ABCA7 Genotype Moderates the Effect of Aerobic Exercise Intervention on Generalization of Prior Learning in Healthy Older African Americans

Abstract

African Americans are at elevated risk for age-related cognitive decline, with double the prevalence of Alzheimer's disease (AD) compared to Caucasians Americans. Various behavioral, biological, and lifestyle factors may underlie this health disparity, but little is known about the relative importance and interactions among these different risk factors in African Americans. While the neuroprotective effects of aerobic exercise on biomarkers are well established, few studies have examined the differential benefits of exercise based on genetic risk for AD. Furthermore, evidence is limited regarding the potential moderating effects of ABCA7, a gene known to confer significantly greater AD risk in African Americans. In a case-control matched sample of 56 healthy older African Americans, we investigated the effect of an aerobic exercise intervention on a hippocampus-related assessment of generalization following rule learning, in individuals who were carriers of the ABCA7 rs3764650 non-risk (TT) or high-risk (GG) genotype. Following the exercise-intervention, the non-risk group made significantly fewer generalization errors, while there was no improvement in generalization for the high-risk group. For the controls, no changes in generalization scores were observed regardless of genotype status. Our results indicate that the ongoing adverse effects of ABCA7 high-risk genotype may diminish the benefits associated with aerobic exercise. As such, the potential disease-modifying effects of aerobic exercise on AD-related neuropathology may be limited to carriers of the ABCA7 rs3764650 non-risk genotype.

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

“…Furthermore, the rs3764650G allele has been associated with increased neuritic plaques in human patients 198 , 214 and a limitation of the neuroprotective effects of exercise intervention. 215 These studies support a potential protective role of ABCA7 in AD. To date, three potential roles have been identified for ABCA7 contribution to AD: APP processing, immune response, and lipid metabolism.…”

Neurovascular Dysfunction in Diverse Communities With Health Disparities—Contributions to Dementia and Alzheimer’s Disease

“…Individuals with higher levels of physical activity present with decreased cognitive decline and reduced risk of AD ( Kramer et al, 2005 , 2006 ; Rovio et al, 2005 ; Rolland et al, 2008 ; Lautenschlager et al, 2010 ; Barnes, 2015 ; Allard et al, 2017 ; Gallaway et al, 2017 ; Stephen et al, 2017 ; Barnes and Corkery, 2018 ; Rabin et al, 2018 , 2019 ; Coelho-Junior et al, 2020 ; De la Rosa et al, 2020 ; Pasek et al, 2020 ; Sinha et al, 2020 ). It has been estimated that an increase of 25% in physically active adults would prevent > 230,000 cases of AD in the US ( Barnes and Yaffe, 2011 ).…”

“…This suggested that genotype is an important factor when examining the efficacy of exercise interventions aimed at ADRD risk reduction. This has garnered additional support via a report that aerobic exercise in older African Americans provided no improvement in a hippocampus-related assessment of generalization following rule learning in a high-genetic risk group ( Sinha et al, 2020 ). Interestingly, however, it has been stated that APOE4 status influences the associations between exercise and ADRD risk such that exercise has a greater ability to protect among APOE4 carriers ( Rovio et al, 2005 ; Kaufman et al, 2021 ).…”

“…Interestingly, however, it has been stated that APOE4 status influences the associations between exercise and ADRD risk such that exercise has a greater ability to protect among APOE4 carriers ( Rovio et al, 2005 ; Kaufman et al, 2021 ). Taken together ( Rovio et al, 2005 ; Allard et al, 2017 ; Sinha et al, 2020 ), exercise is still beneficial for genetically at-risk individuals, but the most efficacious exercise prescription has yet to be elucidated. Notably, there is currently limited understanding concerning the ability of resistance exercise to improve vascular health with the goal of reducing ADRD risk ( Gallaway et al, 2017 ; Barnes and Corkery, 2018 ; Landrigan et al, 2020 ), especially within the African American population ( Shin and Doraiswamy, 2016 ).…”

Examining the efficacy of a cardio-dance intervention on brain health and the moderating role of ABCA7 in older African Americans: a protocol for a randomized controlled trial

“…ABCA7, or adenosine triphosphate (ATP)-binding cassette member, is a risk gene associated with late-onset AD ( Tosto and Reitz, 2013 ). Our previous findings suggest older African Americans with the risk variant of the ABCA7 (single-nucleotide polymorphism rs3764650) gene derive less cognitive benefit from exercise ( Sinha et al, 2020 ). However, our previous study had several limitations including: limited sample size to elucidate the effect of ABCA7 on exercise-induced changes in MTL dynamic network flexibility; no active control group; and lack of correspondence with the public health recommended guidelines of 150 min of moderate-to-vigorous activity per week.…”