TY - JOUR
T1 - Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals
AU - Lorenzini, Luigi
AU - Collij, Lyduine E.
AU - Tesi, Niccolo
AU - Vilor-Tejedor, Natalia
AU - Ingala, Silvia
AU - Blennow, Kaj
AU - Foley, Christopher
AU - Frisoni, Giovanni B.
AU - Haller, Sven
AU - Holstege, Henne
AU - van der van der Lee, Sven
AU - Martinez-Lage, Pablo
AU - Marioni, Riccardo E.
AU - McCartney, Daniel L.
AU - O' Brien, John
AU - Oliveira, Tiago Gil
AU - Payoux, Pierre
AU - Reinders, Marcel
AU - Ritchie, Craig
AU - Scheltens, Philip
AU - Schwarz, Adam J.
AU - Sudre, Carole H.
AU - Waldman, Adam D.
AU - Wolz, Robin
AU - Chatelat, Gael
AU - Ewers, Michael
AU - Wink, Alle Meije
AU - Mutsaerts, Henk J. M. M.
AU - Gispert, Juan Domingo
AU - Visser, Pieter Jelle
AU - Tijms, Betty M.
AU - Altmann, Andre
AU - Barkhof, Frederik
PY - 2024/9
Y1 - 2024/9
N2 - 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.
AB - 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.
KW - biological pathways
KW - magnetic resonance imaging
KW - polygenic risk
KW - preclinical Alzheimer's disease
KW - APOE
KW - INFLAMMATION
KW - VARIANTS
KW - DEMENTIA
KW - GENOTYPE
KW - NETWORK
U2 - 10.1002/alz.14096
DO - 10.1002/alz.14096
M3 - Article
SN - 1552-5260
VL - 20
SP - 6146
EP - 6160
JO - Alzheimer's & Dementia
JF - Alzheimer's & Dementia
IS - 9
M1 - 14096
ER -