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However, effect of their duration, influenced by non\u2010modifiable factors like chromosomal sex and apolipoprotein E (\n                      <jats:italic>APOE<\/jats:italic>\n                      ) genotype, remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Data from 5644 UKBiobank participants were analyzed using Cox regression model to identify critical tipping points based on age of onset, risk factor (RF) duration and their interaction with sex and\n                      <jats:italic>APOE<\/jats:italic>\n                      genotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Hypertension or diabetes before age 62 exerted greater AD risk than\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 alone. Obesity before age 62 increased AD risk by 54%, with the risk nearly tripling between ages 62\u201372. Hyperlipidemia and depression were associated with age\u2010independent risk increases of 33% and 69%, respectively. After age 72,\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 became the dominant RF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      Duration of AD\u2010risk\u2010factors can have a greater impact than\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54. Identification of critical age\u2010related tipping points highlights temporal dynamics of AD progression and role of multisystem failure in AD progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>AD risk factors impact AD onset, especially diagnosed between ages 62 and 72.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Later diagnoses of hypertension, diabetes, and obesity delayed AD onset.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Hyperlipidemia and depression increased AD risk by 33% and 69%, age\u2010independent.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>APOE\u03b54 carriers regardless of sex exhibited a higher risk increasing with age.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Trajectories differed between APOE\u03b54 carriers and non\u2010carriers across sex.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70249","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T23:34:51Z","timestamp":1746833691000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Multisystem failure, tipping points, and risk of Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Simona","family":"Merlini","sequence":"first","affiliation":[{"name":"Center for Innovation in Brain Science University of Arizona Health Sciences  Tucson Arizona USA"},{"name":"Department of Biomedical Engineering College of Engineering University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward J.","family":"Bedrick","sequence":"additional","affiliation":[{"name":"Center for Biomedical Informatics and Biostatistics University of Arizona  Tucson Arizona USA"},{"name":"Department of Epidemiology and Biostatistics College of Public Health University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta Diaz","family":"Brinton","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science University of Arizona Health Sciences  Tucson Arizona USA"},{"name":"Department of Neurology College of Medicine 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