{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T15:57:48Z","timestamp":1783699068220,"version":"3.55.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471342"],"award-info":[{"award-number":["82471342"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study investigated molecular drivers of AD-associated peripheral immune dysregulation to identify pathogenic genes and therapeutic targets for precision diagnosis and intervention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A large-scale GWAS meta-analysis (n = 894,710) was performed, followed by two-sample Mendelian randomization (MR) using multi-tissue cis-eQTL data to identify putative causal genes. Immune response differential genes (IRDGs) were defined from AD peripheral blood transcriptomes and the MSigDB database. A three-step summary-data-based MR framework integrating blood cis-eQTLs and cis-mQTLs was applied to prioritize causal genes and epigenetic regulatory elements. Findings were validated through colocalization analysis, PBMC scRNA-seq and blood-tissue TWAS. Multi-dimensional clinical validation was performed in the ADNI cohort encompassing gene expression, CSF biomarkers, cognitive measures, immune cell profiles, survival analysis, and plasma proteomics, with cross-cohort transcriptomic replication in AddNeuroMed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Two-sample MR identified eight putative AD pathogenic genes. The three-step SMR and colocalization analysis prioritized five candidate causal genes, whose differential expression in immunocytes was confirmed by scRNA-seq and independently replicated. In the ADNI cohort, PTK2B expression was elevated in AD (ANOVA P\u00a0=\u00a00.0023), inversely correlated with MMSE (r = \u22120.164, P\u00a0=\u00a00.017), and predictive of MCI-to-AD conversion (Cox HR\u00a0=\u00a01.741, P\u00a0=\u00a00.050), with independent replication in AddNeuroMed (FDR P\u00a0=\u00a03.56 \u00d7 10\n                      <jats:sup>\u22124<\/jats:sup>\n                      ). PLEKHA1 and PTK2B expression were strongly associated with peripheral neutrophil and lymphocyte proportions (P &amp;lt; 10\n                      <jats:sup>\u22127<\/jats:sup>\n                      ), and PLEKHA1 correlated with CSF total tau (partial r = 0.102, P\u00a0=\u00a00.036). The prioritized probe cg19863426 at the PLEKHA1 promoter showed progressive hypermethylation across the CN-MCI-AD continuum (F\u00a0=\u00a03.45, P\u00a0=\u00a00.032) and was inversely correlated with PLEKHA1 mRNA (r = \u22120.33, P\u00a0=\u00a02.68 \u00d7 10\n                      <jats:sup>\u2212<\/jats:sup>\n                      \u00b9\u00b2).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Integrating GWAS, multi-omics Mendelian randomization, single-cell transcriptomics, transcriptome-wide association study, and clinical cohort validation, this study identified peripheral immune causal genes for AD whose blood transcriptomic and epigenetic signatures track with CSF pathology, cognitive decline, and disease progression, supporting their translational potential for early diagnosis and therapeutic development.<\/jats:p>\n                  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