Multi-locus genetic dosage shapes cognitive disease progression in Parkinson’s patients: 15-year meta-analysis of 24 cohorts

Journal article

Progression from Parkinson’s disease (PD) to Lewy body dementia is a major clinical concern. Although several progression-associated loci have been identified, their cumulative effects on cognitive decline have not been systematically evaluated. To assess the dose-dependent effect of five candidate progression loci linked to synaptic vulnerability (RIMS2, TMEM108, GBA1) and amyloid–tau pathology (APOE, WWOX), we analyzed 7745 participants from 24 cohorts with 28,737 longitudinal visits over 15 years using random-effects meta-analyses of cohort-specific Cox proportional hazards models. Dementia risk increased monotonically with the number of progression loci (0, 1, 2, or ≥3). A single locus conferred a 1.56-fold increase in risk (hazard ratio (HR) = 1.56, 95% CI: 1.28–1.89), rising to 3.21-fold for two loci (HR = 3.21, 95% CI: 2.19–4.70) and 7.49-fold for three or more loci (HR = 7.49, 95% CI: 4.98–11.28). Individually, GBA1 (HR = 2.09), APOE ε4 (HR = 1.71), RIMS2 (HR = 1.90), TMEM108 (HR = 2.05), and WWOX (HR = 1.56) were associated with dementia risk, but there was heterogeneity between clinical trials, biomarkers, and population-based cohorts. Multi-locus dosage increases dementia risk in a monotonic manner and may improve stratification and clinical trial design in PD.

Authors: Kang, X; Lin, Z; Calikusu, FZ; Miller, LA; Soriano, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: npj Parkinson's Disease
• Volume: 12
• Issue: 1
• Publication date: 2026-05-14
• Acceptance date: 2026-04-16
• DOI: 10.1038/s41531-026-01367-y
• EISSN: 2373-8057
• ISSN: 2373-8057
• Language: English
• Keywords: Cognitive aging; Pharmacogenomics; Neurology; Cognition; Disease; MEDLINE