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

This article investigates how genetic risk variants associated with Parkinson's disease (PD) and Alzheimer's disease (AD) influence neuropathological heterogeneity in Lewy body disease (LBD), which encompasses PD and dementia with Lewy bodies (DLB). Using polygenic risk scores (PRS) derived from genome-wide association studies, the study analyzed two independent post-mortem cohorts from the Netherlands Brain Bank and Mayo Clinic Brain Bank, focusing on associations with Lewy pathology and AD co-pathology (amyloid-β and tau). The findings show that AD-PRS correlates with the extent of AD-related neuropathology in LBD, while a lysosomal pathway-specific PD-PRS is associated with increased Lewy pathology specifically in LBD cases without significant AD co-pathology. Additionally, both AD-PRS and lysosomal PD-PRS relate to a faster progression to dementia, suggesting that distinct genetic architectures underlie neuropathological subtypes within LBD. These results highlight the potential of pathway-stratified genetic profiling to improve understanding and stratification of LBD for precision medicine approaches.