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However, the mechanisms by which APOEe4 drives distinct molecular changes \u2013 whether by exacerbating pathology or triggering compensatory responses \u2013 remain incompletely understood. We generated and analyzed proteomic, epigenetic, and genetic data from post-mortem dorsolateral prefrontal cortex samples of a uniquely APOEe4-enriched subset of the Religious Orders Study and Memory and Aging Project (ROSMAP). Specifically, we generated DIA LC-MS proteomic data (n = 302), analyzed previously generated DNA methylation profiles from our group (n = 310), and used published whole-genome sequencing data (n = 254) to compute polygenic risk scores (PRS). In this cohort, 69% (n = 214) were APOEe4 carriers, and 19.6% (n = 42) of them showed no pathological evidence of AD based on NIA-Reagan criteria, enabling identification of APOEe4-related risk and resilience mechanisms.<\/jats:p>\n                <jats:p>In the absence of AD, APOEe4 carriers exhibited lower levels of 27 proteins, suggesting early synaptic (e.g., VAMP1, SYN3, CASKIN1) and metabolic (e.g., GLUD1, PI4KA) vulnerability. By contrast, APOEe4 carriers with AD displayed marked upregulation of inflammatory and proteostatic proteins (e.g., GNAO1, AHNAK, FGG, HEBP1, APEX1, RAB4A, SLC12A5, LRP1, BAG6) and hypermethylation of cg06329447 in ELAVL4. Network analyses highlighted convergent disruptions in synaptic transmission, metabolism, and proteostasis \u2013 key pathways altered in APOEe4-associated AD. Mediation analyses identified GRIPAP1 and GSTK1 as top protein mediators (accounting for \u223c26\u201333% of APOEe4\u2019s effect), with VAMP1, CASKIN1, DPP3, SYN3, and FGG each contributing \u223c9\u201315%. ELAVL4 hypermethylation also mediated \u223c12% of the APOEe4 effect, linking epigenetic dysregulation to disease risk.<\/jats:p>\n                <jats:p>To assess whether the identified proteins reflected broader genetic risk for AD or were specific to APOEe4, we calculated PRS both excluding and including the APOE genomic region. While the non-APOE PRS showed no association with identified molecular markers, the APOE-inclusive PRS was significantly associated with eight AD-related proteins in carriers, indicating they are not explained by polygenic risk outside of APOE. Finally, predictive modeling stratified by APOEe4 status revealed that in non-carriers, PRS most effectively classified AD (AUC = 0.73), whereas in carriers, proteomic and epigenetic markers outperformed PRS (AUC up to 0.74).<\/jats:p>\n                <jats:p>Together, these findings demonstrate that APOEe4 confers AD risk through early synaptic and metabolic disruptions and later-stage inflammatory and epigenetic changes, laying the groundwork for genotype-tailored biomarker development and therapeutic strategies.<\/jats:p>\n                <jats:sec>\n                  <jats:title>VISUAL ABSTRACT<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"682426v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.16.682426","type":"posted-content","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T21:15:17Z","timestamp":1760649317000},"source":"Crossref","is-referenced-by-count":4,"title":["Beyond the Genotype: A Multi-Omic Analysis of APOEe4\u2019s Role in Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8778-4909","authenticated-orcid":false,"given":"Yaroslav","family":"Markov","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahana","family":"Priyanka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6789-4959","authenticated-orcid":false,"given":"Leqi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyra","family":"Thrush-Evensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1020-8783","authenticated-orcid":false,"given":"John","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Borrus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Kasamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghav","family":"Sehgal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenel","family":"Fraij","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Becky C.","family":"Carlyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4110-3589","authenticated-orcid":false,"given":"Steve","family":"Horvath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1195-9607","authenticated-orcid":false,"given":"Hongyu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher H.","family":"van Dyck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"TuKiet T","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan E.","family":"Levine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert T.","family":"Higgins-Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025102110451169000_2025.10.16.682426v1.1","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Dementia Forecasting Collaborators. 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