A genetic and proteomic comparison of key AD biomarkers across tissues.

Dominantly Inherited Alzheimer Network; Dominantly Inherited Alzheimer Network (DIAN), Washington University in St. Louis, St. Louis, Missouri, USA.

Publisher: John Wiley & Sons, Ltd Country of Publication: United States NLM ID: 101231978 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-5279 (Electronic) Linking ISSN: 15525260 NLM ISO Abbreviation: Alzheimers Dement Subsets: MEDLINE

Publication: 2020- : Hoboken, NJ : John Wiley & Sons, Ltd.
Original Publication: Orlando, FL : Elsevier, Inc.

Alzheimer Disease*/genetics ; Alzheimer Disease*/cerebrospinal fluid ; Alzheimer Disease*/blood ; Biomarkers*/cerebrospinal fluid ; Biomarkers*/blood ; Genome-Wide Association Study* ; Proteomics*; Humans ; Male ; Female ; Aged ; Quantitative Trait Loci

Introduction: Plasma has been proposed as an alternative to cerebrospinal fluid (CSF) for measuring Alzheimer's disease (AD) biomarkers, but no studies have analyzed in detail which biofluid is more informative for genetics studies of AD.
Method: Eleven proteins associated with AD (α-synuclein, apolipoprotein E [apoE], CLU, GFAP, GRN, NfL, NRGN, SNAP-25, TREM2, VILIP-1, YKL-40) were assessed in plasma (n = 2317) and CSF (n = 3107). Both plasma and CSF genome-wide association study (GWAS) analyses were performed for each protein, followed by functional annotation. Additional characterization for each biomarker included calculation of correlations and predictive power.
Results: Eighteen plasma protein quantitative train loci (pQTLs) associated with 10 proteins and 16 CSF pQTLs associated with 9 proteins were identified. Plasma and CSF shared some genetic loci, but protein levels between tissues correlated weakly. CSF protein levels better associated with AD compared to plasma.
Discussion: The present results indicate that CSF is more informative than plasma for genetic studies in AD.
Highlights: The identification of novel protein quantitative trait loci (pQTLs) in both plasma and cerebrospinal fluid (CSF). Plasma and CSF levels of neurodegeneration-related proteins correlated weakly. CSF is more informative than plasma for genetic studies of Alzheimer's disease (AD). Neurofilament light (NfL), triggering receptor expressed on myeloid cells 2 (TREM2), and chitinase-3-like protein 1 (YKL-40) tend to show relatively strong inter-tissue associations. A novel signal in the apolipoprotein E (APOE) region was identified, which is an eQTL for APOC1.
(© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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Keywords: Alzheimer's disease; CSF; biomarkers; genomics; neurodegenerative disease; plasma; protein quantitative trait loci

0 (Biomarkers)

Date Created: 20240730 Date Completed: 20241023 Latest Revision: 20241213

20241213

PMC11633343

10.1002/alz.14139

39077866