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, but their associations with cognitive outcomes remain unclear.

OBJECTIVES: To examine the associations of LCDs and LFDs with incident dementia and evaluate the modification by genetic susceptibility.

METHODS: We included 5301 dementia-free adults aged ≥55 y from the Health and Retirement Study. Overall LCD and LFD scores were constructed based on macronutrient composition rankings assessed using a food frequency questionnaire in 2013‒2014. Plant-based, animal-based, healthy, and unhealthy subtype 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 apolipoprotein E (APOE) genotype and Alzheimer's disease polygenic risk score (AD-PRS). Cox models estimated hazard ratios (HRs).

RESULTS: During the 9-y follow-up, 506 participants developed dementia. A higher LCD score was associated with lower dementia risk [hazard ratio (HR) per standard deviation (SD) increment: 0.90; 95% confidence interval (CI): 0.82, 0.99], whereas an overall LFD was not (HR per SD: 1.05; 95% CI: 0.96, 1.15). Plant-based and healthy LCDs showed stronger inverse associations (HR per SD: 0.85; 95% CI: 0.78, 0.94 and HR per SD: 0.82; 95% CI: 0.74, 0.90), whereas higher animal-based LFDs (HR per SD: 1.10; 95% CI: 1.00, 1.20) and unhealthy LFDs (HR per SD: 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.

CONCLUSIONS: Higher adherence to LCDs, particularly plant-based and healthy LCDs, is associated with lower dementia risk, consistently across genetic susceptibility strata. These findings underscore the importance of macronutrient quality, in addition to quantity, in promoting cognitive health.