A genetic and proteomic comparison of key AD biomarkers across tissues

Author:

Marsh Thomas W.123ORCID,Western Daniel123,Timsina Jigyasha23,Gorijala Priyanka12,Yang Chengran23,Pastor Pau4,Liu Menghan23,Morris John C.56,Bateman Randall J.67,Schindler Suzanne E.6,Sung Yun Ju23,Cruchaga Carlos23589ORCID,

Affiliation:

1. Division of Biology & Biomedical Sciences Washington University in St. Louis St. Louis Missouri USA

2. Department of Psychiatry Washington University in St. Louis St. Louis Missouri USA

3. Neurogenomics and Informatics Washington University in St. Louis St. Louis Missouri USA

4. Unit of Neurodegenerative diseases Department of Neurology University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona Barcelona Spain

5. Knight Alzheimer's Disease Research Center Washington University in St. Louis St. Louis Missouri USA

6. Department of Neurology Washington University in St Louis St Louis Missouri USA

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

8. Hope Center for Neurological Diseases Washington University in St. Louis St. Louis Missouri USA

9. Department of Genetics Washington University in St. Louis School of Medicine St. Louis Missouri USA

Abstract

AbstractINTRODUCTIONPlasma 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.METHODEleven 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.RESULTSEighteen 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.DISCUSSIONThe 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.

Funder

National Institutes of Health

Chan Zuckerberg Initiative

Michael J. Fox Foundation for Parkinson's Research

U.S. Department of Defense

GlaxoSmithKline

Alzheimer's Association

Alzheimer's Disease Neuroimaging Initiative

Alzheimer Nederland

European Commission

National Institute of Biomedical Imaging and Bioengineering

Selfridges Group Foundation

Biogen

Eli Lilly and Company

Fujirebio US

GE Healthcare

H. Lundbeck A/S

Novartis Pharmaceuticals Corporation

Pfizer

Servier

AbbVie

Fondation Brain Canada

Publisher

Wiley

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