Walking to protect against cognitive decline: the role of APOE genotype and sex

TL;DR

Walking can help slow cognitive decline, especially for people with a genetic risk for Alzheimer's, and the benefits vary by sex.

Contribution

This study identifies how walking mitigates cognitive decline in APOE ε4 carriers and varies by sex.

Findings

APOE ε4 carriers showed steeper cognitive decline compared to ε3 carriers, regardless of sex.

Walking had the strongest protective effect on cognitive decline in APOE ε4 carriers for both sexes.

APOE ε2 was protective for global cognition in females only.

Abstract

The apolipoprotein E (APOE) ε4 allele is a risk factor for late-onset Alzheimer’s disease; however, risk varies by sex and lifestyle. Regular physical activity is known to mitigate cognitive decline; whether the degree of benefit differs by APOE genotype, sex, and race remains unknown.

Analyses utilized data from 2,985 participants in the Health, Aging, and Body Composition (HABC) cohort, comprising community-dwelling black and white older adults followed for 10 years. Cognitive performance was assessed multiple times across the 10 years using the Digit Symbol Substitution Test (DSST) for executive functions and processing speed and the Modified Mini-Mental State Examination (3MS) for global cognition. APOE genotypes were categorized into ε2, ε3, and ε4 groups. Annual self-reported walking time was used to quantify physical activity. Linear mixed models and latent growth curve modeling examined the interactions between APOE genotype, sex, and walking on cognitive trajectories with adjustments for race, study location, health score, age, education attained, and body mass index.

APOE ε4 carriers demonstrated steeper declines in both DSST and 3MS scores compared to ε3 carriers, irrespective of sex (all β<-0.13, all p < 0.004). APOE ε2 was protective longitudinally for 3MS in females only (β = 0.15, p < 0.002). Walking showed the strongest protective effect in APOE ε4 carriers for females and males in the rate of change of DSST and 3MS scores (all β > 0.27, all p < 0.044).

These findings underscore the importance of public messaging about the benefits of regular physical activity for retaining cognitive function especially for persons genetically at heightened risk.

The online version contains supplementary material available at 10.1186/s13293-026-00860-6.

As we age, it is common for thinking skills such as memory, attention, and processing speed to decline. The rate of this decline differs greatly between people, with genes and lifestyle playing important roles. One gene linked to Alzheimer’s disease risk is called APOE. People who carry the ε4 version of this gene are at a greater risk of cognitive decline. However, carrying the ε2 version may offer some protection. These genetic effects can also differ between females and males. In this study, about 3,000 Black and White adults were followed over 10 years to understand how APOE gene versions, biological sex, and physical activity interact to influence thinking abilities in their 70 and 80s. Participants also reported the number of minutes spent walking per week across the study on average. We found that both females and males who carried the APOE ε4 version experienced faster declines in thinking abilities. However, for these individuals at the greatest genetic risk, those who maintained their walking levels over time showed much slower declines in memory and thinking speed. We also found that higher walking levels at the start of the study were linked to better thinking abilities in females who carried the APOE ε2 or ε3 versions. Overall, our findings suggest that regular walking may help slow age-related cognitive decline, particularly in people at higher genetic risk for Alzheimer’s disease, and that these benefits can differ between females and males.

The online version contains supplementary material available at 10.1186/s13293-026-00860-6.

Global cognition and executive functions were assessed over 10 years in community dwelling older adults.

APOE ε4 carriers displayed steeper declines in cognition in both sexes compared to APOE ε3.

APOE ε2 was protective for global cognition in females only .

For both sexes, more walking in APOE ε4 carriers was associated with attenuated cognitive decline.

Walking is an accessible, targeted strategy to slow cognitive decline in older adults at elevated genetic risk.

The online version contains supplementary material available at 10.1186/s13293-026-00860-6.

Figures