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 with frontotemporal lobar degeneration carrying C9orf72 repeat expansions showed elevated polygenic risk for multiple disorders, indicating that genetic variation may modify monogenic disease expression. Neuropsychiatric symptoms were associated with distinct personality-trait polygenic risk profiles across disorders, highlighting diagnosis-dependent genetic contributions to clinical heterogeneity. Together, our findings demonstrate the value of this unique resource and reveal a dynamic interplay of genetic risk across brain disorders.