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We analyzed 6069 cognitively unimpaired women (mean age\u2009=\u200970.0\u2009\u00b1\u20093.8\u2009years) in the Women's Health Initiative Memory Study to examine the association of accelerated biological aging, measured with second and third\u2010generation epigenetic clocks (AgeAccelPheno and AgeAccelGrim2, and DunedinPACE, respectively) with incident mild cognitive impairment (MCI) and probable dementia. Multivariable Cox proportional hazards models adjusted for age, education, race, ethnicity, smoking, hormone therapy regimen, physical activity, body mass index, and estimated white blood cell counts. For comparison, we also examined first\u2010generation epigenetic clocks (AgeAccelHorvath; AgeAccelHannum). We evaluated effect modification by age, race\/ethnicity, hormone therapy regimen, menopause type (natural vs. surgical), and\n                    <jats:italic>APOE \u03b54<\/jats:italic>\n                    carriage. There were 1307 incident MCI or probable dementia events over a median follow\u2010up of 9.3 (25th percentile\u2009=\u20096.1, 75th percentile\u2009=\u200916.1) years. The adjusted HRs (95% CI;\n                    <jats:italic>p<\/jats:italic>\n                    \u2010value) for incident MCI\/probable dementia per one\u2010standard deviation increment were 1.07 (1.01\u20131.15;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.03) for DunedinPACE, 1.11 (1.02\u20131.20;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.01) for AgeAccelGrim2, and 1.01 (0.95\u20131.07;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.74) for AgeAccelPheno. Only AgeAccelGrim2 remained significant under the Bonferroni\u2010corrected threshold for significance (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.02). Other epigenetic clocks were not associated with incident MCI\/probable dementia. There was no effect modification in most subgroup analyses (\n                    <jats:italic>p<\/jats:italic>\n                    \u2010interaction \u2265\u20090.05). In this cohort study of older women, accelerated biological aging measured by AgeAccelGrim2 was associated with higher risk of incident MCI\/probable dementia. These findings provide evidence linking epigenetic biomarkers of biological aging with MCI and dementia development, independent of chronological age.\n                  <\/jats:p>","DOI":"10.1111\/acel.70424","type":"journal-article","created":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T14:04:28Z","timestamp":1771682668000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Epigenetic Clocks of Biological Aging and Risk of Incident Mild Cognitive Impairment and Dementia: The Women's Health Initiative Memory Study"],"prefix":"10.1111","volume":"25","author":[{"given":"Steve","family":"Nguyen","sequence":"first","affiliation":[{"name":"Herbert Wertheim School of Public Health and Human Longevity Science University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ake T.","family":"Lu","sequence":"additional","affiliation":[{"name":"Altos Labs  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4110-3589","authenticated-orcid":false,"given":"Steve","family":"Horvath","sequence":"additional","affiliation":[{"name":"Altos Labs  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Espeland","sequence":"additional","affiliation":[{"name":"Division of Gerontology and Geriatric Medicine, School of Medicine Wake Forest University  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen R.","family":"Rapp","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Medicine Wake Forest School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam X.","family":"Maihofer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of California San Diego  La Jolla California USA"},{"name":"Research Service, Veterans Affairs San Diego Healthcare System  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline M.","family":"Nievergelt","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of California San Diego  La Jolla California USA"},{"name":"Research Service, Veterans Affairs San Diego Healthcare System  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Z.","family":"LaCroix","sequence":"additional","affiliation":[{"name":"Herbert Wertheim School of Public Health and Human Longevity Science University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda K.","family":"McEvoy","sequence":"additional","affiliation":[{"name":"Kaiser Permanente Washington Health Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Resnick","sequence":"additional","affiliation":[{"name":"Laboratory of Behavioral Neuroscience National Institute on Aging, National Institutes of Health  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Beckman","sequence":"additional","affiliation":[{"name":"Genomics Center University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aladdin H.","family":"Shadyab","sequence":"additional","affiliation":[{"name":"Herbert Wertheim School of Public Health and Human Longevity Science University of California San Diego  La Jolla California USA"},{"name":"Division of Geriatrics, Gerontology, and Palliative Care, Department of Medicine University of California San Diego  San Diego California 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