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<p>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 (<i>RIMS2, TMEM108, GBA1</i>) and amyloid–tau pathology (<i>APOE, WWOX</i>), 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, <i>GBA1</i> (HR = 2.09), <i>APOE ε4</i> (HR = 1.71), <i>RIMS2</i> (HR = 1.90), <i>TMEM108</i> (HR = 2.05), and <i>WWOX</i> (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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • 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

摘要

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.