Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non‐demented individuals - Inria - Institut national de recherche en sciences et technologies du numérique
Article Dans Une Revue Alzheimer's & Dementia : the Journal of the Alzheimer's Association Année : 2024

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non‐demented individuals

Luigi Lorenzini
Sven van der van der Lee
  • Fonction : Auteur
Pablo Martinez‐lage
  • Fonction : Auteur
Riccardo E Marioni
  • Fonction : Auteur
Daniel L Mccartney
  • Fonction : Auteur
John O’ Brien
  • Fonction : Auteur
Tiago Gil Oliveira
  • Fonction : Auteur
Marcel Reinders
  • Fonction : Auteur
Craig Ritchie
  • Fonction : Auteur
Philip Scheltens
  • Fonction : Auteur
Adam J Schwarz
  • Fonction : Auteur
Carole H Sudre
  • Fonction : Auteur
Adam D Waldman
  • Fonction : Auteur
Robin Wolz
  • Fonction : Auteur
Gael Chatelat
  • Fonction : Auteur
Michael Ewers
  • Fonction : Auteur
Henk J M M Mutsaerts
  • Fonction : Auteur
Juan Domingo Gispert
  • Fonction : Auteur
Pieter Jelle Visser
  • Fonction : Auteur
Betty M Tijms
  • Fonction : Auteur
Andre Altmann
  • Fonction : Auteur
Frederik Barkhof
  • Fonction : Auteur

Résumé

INTRODUCTION Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS We computed pathway‐specific genetic risk scores (GRSs) in non‐demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD‐associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. Highlights Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway‐specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.
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hal-04870979 , version 1 (07-01-2025)

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Luigi Lorenzini, Lyduine E Collij, Niccoló Tesi, Natàlia Vilor‐tejedor, Silvia Ingala, et al.. Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non‐demented individuals. Alzheimer's & Dementia : the Journal of the Alzheimer's Association, 2024, 20 (9), pp.6146-6160. ⟨10.1002/alz.14096⟩. ⟨hal-04870979⟩
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