Walking and Diet Boost Cognition in At-Risk Adults

Growing evidence suggests that lifestyle interventions such as walking may help slow cognitive decline in individuals with the apolipoprotein E (APOE) ε4 allele, who have a genetically higher risk of developing Alzheimer’s disease (AD) — and may even provide greater benefits than in noncarriers.

Preliminary findings from a new study show that while men and women APOE ε4 carriers experienced steeper declines in cognition over a 10-year period, regular walking appeared to mitigate these effects by preserving global cognition and executive function.

The results underscore the value of accessible physical activity programs for individuals genetically at risk for AD, study investigator Cindy Barha, PhD, Canada Research Chair in Neuroscience, Brain Health, and Exercise, and assistant professor, Faculty of Kinesiology, University of Calgary, Alberta, Canada, told Medscape Medical News.

“We can start telling people that if you’re at risk, we know this one thing — walking — will be beneficial for you,” Barha said, adding this is part of an overall effort to “start personalizing our interventions so we can maximize benefit.”

The findings were presented on July 29 at the Alzheimer’s Association International Conference (AAIC) 2025.

Risk Variation by Sex

APOE ε4 accounts for almost 50% of the genetic risk for late-onset AD, but evidence suggests the risk is more pronounced in women than men. One copy of this allele is associated with a twofold increased risk in men and an eightfold greater risk in women, while two copies are associated with a fourfold increased risk in men and a 12-fold increased risk in women, Barha said.

“We know exercise and walking are good for the brain, and we wondered whether they would be even more beneficial for ε4 carriers and if they’re sex-dependent.”

Meanwhile, research showed that the ε2 version of APOE may protect against cognitive decline compared with the ε3 allele, which is the most common and neutral variant.

“We also wondered if exercise would provide a kind of ‘double hit’ in ε2 carriers,” Barha said. “If you’re an ε2 carrier and you’re walking a lot, maybe you’re going to be super protected.”

The analysis included 2981 participants with a mean age of 74 years, from the Health, Aging, and Body Composition (Health ABC) study. It began in 1997 with a cohort of cognitively unimpaired community-dwelling older adults in Memphis, Tennessee, and Pittsburgh.

Walking was self-reported and assessed annually. Participants were queried about their walking habits, and walkers were asked about the total number of minutes they engaged in this activity over the past 7 days.

To assess cognition, researchers used the Digit Symbol Substitution Test (DSST), which measures a range of cognitive functions such as attention, working memory, and information processing, and the Modified Mini-Mental State Exam (3MS), a tool for evaluating global cognition. Both tests were administered at baseline and approximately every 2 years over a 10-year period. Researchers categorized APOE genotypes into ε2, ε3, and ε4 groups.

Study results showed that APOE ε4 carriers — both men and women — experienced steeper declines on both cognitive tests than ε3 carriers. Among women, the decline was significant on the DSST (β = -0.10; P < .001) and the 3MS (β = -0.13; P < .001). In men, the decline was also significant on the DSST (β = -0.07; P = .005) and more pronounced on the 3MS (β = -0.22; P < .001).

The APOE ε2 allele appeared protective against cognitive decline, but only in women on the 3MS (β = 0.15; P = .002).

Simple Activity, Strong Impact

Walking showed the strongest protective effect on both cognitive measures in APOE ε4 carriers of both sexes. A 10% increase in walking was associated with a 4.7% improvement in complex thinking performance over time in women and a 2.6% improvement in men. For global cognitive performance, the same increase in walking was linked to an 8.5% improvement in women and a 12.0% improvement in men.

Regular walking may help preserve cognition through several potential mechanisms, the authors noted. These include enhancing cerebral blood flow — improving the delivery of oxygen and nutrients to the brain — increasing levels of brain-derived neurotrophic factor, which supports neurogenesis and synaptic plasticity, promoting angiogenesis, and reducing neuroinflammation and oxidative stress.

