Counterfactual analysis of differential comorbidity risk factors in Alzheimer’s disease and related dementias

Alzheimer’s disease and related dementias (ADRD) is a multifactorial disease that involves several different etiologic mechanisms with various comorbidities. There is also significant heterogeneity in the prevalence of ADRD across diverse demographics groups. Association studies on such heterogeneous comorbidity risk factors are limited in their ability to determine causation. We aim to compare counterfactual treatment effects of various comorbidity in ADRD in different racial groups (African Americans and Caucasians). We used 138,026 ADRD and 1:1 matched older adults without ADRD from nationwide electronic health records, which extensively cover a large population’s long medical history in breadth. We matched African Americans and Caucasians based on age, sex, and high-risk comorbidities (hypertension, diabetes, obesity, vascular disease, heart disease, and head injury) to build two comparable cohorts. We derived a Bayesian network of 100 comorbidities and selected comorbidities with potential causal effect to ADRD. We estimated the average treatment effect (ATE) of the selected comorbidities on ADRD using inverse probability of treatment weighting. Late effects of cerebrovascular disease significantly predisposed older African Americans (ATE = 0.2715) to ADRD, but not in the Caucasian counterparts; depression significantly predisposed older Caucasian counterparts (ATE = 0.1560) to ADRD, but not in the African Americans. Our extensive counterfactual analysis using a nationwide EHR discovered different comorbidities that predispose older African Americans to ADRD compared to Caucasian counterparts. Despite the noisy and incomplete nature of the real-world data, the counterfactual analysis on the comorbidity risk factors can be a valuable tool to support the risk factor exposure studies.