Apolipoprotein E ε4 carriers who engaged in regular walking demonstrated significantly slower cognitive decline compared with sedentary ε4 carriers, with protective effects varying by sex and race, according to a 10-year longitudinal analysis of 2,984 community-dwelling older adults from the Health, Aging, and Body Composition cohort, presented at the Alzheimer's Association International Conference.

The study reported that "walking showed the strongest protective effect in ε4 carriers, slowing the decline in DSST among Black females (β = 0.39, P = .04), White females (β = 0.60, P = .01), and White males (β = 0.45, P = .01)." For global cognition, assessed using the Modified Mini-Mental State Examination (3MS), "walking was associated with slower decline across ε4 carriers, with slightly greater associations in Black individuals (βs > 1.11, P < .001) compared with White individuals (βs > 0.67, P = .03)."

Importantly, these effects were specific to apolipoprotein E (APOE) ε4 carriers. The investigators found that walking was not associated with cognitive decline in ε2 or ε3 carriers, suggesting a genotype-specific response to physical activity interventions.

Study Design and Population

The analysis utilized data from the Health, Aging, and Body Composition cohort, which included community-dwelling Black and White older adults followed for 10 years. Cognitive performance was assessed longitudinally using two validated tools:

• The Digit Symbol Substitution Test (DSST) for executive function and processing speed.

• The Modified Mini-Mental State Examination (3MS) for global cognition.

APOE genotypes were categorized as ε2, ε3, or ε4. Physical activity was quantified via self-reported annual walking time. The investigators applied linear models and latent growth curve modeling to assess interactions between APOE genotype, sex, race, and walking on cognitive trajectories. Analyses were adjusted for study location, health score, age, education level, and body mass index.

Genotype-Specific Cognitive Decline Patterns

Consistent with prior research, the study found that "APOE ε4 carriers demonstrated steeper declines in both DSST and 3MS scores compared with ε3 carriers, irrespective of sex and race (βs > −0.07, all P < .034)." There was also "some evidence that APOE ε2 was protective against cognitive decline;" though the patterns varied by sex and race.

Sex and Race Differences in Walking Benefits

Among APOE ε4 carriers, the protective effects of walking differed by demographic subgroup. For DSST scores, which measured executive function and processing speed, walking was protective across all examined sex and race subgroups, with the strongest effect observed in White females.

In terms of global cognition (3MS), walking was more strongly associated with slower cognitive decline in Black ε4 carriers compared with White ε4 carriers.

Clinical Implications

These findings have important implications for personalized medicine approaches. The investigators concluded that "APOE ε4 carriers displayed an elevated risk of cognitive decline; greater physical activity was significantly protective in this at-risk group." The study emphasized the need for tailoring physical activity messaging to at-risk populations and highlighted the intersection of genetic, sex, racial, and lifestyle factors in cognitive aging research.

Limitations and Future Directions

The study relied on self-reported walking data, which may introduce recall bias. Additionally, the analysis focused exclusively on walking as a form of physical activity. The inconsistent associations observed for the ε2 allele across sex and race subgroups warrant further investigation in larger, stratified cohorts.

Conclusion

This longitudinal analysis provided evidence for genotype-specific benefits of physical activity in cognitive aging, with walking demonstrating significant protective effects exclusively in APOE ε4 carriers. The results point to the value of adapting physical activity communication for populations at increased risk and emphasize the combined influence of genetic, sex-based, demographic, and lifestyle factors in studies of cognitive aging.

The study referenced were supported by the Government of Canada’s Canadian Research Chairs Program and NordForsk, with additional funding from the Alzheimer’s Disease Data Initiative.

Source: AAIC 2025 Abstract