Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals
Luigi Lorenzini (Vrije Universiteit Amsterdam, Amsterdam UMC)
Lyduine E. Collij (Vrije Universiteit Amsterdam, Lund University, Amsterdam UMC)
Niccoló Tesi (Amsterdam UMC, Vrije Universiteit Amsterdam, TU Delft - Pattern Recognition and Bioinformatics)
Natàlia Vilor-Tejedor (Erasmus MC, Pompeu Fabra University, Pasqual Maragall Foundation, Barcelona Institute of Science and Technology)
Silvia Ingala (Cerebriu, Copenhagen University Hospital)
Kaj Blennow (University of Gothenburg, Sahlgrenska University Hospital/Östra)
Christopher Foley (GE Healthcare)
Giovanni B. Frisoni (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, University Hospital of Geneva)
Marcel Reinders (TU Delft - Pattern Recognition and Bioinformatics)
undefined More Authors
More Info
expand_more
Other than for strictly personal use, it is not permitted to download, forward or distribute the text or part of it, without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license such as Creative Commons.
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 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.
help_outline