{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:54:00Z","timestamp":1792457640852,"version":"4.5.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T00:00:00Z","timestamp":1618185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["T32AG049663"],"award-info":[{"award-number":["T32AG049663"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["K01AG062722"],"award-info":[{"award-number":["K01AG062722"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG057869"],"award-info":[{"award-number":["R01AG057869"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["K24AG031155"],"award-info":[{"award-number":["K24AG031155"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["RF1AG052132"],"award-info":[{"award-number":["RF1AG052132"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG059872"],"award-info":[{"award-number":["R01AG059872"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Weight loss or lower body mass index (BMI) could be an early symptom of Alzheimer disease (AD), but when this begins to emerge is difficult to estimate with traditional observational data. In an extension of Mendelian randomization, we leveraged variation in genetic risk for late-onset AD risk to estimate the causal effect of AD on BMI and the earliest ages at which AD-related weight loss (or lower BMI as a proxy) occurs. We studied UK Biobank participants enrolled in 2006\u20132010, who were without dementia, aged 39\u201373, with European genetic ancestry. BMI was calculated with measured height\/weight (weight (kg)\/height (m)2). An AD genetic risk score (AD-GRS) was calculated based on 23 genetic variants. Using linear regressions, we tested the association of AD-GRS with BMI, stratified by decade, and calculated the age of divergence in BMI trends between low and high AD-GRS. AD-GRS was not associated with BMI in 39- to 49-year-olds (\u03b2 = 0.00, 95% confidence interval (CI): \u22120.03, 0.03). AD-GRS was associated with lower BMI in 50- to 59-year-olds (\u03b2 = \u22120.03, 95% CI: \u22120.06, \u22120.01) and 60- to 73-year-olds (\u03b2 = \u22120.09, 95% CI:\u22120.12, \u22120.07). Model-based BMI age curves for high versus low AD-GRS began to diverge after age 47 years. Sensitivity analyses found no evidence for pleiotropy or survival bias. Longitudinal replication is needed; however, our findings suggest that AD genes might begin to reduce BMI decades prior to dementia diagnosis.<\/jats:p>","DOI":"10.1093\/aje\/kwab103","type":"journal-article","created":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T23:14:53Z","timestamp":1617837293000},"page":"2163-2171","source":"Crossref","is-referenced-by-count":28,"title":["Extension of Mendelian Randomization to Identify Earliest Manifestations of Alzheimer Disease: Association of Genetic Risk Score for Alzheimer Disease With Lower Body Mass Index by Age 50 Years"],"prefix":"10.1093","volume":"190","author":[{"given":"Willa D","family":"Brenowitz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott C","family":"Zimmerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa J","family":"Filshtein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine","family":"Yaffe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Jorgenson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A","family":"Whitmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Maria","family":"Glymour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,12]]},"reference":[{"issue":"3","key":"2021110908014488800_ref1","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jalz.2011.03.003","article-title":"Toward defining the preclinical stages of Alzheimer\u2019s disease: recommendations from the National Institute on Aging\u2013Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Sperling","year":"2011","journal-title":"Alzheimers Dement"},{"issue":"3","key":"2021110908014488800_ref2","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.neuron.2014.10.038","article-title":"The evolution of preclinical Alzheimer\u2019s disease: implications for prevention trials","volume":"84","author":"Sperling","year":"2014","journal-title":"Neuron"},{"key":"2021110908014488800_ref3","doi-asserted-by":"crossref","DOI":"10.3389\/fnagi.2019.00074","article-title":"Identifying changepoints in biomarkers during the preclinical phase of Alzheimer\u2019s disease","volume":"11","author":"Younes","year":"2019","journal-title":"Front Aging Neurosci"},{"issue":"4","key":"2021110908014488800_ref4","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1001\/jamaneurol.2015.4756","article-title":"Decline in weight and incident mild cognitive impairment: Mayo Clinic Study of Aging","volume":"73","author":"Alhurani","year":"2016","journal-title":"JAMA Neurol"},{"issue":"62","key":"2021110908014488800_ref5","doi-asserted-by":"crossref","first-page":"104706","DOI":"10.18632\/oncotarget.22218","article-title":"Weight loss in the healthy elderly might be a non-cognitive sign of preclinical Alzheimer\u2019s disease","volume":"8","author":"Jimenez","year":"2017","journal-title":"Oncotarget"},{"issue":"10","key":"2021110908014488800_ref6","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0185960","article-title":"Weight loss from 20 years of age is associated with cognitive impairment in middle-aged and elderly individuals","volume":"12","author":"Kitamura","year":"2017","journal-title":"PloS One"},{"issue":"1","key":"2021110908014488800_ref7","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1038\/s41598-017-01327-w","article-title":"Decreased body mass index in the preclinical stage of autosomal dominant Alzheimer\u2019s disease","volume":"7","author":"M\u00fcller","year":"2017","journal-title":"Sci Rep"},{"key":"2021110908014488800_ref8","doi-asserted-by":"crossref","first-page":"471","DOI":"10.3389\/fncel.2018.00471","article-title":"Disorders of body weight, sleep and circadian rhythm as manifestations of hypothalamic dysfunction in Alzheimer\u2019s disease","volume":"12","author":"Hiller","year":"2018","journal-title":"Front Cell Neurosci"},{"issue":"78","key":"2021110908014488800_ref9","doi-asserted-by":"crossref","first-page":"34691","DOI":"10.18632\/oncotarget.26162","article-title":"Obesity and Alzheimer\u2019s disease, does the obesity paradox really exist? 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