The effect of the APOE4 genotype on physiological and cognitive health in randomised controlled trials with an exercise intervention: a systematic review and meta-analysis

Abstract

Abstract Background Alzheimer's disease is the most common form of dementia and has multiple causes, including modifiable and non-modifiable risk factors. Randomized controlled trials have investigated whether the strongest genetic risk factor for Alzheimer’s disease, APOE4, impacts the effectiveness of exercise on health outcomes. To date, there are no systematic reviews evaluating the effect of exercise on physical and cognitive outcomes in APOE genotyped participants. A thorough assessment of the quality 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 21 studies met the inclusion criteria for systematic review, and 11 studies in the meta-analysis. Within the current review, six studies reported that, after exercise, APOE4 carriers showed improvement in cognitive (e.g., executive function and learning) and physical (e.g., relative telomere length, inflammatory markers) outcomes. The benefits for APOE4 non-carriers over carriers were limited to a smaller range of outcomes but were seen in physical (serum BDNF, gait speed) and cognitive (global cognition, verbal memory) markers in four studies. The meta-analysis indicated that physical activity levels (16.04% higher in exercise than control group), executive function (19.34% higher in exercise than control group), and quality of life (3.05% higher in exercise than control group) increased following exercise intervention. Physiological health outcomes were not dependent on APOE genotype. The overall quality of evidence was low-to-moderate, and several areas of study design and reporting were identified as needing improvement. Discussion This systematic review demonstrates that the physiological and cognitive health of both APOE4 carriers and non-carriers respond to exercise interventions, suggesting that exercise can be beneficial regardless of APOE status. Further randomised controlled trials, stratifying participants by APOE status, and exploring optimal exercise are required to better understand the relationship between carrying APOE and the effect of exercise on health-related outcomes. Registration: This review was registered with PROSPERO (CRD420234368420).