Dataset Information

SNP-by-CpG Site Interactions in ABCA7 Are Associated with Cognition in Older African Americans.

ABSTRACT: SNPs in ABCA7 confer the largest genetic risk for Alzheimer's Disease (AD) in African Americans (AA) after APOE ε4. However, the relationship between ABCA7 and cognitive function has not been thoroughly examined. We investigated the effects of five known AD risk SNPs and 72 CpGs in ABCA7, as well as their interactions, on general cognitive function (cognition) in 634 older AA without dementia from Genetic Epidemiology Network of Arteriopathy (GENOA). Using linear mixed models, no SNP or CpG was associated with cognition after multiple testing correction, but five CpGs were nominally associated (p < 0.05). Four SNP-by-CpG interactions were associated with cognition (FDR q < 0.1). Contrast tests show that methylation is associated with cognition in some genotype groups (p < 0.05): a 1% increase at cg00135882 and cg22271697 is associated with a 0.68 SD decrease and 0.14 SD increase in cognition for those with the rs3764647 GG/AG (p = 0.004) and AA (p = 2 × 10^-4) genotypes, respectively. In addition, a 1% increase at cg06169110 and cg17316918 is associated with a 0.37 SD decrease (p = 2 × 10^-4) and 0.33 SD increase (p = 0.004), respectively, in cognition for those with the rs115550680 GG/AG genotype. While AD risk SNPs in ABCA7 were not associated with cognition in this sample, some have interactions with proximal methylation on cognition.

SUBMITTER: Chaar DL

PROVIDER: S-EPMC9691156 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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SNP-by-CpG Site Interactions in ABCA7 Are Associated with Cognition in Older African Americans.

Chaar Dima L DL Nguyen Kim K Wang Yi-Zhe YZ Ratliff Scott M SM Mosley Thomas H TH Kardia Sharon L R SLR Smith Jennifer A JA Zhao Wei W

Genes 20221118 11

SNPs in ABCA7 confer the largest genetic risk for Alzheimer's Disease (AD) in African Americans (AA) after APOE ε4. However, the relationship between ABCA7 and cognitive function has not been thoroughly examined. We investigated the effects of five known AD risk SNPs and 72 CpGs in ABCA7, as well as their interactions, on general cognitive function (cognition) in 634 older AA without dementia from Genetic Epidemiology Network of Arteriopathy (GENOA). Using linear mixe ...[more]

PMID: 36421824

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Project description:IntroductionRegular physical activity lowers risk for cognitive decline and neurodegenerative disorders. Older African Americans (AAs) have been underrepresented in trials that increased physical activity to improve cognitive outcomes.Methods56 sedentary, older, cognitively healthy AAs (avg. 69.2 ± 3.4 yrs. old) were randomized in 1:1 ratio into either a 12-week successful aging group (SAG) or a 12-week physical activity group (PAG). Participants in SAG attended weekly 60-min educational sessions in which healthy aging topics were discussed. Participants in PAG attended supervised physical activity sessions twice per week at local YMCAs (90-120 min/week) and were prescribed 2-3 days per week of home-based activity. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) assessed cognitive function. ANCOVA models compared mean 12-week change in global cognition and subdomain scores between groups with secondary analyses for sex differences. Effect sizes for RBANS were calculated.ResultsThe RBANS global cognition score (SAG Est. 5.6 ± 1.8, effect size = 0.37, p = 0.003) and several subdomain scores (one-sample T tests, all p < 0.05) increased significantly within the SAG. Scores for global cognition increased more in SAG than in PAG (Change Estimate, PAG minus SAG: -4.6 ± 2.5 points, effect size = 0.31) at a trend level (p = 0.072). SAG females increased their global cognition score more than PAG females and more than males in either PAG or SAG (all p < 0.035).DiscussionA 12-week physical activity intervention (PAG) did not improve cognitive functioning among older AAs but a comparator healthy aging education program did. Inadequate physical activity dosage or duration, SAG members acting on health-related information from educational sessions, and/or social stimulation within the SAG may have contributed to these results. Future studies should combine socially engaging activities with vigorous physical activity for cognitive enhancement among cognitively healthy older African Americans.Clinical trial registrationwww.ClinicalTrials.gov, identifier NCT03474302.

Project description: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 A? 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.

Dataset Information

SNP-by-CpG Site Interactions in ABCA7 Are Associated with Cognition in Older African Americans.

Publications

SNP-by-CpG Site Interactions in <i>ABCA7</i> Are Associated with Cognition in Older African Americans.

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