Multi-locus genetic dosage shapes cognitive disease progression in Parkinson’s patients: 15-year meta-analysis of 24 cohorts
Year: 2026
Type: review
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.
Source: npj Parkinson s Disease
Authors: Xiaoying Kang, Zechuan Lin, Fatma Zehra Calikusu, Lauren A. Miller, Sofia Soriano, Joseph J. Locascio, Jean-Christophe Corvol, Jodi Maple-Grødem, Yangyi Fan, Kara Mead, Meghan C. Campbell, Alexis Elbaz, Suzanne Lesage, Alexis Brice, Albert Y. Hung, Michael A. Schwarzschild, Michael T. Hayes, Anne-Marie Wills, Todd M. Herrington, Ganqiang Liu, Bernard Ravina, Pille Taba, Sulev Kõks, Tanya Simuni, Lars Forsgren, Carl Counsell, Angus D. Macleod, Thomas G. Beach, Guido Alves, Ole-Bjørn Tysnes, Joel S. Perlmutter, Peter Heutink, Meike Kasten, Brit Mollenhauer, Claudia Trenkwalder, Christine Klein, Dagmar H. Hepp, David Backstrom, Per Svenningsson, Michele T. Hu, Caroline H. Williams-Gray, Roger A. Barker, Clemens R. Scherzer
Institutions: Yale University, Harvard University, Massachusetts General Hospital, Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, Stavanger University Hospital, University of Stavanger, Peking University People's Hospital, Washington University in St. Louis, Université de Versailles Saint-Quentin-en-Yvelines, Centre de recherche en Epidémiologie et Santé des Populations, Brigham and Women's Hospital, Sun Yat-sen University, University of Rochester Medicine, University of Rochester, Tartu University Hospital, University of Tartu, Murdoch University, Perron Institute for Neurological and Translational Science, Northwestern University, Umeå University, University of Aberdeen, Banner Sun Health Research Institute, Haukeland University Hospital, University of Bergen, University Hospital Schleswig-Holstein, University of Lübeck, Universitätsmedizin Göttingen, Paracelsus Elena Klinik Kassel, Leiden University Medical Center, Karolinska Institutet, University of Oxford, University of Cambridge, Wellcome/MRC Cambridge Stem Cell Institute
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,890
OpenAlex ID: W7161133917