Additionally, the ABCA7 mRNA expression level in AD subjects was significantly correlated with Mini-Mental State Examination recall, the Alzheimer's Disease Assessment Scale total score, and the Clinical Dementia Rating score.
All patients carrying a loss-of-function mutation in ABCA7 exhibited a classical Alzheimer disease phenotype, though with a striking wide onset age range, suggesting the influence of unknown modifying factors.
Although the effect size for the association of ABCA7 loss-of-function variants with AD risk is lower in our study (odds ratio = 1.54) compared to the original report (odds ratio = 2.2), the replication of the findings of the original report provides a stronger foundation for future functional applications.
An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility.
ATP-binding cassette transporter A7 (ABCA7) gene, regulating the transport of cholesterol, has been recently identified as a susceptible gene of AD by several large genome-wide association studies.
Besides associations with disease status, these genetic and epigenetic ABCA7 markers also showed significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology.
Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden.
Brain regions most significantly associated with AD risk variants were the left postcentral gyrus with ABCA7 (rs4147929, p = 4.45 × 10<sup>-6</sup>), right superior frontal gyrus by ZCWPW1 (rs1476679, p = 5.12 × 10<sup>-6</sup>), and right postcentral gyrus by APOE (p = 6.91 × 10<sup>-6</sup>).
Clarifying the effect of APOE-ABCA7 interactions on the default mode network and memory is critical to exploring the complex pathogenesis of Alzheimer's disease and refining a potential therapy.
Five genomewide association studies (GWAS) in white populations have recently identified and confirmed 9 novel Alzheimer's disease (AD) susceptibility loci (CLU, CR1, PICALM, BIN1, ABCA7, MS4A gene cluster, CD2AP, CD33, and EPHA1).
Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.
Genome-wide association studies have indicated that ABCA7 single nucleotide polymorphisms confer increased risk for late-onset AD; however, the role that ABCA7 plays in the brain in the AD context is unknown.