Low-carbohydrate and low-fat diets, genetic susceptibility, and long-term risk of dementia: A prospective cohort study.

BACKGROUND: Low-carbohydrate and low-fat diets (LCDs and LFDs) are promoted for cardiometabolic prevention. OBJECTIVE: This study examined associations of LCDs and LFDs with incident dementia and evaluated modification by genetic susceptibility. METHODS: We included 5301 dementia-free adults aged ≥55 years from the Health and Retirement Study. Overall LCD and LFD indices were constructed based on macronutrient composition rankings assessed using a food frequency questionnaire in 2013-2014. Plant-based, animal-based, healthy, and unhealthy sub-scores were derived to characterize macronutrient sources and quality. Incident dementia was defined using the Langa-Weir algorithm through 2022. Genetic susceptibility was assessed using APOE genotype and Alzheimer disease polygenic risk score (AD-PRS). Cox models estimated hazard ratios (HRs). RESULTS: During the 9-year follow-up, 506 participants developed dementia. Greater LCD score was associated with lower dementia risk (HR per SD increment 0.90, 95% CI, 0.82, 0.99), whereas an overall LFD was not (1.05, 95% CI, 0.96, 1.15). Plant-based and healthy LCDs showed stronger inverse associations (0.85, 95% CI, 0.78, 0.94 and 0.82, 95% CI, 0.74, 0.90), while higher animal-based (1.10; 95% CI, 1.00, 1.20) and unhealthy LFDs (1.13; 95% CI, 1.04, 1.24) were linked to higher dementia risk. Associations were consistent across APOE genotype and AD-PRS strata. Higher plant-based and healthy LCDs were also associated with better global and domain-specific cognitive performance. CONCLUSION: Adherence to LCDs, particularly plant-based and higher-quality LCDs, was associated with lower dementia risk, consistently across genetic susceptibility strata. These findings underscored the importance of macronutrient quality, in addition to quantity, in promoting cognitive health.