Authors
Keenan A Walker, Cassandra Blew, Michael R Duggan, Cassie Joynes, Gabriela T Gomez, Shannon Drouin, Jenifer Cordon, Jingsha Chen, Jingning Zhang, Balint File, Tibor Nanasi, Benoit Lehallier, Hamilton Oh, Aditya Surapaneni, Morgan E Grams, Priya Palta, Kevin J Sullivan, Alexa Pichet Binette, Lang Wu, Jingjing Zhu, Hampton Leonard, Andrew B Singleton, Myriam Fornage, Rebecca F Gottesman, Thomas H Mosley, Nilanjan Chatterjee, Eric Boerwinkle, Luigi Ferrucci, Josef Coresh, Pascal Schlosser
Published in
Science translational medicine. Volume 18. Issue 856. Pages eadx4852. Epub Jul 01, 2026.
Abstract
The rapid expansion of plasma proteomic data and protein quantitative trait loci (pQTLs) provides an opportunity to identify genes that confer disease risk through their effect on plasma protein abundance. We conducted an Alzheimer's disease (AD) proteome-wide association study (PWAS) integrating publicly available plasma cis-pQTL data (1348 European American and 1385 African American genetically determined protein models) with AD dementia GWAS summary statistics. Whereas the African American PWAS identified one candidate [apolipoprotein E (APOE)] and multiple suggestive genes, the European American PWAS identified 18 genes with putative causal relationships with AD through cis regulation of plasma protein abundance. Thirteen of these candidate genes were additionally supported by colocalization and complementary causal-inference analyses such as summary data-based Mendelian randomization. Four of these proteins were not previously detected in AD GWAS [complement decay-accelerating factor (CD55), leukocyte immunoglobulin-like receptor B1 (LILRB1), scavenger receptor class A member 5 (SCARA5), and signal regulatory protein alpha (SIRPA)]. A subset of candidate gene-associated proteins was associated with 8- and 20-year dementia risk, markers of AD pathology, and a CSF proteomic signature enriched for immune and metabolic processes. Putative causal proteins were enriched for adaptive (lymphocyte-mediated) immunity and, compared with GWAS candidates, showed less enrichment for synaptic and amyloid regulatory processes. LILRB1 and SIRPA, two immunoregulatory proteins not previously implicated in AD GWAS, showed the strongest mechanistic link to AD in the European American PWAS. These results shed additional light on AD etiology and enable the prioritization of potential AD therapeutic targets in peripheral circulation.
PMID:
42384774
Bibliographic data and abstract were imported from PubMed on 02 Jul 2026.
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