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

Abstract

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 Aβ 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.

The role of ABCA7 in Alzheimer’s disease: evidence from genomics, transcriptomics and methylomics

“…Wachinger et al used MRI to study asymmetry in four pre-selected brain regions (hippocampus, amygdala, putamen, and caudate) and found significant association between rs4147929 and hippocampal asymmetry, particularly within the AD subgroup [52]. Additionally, studies with relatively smaller study populations reported associations between ABCA7 GWAS SNPs and decreased gray-matter density in dementia patients [50], increased cortical and hippocampal atrophy in controls and individuals with MCI [48], and dissociation of entorhinal cortex resting-state functional connectivity based on functional MRI in cognitively healthy elderly [51]. In summary, evidence is presently linking AD-associated ABCA7 common variants to increased brain atrophy already at preclinical stages of AD (Table 2).…”

“…On the one hand, correlations between ABCA7 SNPs and clinical symptoms have been observed, yet based on relatively small cohorts, or with associations not passing multiple-testing correction. These include: association with baseline cognitive performance and linear rate of change [59], increased likelihood of clinical symptoms in individuals with AD neuropathology [60], later age at onset and shorter disease duration [53], and behavioral generalization deficits [51]. On the other hand, large-scale studies found no, or complex associations between ABCA7 sentinel SNPs and cognitive decline.…”

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

“…Consistent with this, in our current sample of cognitively healthy older African Americans, we did not see any difference in generalization errors or performance on the standardized neuropsychological assessments between carriers of the risk vs. non-risk genotype. Furthermore, in a previous study we investigated the effect of ABCA7 rs115550680, a variant with a significantly increased risk for AD exclusively in African-Americans (Reitz et al, 2013), on the same behavioral paradigm; we found that non-demented African American elderly with the ABCA7 rs115550680 risk genotype had impairments in generalization, mediated by cortico-hippocampal network dysfunction (Sinha et al, 2018). Taken together, these results indicate that in African Americans, ABCA7 rs3764650 does not confer a direct AD risk, but rather indirectly increases the risk of AD by diminishing the benefits of aerobic fitness.…”

“…Another variant, ABCA7 rs115550680, has been linked to the development of late-onset AD in African Americans (Reitz et al, 2013). We have previously demonstrated that in non-demented African American elderly, rs115550680 corresponds to impairments in MTL network function commensurate with hippocampus-related cognitive deficits (Sinha et al, 2018). Despite ABCA7 rs3764650 not being directly implicated in AD in African Americans, we hypothesized that it may yield an indirect risk through its interaction with other risk factors, which in turn, could account for the higher incidence rate of dementia and AD in this population.…”

Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease

“…Whether or not ABCA7 knockout impacts cognitive function needs to be studied. Suggestive of an effect on synaptic function, a recent study found that healthy ABCA7 carriers show impaired cortical connectivity (Sinha et al, 2019). Interestingly, there might be genetic interactions between APOE4 with ABCA7 that impact memory (Chang et al, 2019).…”