Huh Young Eun, Jang Beomjin, Jung Sang-Hyuk, Kim Dokyoon, Raj Towfique, Won Hong-Hee
Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam-si, Republic of Korea.
Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea.
Mov Disord. 2025 Jun 25. doi: 10.1002/mds.30276.
Resilience factors are crucial in the progression of neurodegenerative diseases. However, it remains unclear whether a genetic predisposition to cognitive reserve influences clinical heterogeneity in the prognosis of Parkinson's disease (PD).
The aim is to evaluate the utility of polygenic scores (PGSs) for cognitive reserve proxies, including intelligence (INT), educational attainment (EA), and occupational attainment (OA), in predicting the clinical progression of PD.
Genetic and clinical data for progression of PD (progression to Hoehn and Yahr stage ≥3, progression to a Montreal Cognitive Assessment score ≤24, and occurrence of psychosis) were obtained from the Accelerating Medicine Partnership Parkinson's Disease database. We conducted multivariate Cox regression analysis, adjusting for relevant covariates, including years of education, variants in APOE, GBA1, LRRK2, and other cognitive reserve-related PGSs.
All cognitive reserve-related PGSs significantly reduced the risk of cognitive decline, and EA-PGS (hazard ratio [HR], 0.550; 95% confidence interval [CI], 0.447-0.676; P < 0.001) remained significant after controlling for INT-PGS and OA-PGS. EA-PGS (HR, 0.805; 95% CI, 0.672-0.964; P = 0.019) was significantly associated with better motor prognosis after controlling for other PGSs. OA-PGS was linked to a decreased risk of developing psychosis in PD and remained significant after adjusting for others (HR, 0.784; 95% CI, 0.631-0.975; P = 0.029).
Genetic proxies of cognitive reserve are associated with a reduced risk of cognitive decline, motor progression, and development of psychosis in PD. These findings may enhance our understanding of individual differences in resilience in progression of PD. © 2025 International Parkinson and Movement Disorder Society.
复原力因素在神经退行性疾病的进展中至关重要。然而，认知储备的遗传易感性是否会影响帕金森病（PD）预后的临床异质性仍不清楚。
旨在评估多基因评分（PGS）用于认知储备替代指标（包括智力（INT）、教育程度（EA）和职业成就（OA））在预测PD临床进展中的效用。
从加速医学合作帕金森病数据库中获取PD进展（进展至Hoehn和Yahr分期≥3、进展至蒙特利尔认知评估得分≤24以及出现精神病）的遗传和临床数据。我们进行了多变量Cox回归分析，并对相关协变量进行了调整，包括受教育年限、APOE、GBA1、LRRK2中的变异以及其他与认知储备相关的PGS。
所有与认知储备相关的PGS均显著降低了认知衰退的风险，并且在控制INT - PGS和OA - PGS后，EA - PGS（风险比[HR]，0.550；95%置信区间[CI]，0.447 - 0.676；P < 0.001）仍然显著。在控制其他PGS后，EA - PGS（HR，0.805；95% CI，0.672 - 0.964；P = 0.019）与更好的运动预后显著相关。OA - PGS与PD中发生精神病的风险降低有关，并且在调整其他因素后仍然显著（HR，0.784；95% CI，0.631 - 0.975；P = 0.029）。
认知储备的遗传替代指标与PD中认知衰退、运动进展和精神病发生的风险降低相关。这些发现可能会增强我们对PD进展中复原力个体差异的理解。© 2025国际帕金森和运动障碍协会。