Barha speculated that because APOE ε4 carriers begin with lower cognitive performance and decline more rapidly, they may have more room to improve and therefore stand to gain more from walking interventions. The findings highlight a key takeaway for people at elevated risk for dementia: Doctors should promote regular walking for their patients, especially as they age and if they have an elevated risk for dementia, she said.

Still to be determined are the optimal intensity and frequency of walking — and whether other forms of exercise may offer similar benefits for ε4 carriers.

Looking ahead, the research team plans to study the impact of physical activity earlier in life. “A lot of Alzheimer’s disease biomarkers start to accumulate in the brain during midlife — not when you’re 70 years old or already showing signs of cognitive decline, but 20 years before that,” Barha noted.

One limitation of the study is that walking was self-reported; however, Barha noted that data collected through actigraphy closely correlates with self-reported activity levels.

Another limitation of the study was its focus solely on walking. The authors noted that if data on more vigorous activities like running and weight training had been included, the observed impact on slowing cognitive decline in this high-risk group might have been even greater. Additionally, the study did not account for other factors known to affect cognition, such as diet, stress, and sleep.

Greater Cognitive Gains for APOE ε4 Carriers

Building on these findings, results from another study presented on July 28, 2025, at the AAIC suggested that the benefits of physical activity and other lifestyle interventions may be even greater for APOE ε4 carriers than noncarriers.

The meta-analysis pooled data from three randomized clinical trials involving older adults at risk for dementia or with mild cognitive impairment (MCI) who had known APOE status: the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER; n = 1109), the Multidomain Alzheimer Preventive Trial (MAPT; n = 934), and the Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT; n = 426).

FINGER and J-MINT randomly assigned participants to lifestyle interventions — including physical activity, healthy diet, cognitive training, and risk monitoring — or control groups. 

The MAPT combined lifestyle interventions with omega-3 supplements; for this analysis, participants receiving only supplements were excluded, and those receiving lifestyle interventions with or without supplements were combined.

Researchers estimated cognitive change using each trial’s original primary outcome: A composite cognition score based on multiple neurocognitive tests. The analysis compared carriers of one or two APOE ε4 alleles with noncarriers.

Preliminary results showed greater benefits of the intervention among APOE ε4 carriers than noncarriers at 24 months for both global cognition and executive function. The overall effect size for the composite score among carriers was 0.282 (95% CI, 0.111-0.454; P = .001), with the largest effect observed in J-MINT, followed by FINGER and MAPT.

Multiple Mechanisms at Play

Healthy eating and exercise likely affect brain health through multiple mechanisms — possibly those related to cholesterol metabolism and vascular mechanisms, study investigator Jenni Lehtisalo, PhD, researcher at the Finnish Institute for Health and Welfare, Helsinki, Finland, told Medscape Medical News.

Lehtisalo noted that cognitive benefits among APOE ε4 carriers appeared consistent across diverse populations — Asian and European — and cognitive groups, including at-risk individuals and those with MCI. The research team plans to examine additional studies to see if these findings hold in more geographically and ethnically diverse populations.

These findings offer hope for patients with a family history of AD who may feel powerless to reduce their risk. Individuals can still act and benefit from lifestyle changes, Lehtisalo said. While carriers may derive greater benefit from lifestyle interventions, she emphasized that everyone gains from healthy habits.

The analysis could not determine which specific components of the intervention — physical activity, healthy diet, cognitive training, or risk factor monitoring — most benefited APOE ε4 carriers. Lehtisalo noted that healthy habits often cluster; for example, physically active individuals tend to eat healthier diets. The study also did not assess sex differences.

Commenting on the two studies for Medscape Medical News, Rebecca M. Edelmayer, PhD, vice president of Scientific Engagement at the Alzheimer’s Association, noted the importance of understanding what puts people at risk for AD, including genetics.

“That’s why looking at these associations between genetic risk and some type of lifestyle intervention is critical,” she said.

The Health ABC study was supported by the National Institutes of Health’s National Institute on Aging (NIA) and the National Institute of Nursing Research. The current analysis was funded in part by the Intramural Research Program of the NIA.