@article{8c96b18db5524c55bad88f5eed85c864,
title = "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.",
keywords = "ABCA7, African American, Alzheimer's disease, entorhinal cortex, high-resolution fMRI functional connectivity",
author = "Neha Sinha and Reagh, {Zachariah M.} and Tustison, {Nicholas J.} and Berg, {Chelsie N.} and Ashlee Shaw and Myers, {Catherine E.} and Diane Hill and Yassa, {Michael A.} and Gluck, {Mark A.}",
note = "Funding Information: This work was supported by grants to MAG from the NIH/National Institute on Aging (R56AG053961, R01AG053961) and by support from the Chancellor's and Provost's offices at Rutgers University-Newark. Additional support came from grants to MAY from NIH/National Institute on Aging grants P50AG05146, R21AG049220, and R01AG053555. The authors thank Stephen Hanson, and the staff of the Rutgers University Brain Imaging Center (RUBIC), for their guidance and support in the brain imaging data collection. Funding Information: information National Institute on Aging, Grant/Award Numbers: P50AG05146R01AG053555R01A G053961R21AG049220R56AG053961, R01AG053555, R21AG049220, P50AG05146, R01AG053961, R56AG053961 This work was supported by grants to MAG from the NIH/National Institute on Aging (R56AG053961, R01AG053961) and by support from the Chancellor's and Provost's offices at Rutgers University-Newark. Additional support came from grants to MAY from NIH/National Institute on Aging grants P50AG05146, R21AG049220, and R01AG053555. The authors thank Stephen Hanson, and the staff of the Rutgers University Brain Imaging Center (RUBIC), for their guidance and support in the brain imaging data collection. Our ongoing research studies with older African Americans in Greater Newark would not be possible without the guidance, input, and support of the Community Advisory Board of the Rutgers-Newark African American Brain Health Initiative, including Tania Cajuste (East Orange Office of Senior Services), Margaret Cammarieri (American Heart Association|American Stroke Association), Honorable Mildred Crump (City of Newark City Council), Mary Dawkins (Hillside Senior Recreation Group), Mildred English (St. James AME Church), Jaklyn De Vore (Essex County Senior Services), Deacon Francis Dixon (The New Hope Baptist Church), Robin Lateef-Pharms (Bethany Senior Center), Louise Layton (Rutgers Aging Advisory Council), Yolanda Mack (Greater Newark Healthcare Coalition), Rev. Dr. Jacqueline Reeves (St. James AME Church), Joan Reeves (East Orange Office of Senior Services), Donna Sparks (Bethany Baptist Church), Sheltry Ward (New Jersey Black Nurses Association), Pastor Glenn Wilson (Pilgrim Baptist Church), Geri Woods-Coles (Bethany Baptist Church), and Glenda Wright (New Jersey Association of Public and Subsidized Housing). Publisher Copyright: {\textcopyright} 2018 Wiley Periodicals, Inc.",
year = "2019",
month = jun,
doi = "https://doi.org/10.1002/hipo.23042",
language = "English (US)",
volume = "29",
pages = "527--538",
journal = "Hippocampus",
issn = "1050-9631",
publisher = "Wiley-Liss Inc.",
number = "6",
}