| Title: |
Alzheimer's disease proteome-wide association study implicates adaptive immunity and identifies risk genes LILRB1 and SIRPA. |
| Authors: |
Walker, Keenan A.; Blew, Cassandra; Duggan, Michael R.; Joynes, Cassie; Gomez, Gabriela T.; Drouin, Shannon; Cordon, Jenifer; Chen, Jingsha; Zhang, Jingning; File, Balint; Nanasi, Tibor; Lehallier, Benoit; Oh, Hamilton; Surapaneni, Aditya; Grams, Morgan E.; Palta, Priya; Sullivan, Kevin J.; Pichet Binette, Alexa; Wu, Lang; Zhu, Jingjing |
| Source: |
Science Translational Medicine; 7/1/2026, Vol. 18 Issue 856, p1-16, 16p |
| Subject Terms: |
Alzheimer's disease; Immunity; Genetic risk score; Membrane glycoproteins; Blood proteins; Locus (Genetics) |
| 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. Editor's summary: Mounting evidence suggests that perturbations outside the central nervous system (CNS) can modulate Alzheimer's disease (AD). Here, Walker and colleagues performed an integrated analysis of genetic and proteomic data to identify genes that confer AD risk through their effect on plasma protein abundance in individuals with European American (EA) and African American (AA) ancestry. The authors identified 18 and 1 candidate proteins in the EA and AA (APOE) datasets, respectively. Many of these candidate proteins are expressed predominantly outside the CNS, and overrepresentation analysis implicated biological processes involved in the regulation of innate and adaptive immunity. Four of the 18 candidate proteins (CD55, LILRB1, SCARA5, and SIRPA) have not been previously identified. —Daniela Neuhofer [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |