Polygenic score integrating neurodegenerative and vascular risk informs dementia risk stratification.
Tim D'Aoust; Santiago Clocchiatti-Tuozzo; Cyprien A Rivier; Aniket Mishra; Tsuyoshi Hachiya; Benjamin Grenier-Boley; Aïcha Soumaré; Marie-Gabrielle Duperron; Quentin Le Grand; Vincent Bouteloup; Cécile Proust-Lima; Cécilia Samieri; Jeanne Neuffer; Muralidharan Sargurupremraj; Geneviève Chêne; Catherine Helmer; Mura Thibault; Philippe Amouyel; Jean-Charles Lambert; Yoichiro Kamatani; Hélène Jacqmin-Gadda; David-Alexandre Tregouët; Michael Inouye; Carole Dufouil; Guido J Falcone; Stéphanie Debette
Abstract
An integrative polygenic risk score (iPRS) capturing the neurodegenerative and vascular contribution to dementia could identify high-risk individuals and improve risk prediction. We developed an iPRS for dementia (iPRS-DEM) in Europeans (aged 65+), comprising genetic risk for Alzheimer's disease (AD) and 23 vascular or neurodegenerative traits (excluding apolipoprotein E [APOE]). iPRS-DEM was evaluated across cohorts comprising older community-dwelling people (N = 3702), a multi-ancestry biobank (N = 130,797 Europeans; 105,404 non-Europeans), and dementia-free memory clinic participants (N = 2032). iPRS-DEM was associated with dementia risk independently of APOE in the elderly (subdistribution hazard ratio [sHR]<sub>per1SD </sub>= 1.15, 95% confidence interval [CI]: 1.03 to 1.28), which generalized to Europeans (EUR-sHR<sub>per1SD </sub>= 1.28, 95% CI: 1.09 to 1.51]), East-Asians (EAS-sHR<sub>per1SD </sub>= 5.29, 95% CI: 1.43 to 34.36), and memory-clinic participants (sHR<sub>per1SD </sub>= 1.25, 95% CI: 1.11 to 1.42). Prediction was comparable to clinical risk factors in older community-dwelling people, with improved performance among memory-clinic patients. Risk stratification was enhanced by defining four genetic risk groups with iPRS-DEM and APOE ε4, reaching five-fold increased risk in APOE ε4+/iPRS-DEM+ memory-clinic participants. Alongside APOE ε4, iPRS-DEM may refine risk stratification for the enrichment of dementia clinical trials and prevention programs. iPRS-DEM reflects neurodegenerative and vascular contribution to dementia. We show iPRS-DEM captures additional dementia genetic risk beyond APOE and AD-PRS. iPRS-DEM, in combination with APOE ε4, shows promise for dementia risk stratification. Our results generalize across both population-based and memory-clinic settings. We show transportability of iPRS-DEM to East Asian ancestry.
| Journal | ALZHEIMER'S & DEMENTIA : THE JOURNAL OF THE ALZHEIMER'S ASSOCIATION |
| ISSN | 1552-5279 |
| Published | 01 Mar 2025 |
| Volume | 21 |
| Issue | 3 |
| Pages | e70014 |
| DOI | 10.1002/alz.70014 |
| Type | Journal Article |
| Sponsorship |