Polygenic score integrating neurodegenerative and vascular risk informs dementia risk stratification Article Swipe

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Tim D'Aoust , Santiago Clocchiatti‐Tuozzo , Cyprien 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 , M. C. Thibault , Philippe Amouyel , Jean‐Charles Lambert , Yoichiro Kamatani , Hélène Jacqmin‐Gadda , David‐Alexandre Trégouët , Michael Inouye , Carole Dufouil , Guido J. Falcone , Stéphanie Debette ·

YOU? · · 2025 · Open Access · · DOI: https://doi.org/10.1002/alz.70014

INTRODUCTION An integrative polygenic risk score (iPRS) capturing the neurodegenerative and vascular contribution to dementia could identify high‐risk individuals and improve risk prediction. METHODS 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). RESULTS iPRS‐DEM was associated with dementia risk independently of APOE in the elderly (subdistribution hazard ratio [sHR] per1SD = 1.15, 95% confidence interval [CI]: 1.03 to 1.28), which generalized to Europeans (EUR‐sHR per1SD = 1.28, 95% CI: 1.09 to 1.51]), East‐Asians (EAS‐sHR per1SD = 5.29, 95% CI: 1.43 to 34.36), and memory‐clinic participants (sHR per1SD = 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. DISCUSSION Alongside APOE ε4, iPRS‐DEM may refine risk stratification for the enrichment of dementia clinical trials and prevention programs. Highlights 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.

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Concepts

Dementia Apolipoprotein E Vascular dementia Hazard ratio Gerontology Medicine Confidence interval Internal medicine Demography Disease Sociology

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Type: article
Language: en
Landing Page: https://doi.org/10.1002/alz.70014
PDF: https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/alz.70014
OA Status: bronze
Cited By: 4
References: 77
Related Works: 10
OpenAlex ID: https://openalex.org/W4408245547

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OpenAlex ID: https://openalex.org/W4408245547

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DOI: https://doi.org/10.1002/alz.70014

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Title: Polygenic score integrating neurodegenerative and vascular risk informs dementia risk stratification

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Type: article

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Language: en

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Publication year: 2025

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Publication date: 2025-03-01

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Authors: Tim D'Aoust, Santiago Clocchiatti‐Tuozzo, Cyprien 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, M. C. Thibault, Philippe Amouyel, Jean‐Charles Lambert, Yoichiro Kamatani, Hélène Jacqmin‐Gadda, David‐Alexandre Trégouët, Michael Inouye, Carole Dufouil, Guido J. Falcone, Stéphanie Debette

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Landing page: https://doi.org/10.1002/alz.70014

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Concepts: Dementia, Apolipoprotein E, Vascular dementia, Hazard ratio, Gerontology, Medicine, Confidence interval, Internal medicine, Demography, Disease, Sociology

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Cited by: 4

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