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Background <p>The apolipoprotein E (<i>APOE</i>) 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 <i>APOE</i> genotype, sex, and race remains unknown.</p> Methods <p>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. <i>APOE</i> 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 <i>APOE</i> genotype, sex, and walking on cognitive trajectories with adjustments for race, study location, health score, age, education attained, and body mass index.</p> Results <p><i>APOE</i> ε4 carriers demonstrated steeper declines in both DSST and 3MS scores compared to ε3 carriers, irrespective of sex (all β&lt;-0.13, all <i>p</i> &lt; 0.004). <i>APOE</i> ε2 was protective longitudinally for 3MS in females only (β = 0.15, <i>p</i> &lt; 0.002). Walking showed the strongest protective effect in <i>APOE</i> ε4 carriers for females and males in the rate of change of DSST and 3MS scores (all β &gt; 0.27, all <i>p</i> &lt; 0.044).</p> Discussion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月21日

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  • Joel S. Burma,
  • Caterina Rosano,
  • John R. Best,
  • Eleanor M. Simonsick,
  • Teresa Liu-Ambrose,
  • Cindy K. Barha

摘要

Background

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.

Methods

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.

Results

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).

Discussion

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.