Lysosomal polygenic risk is associated with the severity of neuropathology in Lewy body disease.

Intraneuronal accumulation of misfolded α-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. Using summary statistics from Parkinson's disease and Alzheimer's disease genome-wide association studies, we calculated polygenic risk scores and investigated the relationship with Lewy, amyloid-β and tau pathology. Associations were nominated in neuropathologically defined samples with Lewy body disease from the Netherlands Brain Bank (n = 217) and followed up in an independent sample series from the Mayo Clinic Brain Bank (n = 394). We also generated stratified polygenic risk scores based on single-nucleotide polymorphisms annotated to eight functional pathways or cell types previously implicated in Parkinson's disease and assessed for association with Lewy pathology in subgroups with and without significant Alzheimer's disease co-pathology. In an ordinal logistic regression model, the Alzheimer's disease polygenic risk score was associated with concomitant amyloid-β and tau pathology in both cohorts. Moreover, both cohorts showed a significant association between lysosomal pathway polygenic risk and Lewy pathology, which was more consistent than the association with a general Parkinson's disease risk score and specific to the subset of samples without significant concomitant Alzheimer's disease related neuropathology. Our findings provide proof of principle 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 disease co-pathology. Our findings hold promise that genetic profiling may help predict the vulnerability to specific neuropathologies in Lewy body disease, with potential relevance for the further development of precision medicine in these disorders.