Exercise as Potential Therapeutic Target to Modulate Alzheimer’s Disease Pathology in APOE ε4 Carriers: A Systematic Review

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease for which no effective treatment exists at present. Previous research has found that exercise reduces the risk of AD. Since the apolipoprotein E (APOE) ε4 allele increases the risk of AD and is associated with faster disease progression than the other isoforms, we aimed to highlight the impact of exercise on AD pathology in APOE ε4 carriers. This review focuses on the effect of exercise on cognitive function, dementia risk, amyloid-β (Aβ) metabolism, lipid metabolism, neuroinflammation, neurotrophic factors and vascularization in APOE ε4 carriers. We searched the literature in the PubMed electronic database using the following search terms: physical activity, exercise, aerobic fitness, training, sport, APOE4, Alzheimer’s disease, AD and dementia. By cross-referencing, additional publications were identified. Selected studies required older adults to take part in an exercise intervention or to make use of self-reported physical activity questionnaires. All included studies were written and published in English between 2000 and 2020. From these studies, we conclude that exercise is a non-pharmacological treatment option for high-risk APOE ε4 carriers to ameliorate the AD pathological processes including reducing Aβ load, protecting against hippocampal atrophy, improving cognitive function, stabilizing cholesterol levels and lowering pro-inflammatory signals. Variation in study design related to age, cognitive outcomes and the type of intervention explained the differences in study outcomes. However, exercise seems to be effective in delaying the onset of AD and may improve the quality of life of AD patients.

Association between driving a car and retention of brain volume in Japanese older adults

“…36,37 Many studies have suggested that physical activity may be involved in the reduction of beta-amyloid accumulation and in increasing cognitive function, as well as of neuroinflammation factors such as tumor necrosis factor alpha, interleukin-1-beta, and interleukin-6, high-density lipoprotein levels, cerebral blood flow, and brainderived neurotrophic factor, and that these factors may contribute to brain health during aging. 38 Physical inactivity has become endemic in industrialized countries, particularly among certain occupations, such as professional drivers. 39 Inactivity is attributed to the fact that the overall risk for coronary heart disease in particular (and possibly other conditions) is higher than any other lifestyle risk factor.…”

ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies

“…Lifestyle changes, such as physical exercise and diets, can potentially attenuate AD pathology. Physical activity has been shown to reduce Aβ accumulation, improve cholesterol levels, reduce neuroinflammation, and enhance cognitive function [ 246 ]. Despite some contradictory evidence in the field, it is becoming increasingly apparent that the beneficial effects of exercise and diet are likely dependent on APOE genotype [ 247 ].…”

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

“…Few exercise studies discriminate between APOE genotypes, and among those who do, results are diverse, as reported by recent systematic reviews [ 605 , 606 ]. Regarding the risk of getting diagnosed with AD, some studies show that the lower risk of developing all-cause dementia and AD among highly active persons is more pronounced in APOE4 non-carriers [ 586 , 587 , 607 , 608 ].…”

“…The discrepancy between studies may be attributable to several factors, such as the type of exercise assessment and outcome measurement. For instance, a recent systematic review concluded that most studies with conflicting results used outcomes such as clinical diagnosis, which are not sensitive to preclinical cognitive fluctuations [ 606 ]. Timing of exercise intervention or physical activity lifestyle assessment are also relevant parameters to consider since physical activity may need to occur when it is still possible to prevent the pathological process.…”