Key result
Exercise interventions show no difference in physical function outcomes between APOE4 carriers and non-carriers.
Why the study?
Systematic reviews had not yet evaluated the impact of the APOE4 genotype on the effectiveness of exercise interventions on physical and cognitive outcomes.
Does exercise intervention improve physical and cognitive outcomes differently in APOE4 carriers versus non-carriers?
Meta-Analysis
Does exercise intervention improve physical and cognitive outcomes differently in APOE4 carriers versus non-carriers?
There is currently very limited and low-quality evidence regarding whether the APOE4 genotype influences the effectiveness of exercise interventions on cognitive and physical health.
Low-quality evidence precludes APOE4-guided exercise prescriptions; leaves open differential physical function effects.
BACKGROUND: Alzheimer's disease is caused by modifiable and non-modifiable risk factors. Randomised controlled trials have investigated whether the strongest genetic risk factor for Alzheimer's disease, APOE4, impacts the effectiveness of exercise on health. Systematic reviews are yet to evaluate the effect of exercise on physical and cognitive outcomes in APOE genotyped participants. A quality assessment of these randomised controlled trials is needed to understand the impact genotype has on the potential success of intervention. This systematic review aimed to determine if the APOE4 genotype influences the effectiveness of exercise-based randomised controlled trials. METHOD: Searches on MEDLINE, EMBASE, and PsycINFO identified eligible exercise based randomised controlled trials incorporating participants with varied cognitive abilities. Quality assessments were conducted. RESULTS: Nineteen studies met the inclusion criteria for systematic review, and 3 for the meta-analysis. Very low to moderate quality evidence showed that APOE4 carriers benefitted more than APOE4 non-carriers on cognitive (e.g. executive function, learning) and physical (e.g. relative telomere length) outcomes after exercise; and that APOE4 non-carriers benefited over carriers for physical (serum BDNF, gait speed) and cognitive (global cognition, verbal memory) markers. Very low quality evidence indicated that there was no evidence of difference between APOE4 carriers and non-carriers on physical function outcomes in meta-analysis. Several areas of study design and reporting, including maintenance of relative exercise intensity and complete statistical reporting, were identified as needing improvement. DISCUSSION: This systematic review found very limited evidence to suggest that exercise interventions can benefit APOE4 carriers and non-carriers equally, though conclusions were limited by evidence quality. Further randomised controlled trials, stratifying participants by APOE status are required to better understand the relationship between APOE genotype and the effect of exercise on health-related outcomes. TRIAL REGISTRATION: This review was registered with PROSPERO (CRD42023436842). Registered on June 16, 2023.
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Spencer et al. (2025) conducted a meta-analysis in Cognitive impairment and Alzheimer's disease risk. Exercise intervention vs. Control (active stretching, education, social visits, or treatment as usual) was evaluated on Physical and cognitive outcomes (including physical function in meta-analysis). Exercise interventions provided very limited, low-quality evidence suggesting no significant difference between APOE4 carriers and non-carriers on physical function outcomes.
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