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Journal article
Multi-locus genetic dosage shapes cognitive disease progression in Parkinson's patients: 15-year meta-analysis of 24 cohorts
NPJ Parkinson's Disease, In Press
2026
PMID: 42135313
Abstract
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.
Details
- Title
- Multi-locus genetic dosage shapes cognitive disease progression in Parkinson's patients: 15-year meta-analysis of 24 cohorts
- Authors/Creators
- Xiaoying Kang - Yale UniversityZechuan Lin - Yale School of MedicineFatma Zehra Calikusu - Yale School of MedicineLauren A Miller - Yale UniversitySofia Soriano - Yale UniversityJoseph J Locascio - Massachusetts General HospitalJean-Christophe Corvol - Sorbonne UniversitéJodi Maple-Grødem - Stavanger University HospitalYangyi Fan - Peking UniversityKara Mead - Yale UniversityMeghan C Campbell - Washington University in St. LouisAlexis Elbaz - Université Paris-SaclaySuzanne Lesage - Sorbonne UniversitéAlexis Brice - Sorbonne UniversitéAlbert Y Hung - Massachusetts General HospitalMichael A Schwarzschild - Massachusetts General HospitalMichael T Hayes - Brigham and Women's HospitalAnne-Marie Wills - Harvard UniversityTodd M Herrington - Harvard UniversityGanqiang Liu - Sun Yat-sen UniversityBernard Ravina - Precision for Medicine (United States)Pille Taba - Tartu University HospitalSulev Kõks - Murdoch UniversityTanya Simuni - Northwestern UniversityLars Forsgren - Umeå UniversityCarl Counsell - University of AberdeenAngus D Macleod - University of AberdeenThomas G Beach - Banner Sun Health Research InstituteGuido Alves - Stavanger University HospitalOle-Bjørn Tysnes - University of BergenJoel S Perlmutter - Washington University in St. LouisPeter Heutink - University of LübeckMeike Kasten - University of LübeckBrit Mollenhauer - Universitätsmedizin GöttingenClaudia Trenkwalder - Universitätsmedizin GöttingenChristine Klein - University of LübeckDagmar H Hepp - Leiden University Medical CenterDavid Backstrom - Umeå UniversityPer Svenningsson - Karolinska InstitutetMichele T Hu - University of OxfordCaroline H Williams-Gray - University of CambridgeRoger A Barker - University of CambridgeClemens R Scherzer - Brigham and Women's HospitalInternational Genetics of Parkinson Disease Progression (IGPP) Consortium
- Publication Details
- NPJ Parkinson's Disease, In Press
- Publisher
- Springer Nature
- Identifiers
- 991005883835907891
- Copyright
- © The Author(s) 2026.
- Murdoch Affiliation
- Personalised Medicine Centre
- Language
- English
- Resource Type
- Journal article
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