A genetic and proteomic comparison of key AD biomarkers across tissues

• Published in: Alzheimer's & dementia 2024-09, Vol.20 (9), p.6423-6440
• Main Authors: Marsh, Thomas W., Western, Daniel, Timsina, Jigyasha, Gorijala, Priyanka, Yang, Chengran, Pastor, Pau, Liu, Menghan, Morris, John C., Bateman, Randall J., Schindler, Suzanne E., Sung, Yun Ju, Cruchaga, Carlos
• Format: Article
• Language: English
• Subjects: Aged; Alzheimer Disease - blood; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - genetics; Alzheimer's disease; biomarkers; Biomarkers - blood; Biomarkers - cerebrospinal fluid; CSF; Female; Genome-Wide Association Study; genomics; Humans; Male; neurodegenerative disease; plasma; protein quantitative trait loci; Proteomics; Quantitative Trait Loci
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.14139

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.