ABCA7 Risk Genotype Diminishes the Neuroprotective Value of Aerobic Fitness in Healthy Older African Americans

Abstract

Although the association of ABCA7 risk variants with Alzheimer’s disease (AD) has been established worldwide, its effect size on the relative odds of being diagnosed with AD is significantly higher in African Americans. Across ethnicities, two common ABCA7 loci (rs115550680 and rs3764650) have been confirmed to increase the risk of AD. While ABCA7 rs115550680 has been linked to the development of late-onset AD in African Americans, no association between ABCA7 variant rs3764650 and AD has been found in this population. In order to elucidate the influence of ABCA7 rs3764650 on AD risk in African Americans, we sought to investigate the relationship between this variant, aerobic fitness, and cognition. The present study tested the hypothesis that in African Americans, ABCA7 rs3764650 confers an indirect risk for AD via its interaction with aerobic fitness, a modifiable lifestyle factor known to attenuate AD-related neuropathology. In a case-control sample of 100 healthy African Americans, we observed that ABCA7 rs3764650 genotype modulates the association between aerobic fitness and a cognitive assessment of generalization following rule learning. For carriers of the non-risk genotype, higher levels of aerobic fitness were significantly associated with fewer generalization errors, while carriers of the risk genotype did not show any relationship between aerobic fitness and generalization. Our findings imply that ABCA7 rs3764650 risk genotype may diminish the neuroprotective effects of aerobic fitness, and, they suggest differing risk patterns between cognitive decline and fitness by ABCA7 genotype. Thus, in African Americans the interactive effects of ABCA7 rs3764650 and aerobic fitness likely compound overall ABCA7-related AD risk, and may contribute to health disparities whereby African Americans are at a higher risk for dementia, with double the prevalence of AD.

High-Quality Sleep Mitigates ABCA7-Related Generalization Deficits in Healthy Older African Americans

“…The current study demonstrates that this task may be sensitive to variations sleep quality. Other studies involving involving cognitively healthy older African American samples with varied educational opportunity differences and socio-environmental exposures show that generalization is sensitive to aerobic fitness and body mass index variations [ 45 , 69 ]. As such, the concurrent discrimination and generalization behavioral paradigm may be an especially useful tool for assessing the efficacy of modifying risk factors for AD, particularly among individuals underrepresented in biomedical research and in the earliest phases of prodromal AD when individuals are otherwise cognitively healthy and at ceiling on performance on standardized neuropsychological tests.…”

The Effects of APOE and ABCA7 on Cognitive Function and Alzheimer’s Disease Risk in African Americans: A Focused Mini Review

“…Meanwhile, ABCA7 rs115550680 directly impacts the brain through Aβ facilitated tauopathy, which negatively influences MTL functional connectivity, and consequently, behavioral generalization (Sinha et al, 2019). Although ABCA7 rs3764650 is not a causative variant for AD in African Americans, and does not directly impact brain structure and function, it appears to confer indirect consequences on cognition and AD risk by moderating the effects of aerobic fitness through dysfunctional lipid metabolism and ABCA7 expression (Berg et al, 2019).…”

“…Successful mnemonic flexibility is known to depend on the integrity of the MTL (Myers et al, 2002, 2008), a major site of neuroplasticity that is sensitive to the effects of exercise and aerobic fitness (Cotman et al, 2007). The results of Berg et al (2019) therefore imply that the ABCA7 risk genotype may attenuate the neuro-protective value of aerobic fitness in cognitively healthy older African Americans.…”

“…A study of healthy older African Americans found that ABCA7 rs3764650 modulates the association between aerobic fitness level (as measured by maximal oxygen consumption, VO 2 max) and mnemonic flexibility—the ability to flexibly apply and recombine information from past learning—as measured by generalization following rule learning (Berg et al, 2019). In particular, for carriers of the non-risk genotype, higher levels of aerobic fitness were significantly associated with fewer generalization errors.…”