Longitudinal analysis of electronic health records reveals medical conditions associated with subsequent Alzheimer’s disease development

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BACKGROUND: Several health conditions are known to increase the risk of Alzheimer's disease (AD). We aim to systematically identify medical conditions that are associated with subsequent development of AD by leveraging the growing resources of electronic health records (EHRs). METHODS: This retrospective cohort study used de-identified EHRs from two independent databases (MarketScan and VUMC) with 153 million individuals to identify AD cases and age- and gender-matched controls. By tracking their EHRs over a 10-year window before AD diagnosis and comparing the EHRs between AD cases and controls, we identified medical conditions that occur more likely in those who later develop AD. We further assessed the genetic underpinnings of these conditions in relation to AD genetics using data from two large-scale biobanks (BioVU and UK Biobank, total N = 450,000). RESULTS: We identified 43,508 AD cases and 419,455 matched controls in MarketScan, and 1,320 AD cases and 12,720 matched controls in VUMC. We detected 406 and 102 medical phenotypes that are significantly enriched among the future AD cases in MarketScan and VUMC databases, respectively. In both EHR databases, mental disorders and neurological disorders emerged as the top two most enriched clinical categories. More than 70 medical phenotypes are replicated in both EHR databases, which are dominated by mental disorders (e.g., depression), neurological disorders (e.g., sleep orders), circulatory system disorders (e.g. cerebral atherosclerosis) and endocrine/metabolic disorders (e.g., type 2 diabetes). We identified 19 phenotypes that are either associated with individual risk variants of AD or a polygenic risk score of AD. CONCLUSIONS: In this study, analysis of longitudinal EHRs from independent large-scale databases enables robust identification of health conditions associated with subsequent development of AD, highlighting potential opportunities of therapeutics and interventions to reduce AD risk.

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