{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T11:04:02Z","timestamp":1784631842723,"version":"3.55.0"},"reference-count":75,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG050595"],"award-info":[{"award-number":["R01 AG050595"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ROI AG022381"],"award-info":[{"award-number":["ROI AG022381"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ROI AG076838"],"award-info":[{"award-number":["ROI AG076838"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ROI AG037985"],"award-info":[{"award-number":["ROI AG037985"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ROI AG064955"],"award-info":[{"award-number":["ROI AG064955"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 AG055367"],"award-info":[{"award-number":["P01 AG055367"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The study explores whether frailty at midlife predicts mortality and levels of biomarkers associated with Alzheimer\u2019s disease and related dementias (ADRD) and neurodegeneration by early old age. We also examine the heritability of frailty across this age period.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Participants were 1,286 community-dwelling men from the Vietnam Era Twin Study of Aging at average ages 56, 62 and 68, all without ADRD at baseline. The cumulative deficit frailty index (FI) comprised 37 items assessing multiple physiological systems. Plasma biomarkers at age 68 included beta-amyloid (A\u03b240, A\u03b242), total tau (t-tau) and neurofilament light chain (NfL).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Being frail doubled the risk of all-cause mortality by age 68 (OR\u2009=\u20092.44). Age 56 FI significantly predicted age 68 NfL (P\u2009=\u20090.014), A\u03b240 (P\u00a0=\u20090.001) and A\u03b242 (P\u2009=\u20090.023), but not t-tau. Age 62 FI predicted all biomarkers at age 68: NfL (P\u2009=\u20090.023), A\u03b240 (P\u2009=\u20090.002), A\u03b242 (P\u2009=\u20090.001) and t-tau (P\u2009=\u20090.001). Age 68 FI scores were associated with age 68 levels of NfL (P\u2009=\u20090.027), A\u03b240 (P\u2009&amp;lt;\u20090.001), A\u03b242 (P\u2009=\u20090.001) and t-tau (P\u2009=\u20090.003). Genetic influences accounted for 45\u201348% of the variance in frailty and significantly contributed to its stability across 11\u00a0years.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Frailty during one\u2019s 50s doubled the risk of mortality by age 68. A mechanism linking frailty and ADRD may be through its associations with biomarkers related to neurodegeneration. Cumulative deficit frailty increases with age but remains moderately heritable across the age range studied. With environmental factors accounting for about half of its variance, early interventions aimed at reducing frailty may help to reduce risk for ADRD.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ageing\/afae028","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T08:19:52Z","timestamp":1709885992000},"source":"Crossref","is-referenced-by-count":5,"title":["Midlife cumulative deficit frailty predicts Alzheimer\u2019s disease-related plasma biomarkers in older adults"],"prefix":"10.1093","volume":"53","author":[{"given":"Erik","family":"Buchholz","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University of California San Diego , La Jolla, CA 92093 , USA"},{"name":"Center for Behavior Genetics of Aging, University of California , La Jolla, San Diego, CA 92093 , USA"},{"name":"Department of Information Science, University of Arkansas at Little Rock , Little Rock, AR 72204 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8655-2823","authenticated-orcid":false,"given":"Nathan A","family":"Gillespie","sequence":"additional","affiliation":[{"name":"Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University , VA 23298 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack F","family":"Hunt","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego , La Jolla, CA 92093 , USA"},{"name":"Center for Behavior Genetics of Aging, University of California , La Jolla, San Diego, CA 92093 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandra A","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of California Riverside , Riverside, CA 92521 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"Rissman","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California, San Diego and VA San Diego Healthcare System , La Jolla, CA 92093 , USA"},{"name":"Alzheimer\u2019s Therapeutic Research Institute, University of Southern California , San Diego, CA 92121 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Schroeder","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego , La Jolla, CA 92093 , USA"},{"name":"Center for Behavior Genetics of Aging, University of California , La Jolla, San Diego, CA 92093 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Cortes","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego , La Jolla, CA 92093 , USA"},{"name":"Center for Behavior Genetics of Aging, University of California , La Jolla, San Diego, CA 92093 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Bell","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego , La Jolla, CA 92093 , USA"},{"name":"Center for Behavior Genetics of Aging, University of California , La Jolla, San Diego, CA 92093 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Lyons","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences, Boston University , Boston, MA 02215 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William S","family":"Kremen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego , La Jolla, CA 92093 , USA"},{"name":"Center for Behavior Genetics of Aging, University of California , La Jolla, San Diego, CA 92093 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol E","family":"Franz","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego , La Jolla, CA 92093 , USA"},{"name":"Center for Behavior Genetics of Aging, University of California , La Jolla, San Diego, CA 92093 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,7]]},"reference":[{"key":"2024030807524196600_ref1","first-page":"219","article-title":"Frailty: evaluation and management","volume":"103","author":"Allison","year":"2021","journal-title":"Am Fam Physician"},{"key":"2024030807524196600_ref2","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/S0140-6736(19)31786-6","article-title":"Frailty: implications for clinical practice and public 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