The Joint Effects of Life’s Essential 8 and Genetics on Mild Cognitive Impairment and Dementia Risk in People With Diabetes: Findings From the UK Biobank and All of Us

OBJECTIVE: We examined how cardiovascular health (CVH), measured by Life's Essential 8 (LE8), and genetic risk are jointly associated with risks of mild cognitive impairment (MCI), dementia, and related cognitive outcomes in people with diabetes. RESEARCH DESIGN AND METHODS: We analyzed 41,374 participants without dementia from the UK Biobank (UKB) and 9,766 from All of Us (AoU). LE8, comprising diet, physical activity, nicotine exposure, sleep, body mass index, lipids, blood glucose, and blood pressure, was scored from 0 to 100 and categorized as low, moderate, or high. Genetic risk was assessed using APOE ε4 alleles and polygenic risk scores (PRS) for Alzheimer disease. We used Cox regression to examine associations of LE8 with MCI and dementia and linear regression to assess MRI-based brain functional measures and cognitive test outcomes, adjusting for covariates. Interactions between LE8 and genetic risk were tested on multiplicative and additive scales. RESULTS: Over 15 years of follow-up (UKB), moderate or high CVH versus low CVH was associated with a lower risk of MCI (hazard ratio 0.82 [95% CI 0.71, 0.95], P < 0.05) but not with risk of all-cause dementia (0.97 [0.84, 1.11], P = 0.63). In participants at high genetic risk (high PRS), moderate or high CVH was associated with a lower risk of MCI (0.78 [0.62, 0.98], P for additive interaction < 0.05). AoU results were consistent. CONCLUSIONS: Better CVH was significantly associated with a lower risk of MCI in people with diabetes, accounting for genetic risk. The association between CVH and MCI and dementia was stronger among individuals with low or moderate genetic risk and appeared attenuated among those with high genetic risk.