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Polygenic risk scores (PRS) stratify genetic risk for complex diseases, including AD. Integrating PRS with metabolomics offers a pathway to better understand AD etiology and identify biomarkers for early detection. We explored the association between AD PRS, metabolomics, and dementia risk using data from the UK Biobank. The analysis emphasizes sex-specific associations and the mediating role of metabolites between AD PRS and dementia risk. The study utilized data from 205,219 UK Biobank participants aged\u2009\u2265\u200950 years at baseline. Dementia outcomes were derived using ICD-10 codes. AD PRS were computed using genome-wide association study data, while metabolomic data included 249 biomarkers measured via Nuclear Magnetic Resonance. Time-to-event analyses (Cox proportional hazards models) and generalized structural equation modeling assessed associations and mediation effects, adjusting for age, sex, and genetic principal components. Higher AD PRS was associated with increased risks of all-cause dementia (HR: 1.75, 95% CI: 1.70\u20131.79, P\u2009&lt;\u20090.001) and AD (HR: 2.02, 95% CI: 1.95\u20132.09, P\u2009&lt;\u20090.001), with stronger effects in women for both outcomes when considering the main AD PRS which was related to APOE4 status. Metabolomic analyses identified lipid-related markers as key mediators. LDL phospholipid content was the metabolite marker with the strongest positive relationship with AD genetic risk (effect size,\n                    <jats:italic>b<\/jats:italic>\n                    \u2009= +\u20090.11), while HDL phospholipids percentage showed a similarly strong inverse association (effect size\n                    <jats:italic>b<\/jats:italic>\n                    \u2009=\u2009-0.09). No metabolomic markers were significantly associated with another version of AD PRS that was less correlated with APOE4 status. Mediation analyses applied to the main AD PRS revealed modest effects, with LDL-related metabolomic components partially mediating the effect of genetic risk on dementia incidence, through a protective type of mediation (&lt;\u2009-2%). Nevertheless, most genetic risk operated independently of metabolites. AD PRS is significantly associated with dementia risk, with sex differences and metabolomic pathways providing further insights. Lipid metabolism, particularly LDL-centric measures, emerged as potential mediators. This integrative approach highlights the utility of combining genetic and metabolomic data to identify biomarkers and potential targets for early intervention in AD and dementia.\n                  <\/jats:p>","DOI":"10.1007\/s11357-025-01724-4","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T19:55:54Z","timestamp":1751313354000},"page":"7023-7042","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Alzheimer\u2019s disease polygenic risk\u2019s association with all-cause dementia through the plasma metabolome in the UK Biobank study"],"prefix":"10.1007","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1050-4523","authenticated-orcid":false,"given":"May A.","family":"Beydoun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Han","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiguang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F.","family":"Georgescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hind A.","family":"Beydoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Noren Hooten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keenan A.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustapha","family":"Bouhrara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenore J.","family":"Launer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele K.","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan B.","family":"Zonderman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"issue":"77","key":"1724_CR1","doi-asserted-by":"publisher","first-page":"77sr1","DOI":"10.1126\/scitranslmed.3002369","volume":"3","author":"DM Holtzman","year":"2011","unstructured":"Holtzman DM, Morris JC, Goate AM. 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