Dynamic interplay of polygenic risk across brain disorders, neuropathological endophenotypes, and neuropsychiatric symptoms

Neurodegenerative and psychiatric brain disorders show substantial heterogeneity in clinical and neuropathological manifestations, possibly reflecting both distinct and shared pathogenic mechanisms. Our understanding of brain disorder heterogeneity is limited by the scarcity of deeply phenotyped, multi-modal post-mortem brain bank cohorts. Here, we integrated genotype, clinical and neuropathological data from 2,553 Netherlands Brain Bank donors to investigate how genetic risk contributes to disease manifestations. Disease-specific polygenic risk scores revealed extensive cross-disorder enrichment of genetic risk, suggesting shared pathogenic mechanisms beyond diagnostic boundaries. Donors wi