{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T10:51:25Z","timestamp":1785927085872,"version":"3.56.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Alzheimer's disease (AD) is a highly heterogeneous neurodegenerative disorder and the leading cause of dementia characterized by the progressive accumulation of non-modifiable (age, female sex, APOE-\u03b54 genotype) and modifiable factors [hypertension (HTN), diabetes, obesity (OB), hyperlipidemia (HLP), depression (DEP)]. However, the temporal sequencing and interaction patterns between comorbidity burden and biological subgroups defined by sex and APOE genotype remain not fully understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We applied the Cumulative Event Method (CEM), a novel process mining framework, to longitudinal UK Biobank (UKB) data. Event logs tracked five modifiable risk factors across sex- and APOE-\u03b54-stratified analyses to identify distinct longitudinal comorbidity patterns associated with AD. Sex-specific findings were validated in an independent CureMD cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 1,916 UK Biobank participants, CEM identified 203 distinct comorbidity sequences across 7,316 clinical events. Females more frequently exhibited a hypertension-preceding-AD sequences than males (7.0% vs. 3.8%;\n                      <jats:italic>p<\/jats:italic>\n                      = 0.005), while males exhibited earlier metabolic-vascular patterns involving hyperlipidemia and hypertension (7.7% vs. 4.5%;\n                      <jats:italic>p<\/jats:italic>\n                      = 0.0085). APOE-\u03b54 carriers exhibited accelerated multi-comorbidity patterns, whereas non-carriers more frequently transitioned from hypertension to non-AD (\n                      <jats:italic>p<\/jats:italic>\n                      = 1 \u00d7 10\n                      <jats:sup>\u22124<\/jats:sup>\n                      ). External validation in CureMD confirmed sex-specific patterns across 191 sequences and 5,176 events.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Longitudinal comorbidities patterns preceding AD differ by sex and APOE genotype, supporting Alzheimer's as a multisystem failure disease with subgroup-specific comorbidity sequences and clinically relevant windows for precision prevention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1826377","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T04:38:01Z","timestamp":1781152681000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Comorbidity sequence, sex, and APOE-genotype forecast Alzheimer's disease 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Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amna","family":"Basharat","sequence":"additional","affiliation":[{"name":"CureMD Research","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muddassar","family":"Farooq","sequence":"additional","affiliation":[{"name":"CureMD Research","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta Diaz","family":"Brinton","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science, The University of Arizona","place":["Tucson, AZ, United States"]},{"name":"Department of Neurology, University of Arizona College of Medicine","place":["Tucson, AZ, United States"]},{"name":"Department of Pharmacology, University of Arizona College of Medicine","place":["Tucson, AZ, United 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