Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals
(2024) In Alzheimer's and Dementia 20(9). p.6146-6160- Abstract
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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2024-09
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- biological pathways, magnetic resonance imaging, polygenic risk, preclinical Alzheimer's disease
- in
- Alzheimer's and Dementia
- volume
- 20
- issue
- 9
- pages
- 15 pages
- publisher
- Wiley
- external identifiers
-
- pmid:39073684
- scopus:85199976205
- ISSN
- 1552-5260
- DOI
- 10.1002/alz.14096
- language
- English
- LU publication?
- yes
- id
- 25e6358d-7e95-4254-8a83-345cc921df07
- date added to LUP
- 2024-12-18 15:48:36
- date last changed
- 2025-07-03 08:08:44
@article{25e6358d-7e95-4254-8a83-345cc921df07,
abstract = {{<p>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.</p>}},
author = {{Lorenzini, Luigi and Collij, Lyduine E. and Tesi, Niccoló and Vilor-Tejedor, Natàlia and Ingala, Silvia and Blennow, Kaj and Foley, Christopher and Frisoni, Giovanni B. and Haller, Sven and Holstege, Henne and van der van der Lee, Sven and Martinez-Lage, Pablo and Marioni, Riccardo E. and McCartney, Daniel L. and O’ Brien, John and Oliveira, Tiago Gil and Payoux, Pierre and Reinders, Marcel and Ritchie, Craig and Scheltens, Philip and Schwarz, Adam J. and Sudre, Carole H. and Waldman, Adam D. and Wolz, Robin and Chatelat, Gael and Ewers, Michael and Wink, Alle Meije and Mutsaerts, Henk J.M.M. and Gispert, Juan Domingo and Visser, Pieter Jelle and Tijms, Betty M. and Altmann, Andre and Barkhof, Frederik}},
issn = {{1552-5260}},
keywords = {{biological pathways; magnetic resonance imaging; polygenic risk; preclinical Alzheimer's disease}},
language = {{eng}},
number = {{9}},
pages = {{6146--6160}},
publisher = {{Wiley}},
series = {{Alzheimer's and Dementia}},
title = {{Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals}},
url = {{http://dx.doi.org/10.1002/alz.14096}},
doi = {{10.1002/alz.14096}},
volume = {{20}},
year = {{2024}},
}