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.