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We aim to quantify the overall contribution of modifiable lifestyle, adiposity, socioeconomic status (SES), and health conditions occurring before dementia, to the association between\n                    <jats:italic>\u03b54<\/jats:italic>\n                    genotype and the development of all-cause dementia, with AD examined as a major subtype. A population cohort study of 181,006 white UK Biobank participants aged\u2009\u2265\u200955\u00a0years at baseline was conducted, to examine the associations between\n                    <jats:italic>APOE \u03b54<\/jats:italic>\n                    and all-cause dementia, and specifically AD, including modification and mediation role of lifestyle factors, adiposity, SES, and health conditions occurring before dementia. All risk factors, except for high alcohol intake, low diet quality, and phenotypic obesity, were associated with higher risk of all-cause dementia. The interaction contributions of lifestyle, adiposity, SES, and health conditions occurring before dementia varied by sex and dementia type. Low educational attainment had the strongest interaction effects with the association of\n                    <jats:italic>APOE \u03b54<\/jats:italic>\n                    carriers and AD\/all-cause dementia (up to 32.1%). In women, high deprivation level, abnormal sleep duration, anxiety, and depression showed interaction effects with\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype (5\u201311.6%) as well. Phenotypic adiposity was associated with an increased risk of dementia among\n                    <jats:italic>APOE \u03b54<\/jats:italic>\n                    non-carriers, but with a reduced risk among\n                    <jats:italic>APOE \u03b54<\/jats:italic>\n                    carriers. Educational attainment explained a meaningful proportion of the\n                    <jats:italic>APOE \u03b54<\/jats:italic>\n                    association with dementia. The strength of the association between\n                    <jats:italic>APOE \u03b54<\/jats:italic>\n                    and dementia differed by risk factors and sex.\n                  <\/jats:p>","DOI":"10.1007\/s11357-026-02452-z","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T15:01:38Z","timestamp":1785510098000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heterogeneity in the association between APOE \u03b54 carrier status and dementia risk by modifiable and non-modifiable risk factors"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2391-4416","authenticated-orcid":false,"given":"Mengrong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick K.","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill P.","family":"Pell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Celis-Morales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E. 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