ArticleFrontiers in medicine2026
Comorbidity sequence, sex, and APOE-genotype forecast Alzheimer's disease diagnosis.
Article in Frontiers in medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Not yet cited in PubMed.
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Corrections and comments
- Erratum issued
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7 authors.
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Abstract
Introduction: 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-ε4 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. Methods: 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-ε4-stratified analyses to identify distinct longitudinal comorbidity patterns associated with AD. Sex-specific findings were validated in an independent CureMD cohort. Results: 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%; Conclusion: 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.
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