Increased dynamic flexibility in the medial temporal lobe network following an exercise intervention mediates generalization of prior learning.

Recent work has conceptualized the brain as a network comprised of groups of sub-networks or modules. "Flexibility" of brain network(s) indexes the dynamic reconfiguration of comprising modules. Using novel techniques from dynamic network neuroscience applied to high-resolution resting-state functional magnetic resonance imaging (fMRI), the present study investigated the effects of an aerobic exercise intervention on the dynamic rearrangement of modular community structure-a measure of neural flexibility-within the medial temporal lobe (MTL) network. The MTL is one of the earliest brain regions impacted by Alzheimer's disease. It is also a major site of neuroplasticity that is sensitive to the effects of exercise. In a two-group non-randomized, repeated measures and matched control design with 34 healthy older adults, we observed an exercise-related increase in flexibility within the MTL network. Furthermore, MTL network flexibility mediated the beneficial effect aerobic exercise had on mnemonic flexibility, as measured by the ability to generalize past learning to novel task demands. Our results suggest that exercise exerts a rehabilitative and protective effect on MTL function, resulting in dynamically evolving networks of regions that interact in complex communication patterns. These reconfigurations may underlie exercise-induced improvements on cognitive measures of generalization, which are sensitive to subtle changes in the MTL.

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

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.

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

African Americans have double the prevalence of Alzheimer's disease (AD), as compared to European Americans. However, the underlying causes of this health disparity are due to a multitude of environmental, lifestyle, and genetic factors that are not yet fully understood. Here, we review the effects of the two largest genetic risk factors for AD in African Americans: Apolipoprotein E (APOE) and ABCA7. We will describe the direct effects of genetic variation on neural correlates of cognitive function and report the indirect modulating effects of genetic variation on modifiable AD risk factors, such as aerobic fitness. As a means of integrating previous findings, we present a novel schematic diagram to illustrate the many factors that contribute to AD risk and impaired cognitive function in older African Americans. Finally, we discuss areas that require further inquiry, and stress the importance of racially diverse and representative study populations.

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

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.

ABCA7 risk variant in healthy older African Americans is associated with a functionally isolated entorhinal cortex mediating deficient generalization of prior discrimination training.

Using high-resolution resting state functional magnetic resonance imaging (fMRI), the present study tested the hypothesis that ABCA7 genetic risk differentially affects intra-medial temporal lobe (MTL) functional connectivity between MTL subfields, versus internetwork connectivity of the MTL with the medial prefrontal cortex (mPFC), in nondemented older African Americans. Although the association of ABCA7 risk variants with Alzheimer's disease (AD) has been confirmed worldwide, its effect size on the relative odds of being diagnosed with AD is significantly higher in African Americans. However, little is known about the neural correlates of cognitive function in older African Americans and how they relate to AD risk conferred by ABCA7. In a case-control fMRI study of 36 healthy African Americans, we observed ABCA7 related impairments in behavioral generalization that was mediated by dissociation in entorhinal cortex (EC) resting state functional connectivity. Specifically, ABCA7 risk variant was associated with EC-hippocampus hyper-synchronization and EC-mPFC hypo-synchronization. Carriers of the risk genotype also had a significantly smaller anterolateral EC, despite our finding no group differences on standardized neuropsychological tests. Our findings suggest a model where impaired cortical connectivity leads to a more functionally isolated EC at rest, which translates into aberrant EC-hippocampus hyper-synchronization resulting in generalization deficits. While we cannot identify the exact mechanism underlying the observed alterations in EC structure and network function, considering the relevance of Aß in ABCA7 related AD pathogenesis, the results of our study may reflect the synergistic reinforcement between amyloid and tau pathology in the EC, which significantly increases tau-induced neuronal loss and accelerates synaptic alterations. Finally, our results add to a growing literature suggesting that generalization of learning may be a useful tool for assessing the mild cognitive deficits seen in the earliest phases of prodromal AD, even before the more commonly reported deficits in episodic memory arise.

APOE ε4 status in healthy older African Americans is associated with deficits in pattern separation and hippocampal hyperactivation.

African Americans are 1.4 times more likely than European Americans to carry the apolipoprotein E (APOE) ε4 allele, a risk factor for Alzheimer's disease (AD). However, little is known about the neural correlates of cognitive function in older African Americans and how they relate to genetic risk for AD. In particular, no past study on African Americans has examined the effect of APOE ε4 status on pattern separation-mnemonic discrimination performance and its corresponding neural computations in the hippocampus. Previous work using the mnemonic discrimination paradigm has localized increased activation in the DG/CA3 hippocampal subregions as being correlated with discrimination deficits. In a case-control high-resolution functional magnetic resonance imaging study of 30 healthy African Americans, aged 60 years and older, we observed APOE ε4-related impairments in mnemonic discrimination, coincident with dysfunctional hyperactivation in the DG/CA3, and CA1 regions, despite no evidence of structural differences in the hippocampus between carriers and noncarriers. Our results add to the growing body of evidence that deficits in pattern separation may be an early marker for AD-related neuronal dysfunction.