non-motor features with a heterogenous time of onset.
The exact cause of PD is unknown, but misfolded protein deposits in the brain, particularly alpha-synuclein in Lewy bodies, are central to the disease process. Amyloid-beta and tau proteins, typically linked to Alzheimer's disease (AD), are also common.
Genetic risk factors for PD have been identified, but their role in the disease progression is unclear. The thesis presents three studies investigating the link between genetic risk factors, dementia and key protein pathologies in PD. We hypothesized that specific genetic profiles influence Lewy and AD pathologies, and that both profiles affect dementia onset.
The first study examined APOE and MAPT variants in post-mortem samples, finding these variants accelerate dementia onset in PD patients. The second study used polygenic risk scores (PRS) to assess genetic influence on the most common protein pathologies in post-mortem samples. The results highlight that a PRS related to lysosomal function is linked to increased Lewy pathology and dementia in cases without amyloid-beta and tau deposits. The AD-PRS was associated with amyloid-beta and tau levels, and showed a potential for differentiating between cases with and without these pathologies. The third study assessed the association between the lysosomal PRS and dementia onset in patients from two longitudinal PD cohorts, linking a higher lysosomal PRS to earlier dementia onset in individuals with a low vulnerability to AD pathology.
These studies provide evidence for a connection between genetics, neuropathology, and dementia progression in PD. This insight increases our understanding of genetic risk, which may play a role in developing novel therapeutic strategies for PD.
Additional information
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