Presenter of 2 Presentations
SPECIFIC POLYGENIC RISK SCORES ARE ASSOCIATED WITH DIFFERENT ASPECTS OF NEUROPATHOLOGY IN LEWY BODY DISEASE
Abstract
Aims
Accumulation of misfolded alpha-synuclein is the pathological hallmark of Parkinson’s disease and dementia with Lewy bodies, often co-occurring with variable degrees of Alzheimer’s disease related neuropathology. Genetic association studies have successfully identified common variants associated with disease risk and phenotypic traits in Lewy body disease, yet little is known about the genetic contribution to neuropathological heterogeneity. To address this knowledge gap, we explored the relationship between polygenic risk scores and key neuropathological measures in post-mortem samples with Lewy body disease.
Methods
We calculated Parkinson’s disease and Alzheimer’s disease polygenic risk scores and investigated the relationship with Lewy body, amyloid-beta and tau pathology in samples with Lewy body disease from the Netherlands Brain Bank (n = 220) and the Mayo Clinic Brain Bank (n = 796). We also generated stratified polygenic risk scores based on variants annotated to eight functional pathways or cell types previously implicated in Parkinson’s disease and assessed for association with Lewy body pathology in subgroups with and without significant Alzheimer’s disease co-pathology.
Results
In an ordinal regression model the Alzheimer’s disease polygenic risk score was associated with concomitant amyloid-beta and tau pathology in both datasets. Moreover, both datasets showed a significant association between lysosomal pathway polygenic risk and Lewy body pathology, in samples without significant concomitant Alzheimer’s disease related neuropathology.
Conclusions
Our findings provide proof that the specific risk alleles a patient carries for Parkinson’s and Alzheimer’s disease also influence key aspects of the underlying neuropathology in Lewy body disease. The interrelations between genetic architecture and neuropathology are complex, as our results implicate lysosomal risk loci specifically in the subset of samples without Alzheimer’s co-pathology.