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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. Author summary Alzheimer’s disease (AD) is the sixth leading cause of death in the United States, affecting 6 million Americans aged 65 and older. AD risk develops over the long course of a lifetime and involves various etiologies such as genetic, vascular, and psychosocial factors, of which the complex biological mechanisms are still under investigation. Putative risk factors include race/ethnicity, low educational attainment, socioeconomic status, and comorbidities (hypertension, diabetes). These risk factors may interact with each other and further increase the risk of AD. Most studies find older African Americans are more likely than older Whites to develop AD. Comorbidity risk factors and socioeconomic status are believed to partially account for these differences, as they are more prevalent in African Americans. To disentangle the multifactorial effects of factors predisposing older adults to AD, we quantified counterfactual effect of high-risk comorbidities mediating the AD risk using nationwide electronic health records. We particularly focused on differential counterfactual effects between matched African Americans and Caucasians. Our extensive counterfactual analysis discovered different comorbidities that predispose older African Americans to AD compared to Caucasian counterparts. This differential risk between racial groups will contribute to developing targeted treatment to AD.