Researchers tested whether genetic proxies of cognitive reserve help explain why Parkinson’s disease (PD) progresses differently across individuals. Using the Accelerating Medicines Partnership Parkinson’s Disease database, they built polygenic scores (PGSs) for intelligence (INT), educational attainment (EA), and occupational attainment (OA) and related them to three outcomes: motor progression (Hoehn and Yahr ≥3), cognitive decline (Montreal Cognitive Assessment ≤24), and incident psychosis. Multivariate Cox models adjusted for age, sex, years of education, APOE/GBA1/LRRK2 variants, and the other reserve-related PGSs. The analyses drew on longitudinal clinical follow-up, enabling time-to-event estimates for each outcome.
All three PGSs were linked to lower risk of cognitive decline, with EA-PGS showing a robust effect even after controlling for INT- and OA-PGS (HR 0.550; 95% CI 0.447–0.676; P<0.001). EA-PGS also predicted slower motor progression (HR 0.805; 95% CI 0.672–0.964; P=0.019), and OA-PGS was associated with reduced psychosis risk (HR 0.784; 95% CI 0.631–0.975; P=0.029). Notably, the EA-PGS signals persisted after adjusting for years of education, suggesting genetic contributions to resilience beyond measured schooling. The authors caution that PGSs explain a modest share of variance and require replication in diverse cohorts. However, the results point to heritable components of clinical resilience that could inform prognosis, risk stratification, and trial design in PD.
Reference: Huh YE, Jang B, Jung SH, et al. Protective Effects of Genetic Proxies of Cognitive Reserve in Parkinson’s Disease: A Longitudinal Multi-Cohort Study. Mov Disord. 2025:10.1002/mds.30276. doi: 10.1002/mds.30276.
Link: https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.30276
