Population intervention models of racial ethnic disparities in cognitive outcomes from cardiometabolic risk factors - HABS-HD.

Background: Alzheimer's disease and related dementias are major public health challenges, with the apolipoprotein (APOE) ε4 allele being a significant genetic risk factor. Cardiometabolic risk factors such as diabetes, hypertension, dyslipidemia, obesity, and tobacco use are also linked to cognitive impairment. The objective of this study was to (1) characterize both independent and interactive associations of racial/ethnic group (Non-Hispanic White (NHW), Non-Hispanic Black (NHB) and Hispanic), APOE ε4 genotype, and multiple cardiometabolic risk factors with performance across four cognitive domains. Secondarily, we aimed to quantify the hypothetical population-level cognitive gains that could result from eliminating each modifiable risk factor within each racial/ethnic group.

Methods: We analyzed baseline data from 3,833 HABS-HD participants (1,348 NHW; 1,065 NHB; 1,420 Hispanic; mean age 65.3 ± 8.6 years; 62.0% female). APOE genotype, consensus-determined cardiometabolic status, and harmonized cognitive domain scores (episodic memory, executive function, processing speed, language) were obtained. Multivariable linear regressions assessed independent effects of race/ethnicity, APOE ε4 carriage, and each cardiometabolic factor on domain-specific z-scores, adjusting for age, sex, and education (Bonferroni-corrected). Interaction terms tested effect modification by race/ethnicity. Counterfactual population intervention models estimated the mean cognitive gain from hypothetically eliminating each modifiable risk factor within each racial/ethnic group.

Results: NHB Hispanic, and NHW participants prevalences were APOE ε4 (32.2%, 27.4%, 17.6%), diabetes (26.1%, 35.0%, 13.9%), hypertension (79.0%, 63.6%, 58.2%), obesity (56.8%, 50.3%, 38.5%), and tobacco dependence (12.9%, 7.5%, 3.9%). In adjusted models, NHB and Hispanic ethnicity, APOE ε4, diabetes, hypertension, and tobacco dependence each independently predicted lower performance across all four cognitive domains (adjusted p < .001), whereas obesity showed domain-specific positive associations. No race × risk-factor interactions remained significant after correction. In intervention models, hypothetically eliminating diabetes and hypertension yielded the largest predicted improvements, especially in executive function and language, with the greatest gains projected among NHB and Hispanic racial ethnic group.

Conclusions: Cardiometabolic health markedly contributes to racial ethnic differences in cognitive aging beyond APOE ε4 effects. Population-level interventions targeting diabetes and hypertension could narrow NHB and Hispanic cognitive deficits, informing precision public-health strategies for dementia prevention.