Browsing by Subject "ABCA7"

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    Characterization of the A1527G variant of ABCA7 in an animal model for late‐onset Alzheimer’s disease
    (Wiley, 2025-01-03) Bernabe, Cristian S.; Kotredes, Kevin P.; Pandey, Ravi S.; Carter, Gregory W.; Sasner, Michael; Oblak, Adrian L.; Howell, Gareth R.; Lamb, Bruce T.; Territo, Paul R.; MODEL-AD consortium; Medicine, School of Medicine
    Background: Genome‐wide association studies (GWAS) identified the ATP binding cassette subfamily A member 7 (ABCA7) gene as increasing risk for Alzheimer’s disease (AD). ABC proteins transport various molecules across extra and intra‐cellular membranes. ABCA7 is part of the ABC1 subfamily and is expressed in brain cells including neurons, astrocytes, microglia, endothelial cells and pericytes. However, the mechanisms by which variations in ABCA7 increase risk for AD are not known. Method: The IU/JAX/PITT MODEL‐AD Center identified the A1527G variant in ABCA7 (ABCA7*A1527G) as a putative LOAD risk factor. CRISPR/CAS9 was first used to introduce Abca7*A1527G variant to B6.APOE4.Trem2*R47H (LOAD1) mice to assess the transcriptional profiling on brain hemispheres from different ages. The Abca7*A1527G was then incorporated into B6.APOE4.Trem2*R47H.hAb (LOAD2) mice to further evaluate its contribution to LOAD. Female and male LOAD2.Abca7*A1527G and LOAD2 mice were characterized at 4, 12, and 24 months using the following phenotyping pipeline: behavior, PET/CT, multi‐omics, fluid biomarkers, electrophysiology, cognition, and neuropathology. Result: Brain transcriptional profiling showed that Abca7*A1527G induced changes in gene expression that are similar to some of those observed in human AD (e.g., granulocyte/neutrophil migration, and insulin receptor signaling). LOAD2.Abca7*A1527G showed no aging cognitive deficit but did show significant sex‐ and region‐dependent increases in brain glycolysis paralleled by reduced tissue perfusion yielding progressive age‐related uncoupled phenotypes between 4‐12 and 4‐24 months. While multi‐resolution consensus clustering of regional covariance matrices revealed an increase in cluster number and organization in LOAD2.Abca7*A1527G over LOAD2 for both sexes at 4 months, the cluster number and complexity were reduced by 24 months. Importantly, LOAD2.Abca7*A1527G, but not LOAD2, displayed a similar age‐dependent reduction in cluster number for both sexes. Consistent with the uncoupled phenotype, IL6, IL10, and TNFα were elevated in plasma with genotype, but were not age dependent. Conversely, brain levels of IL4, IL12, TNFα, and CXCL1 were decreased, whereas IL2 and IL10 were elevated in LOAD2.Abca7*A1527G relative to LOAD2. Lastly, assessment of plasma levels of Ab40‐Ab42 revealed an age‐dependent increase in both genotypes. Conclusion: Data collected to date support a model whereby variations in ABCA7 exert risk for AD through interactions between cerebrovasculature, microglia, and peripheral immune cells.
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    Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans
    (Elsevier, 2017-02) Mez, Jesse; Chung, Jaeyoon; Jun, Gyungah; Kriegel, Joshua; Bourlas, Alexandra P.; Sherva, Richard; Logue, Mark W.; Barnes, Lisa L.; Bennett, David A.; Buxbaum, Joseph D.; Byrd, Goldie S.; Crane, Paul K.; Ertekin-Taner, Nilüfer; Evans, Denis; Fallin, M. Daniele; Foroud, Tatiana; Goate, Alison; Graff-Radford, Neill R.; Hall, Kathleen S.; Kamboh, M. Ilyas; Kukull, Walter A.; Larson, Eric B.; Manly, Jennifer J.; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Lunetta, Kathryn L.; Farrer, Lindsay A.; Department of Medical & Molecular Genetics, IU School of Medicine
    INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.