Immunohistochemical analyses of human brain sections from AD and non-AD subjects revealed that ABCA7 is expressed in neuron and microglia cells in the cerebral cortex.
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.
Thus, our study suggested that ABCA7 genotypes contribute to the AD risk through involvement in amyloid-β deposition on in vivo imaging, but not in tau pathology, brain atrophy, or decreased glucose metabolism.
The pooled effect of ABCA7rs3764605 allele G was significantly associated with an increased the risk of AD (OR=1.20, 95% CI: 1.14-1.26, P value <0.001).
Single nucleotide polymorphisms (SNPs) in and near ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, complement receptor 1 (CR1), EPHA1, EXOC3L2, FERMT2, HLA cluster (DRB5-DQA), INPP5D, MEF2C, MS4A cluster (MS4A3-MS4A6E), NME8, PICALM, PTK2B, SLC24A4, SORL1, and ZCWPW1 have been associated with Alzheimer's disease (AD) in large meta-analyses.
Recently, the largest genome-wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)-related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA.
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>).
To examine whether there is a genetic link for these diseases, we performed a case-control study in Chinese population to evaluate the association of AD genome-wide association studies top hits with both PD and cognitive function in PD, investigating 13 single-nucleotide polymorphisms in 9 genes (BIN1, CLU, ABCA7, CR1, PICALM, MS4A6A, CD33, MS4A4E, and CD2AP).
We found that loss-of-function variants in ABCA7 confer risk of Alzheimer's disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10(-13)) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10(-15)).
The effect of loss-of-function mutations on ABCA7 expression was investigated with quantitative real-time PCR in post-mortem brains of patients (n=3) and control individuals (n=4); nonsense mediated mRNA decay was investigated in lymphoblast cell lines from three predicted loss-of-function mutation carriers from the cohort of 772 patients with Alzheimer's disease.
Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aβ.
To probe for a function of ABCA7 in vivo, we crossed Abca7(-/-) mice with J20 mice, an amyloidogenic transgenic AD mouse model [B6.Cg-Tg(PDGFB-APPSwInd)20Lms/J] expressing a mutant form of human APP bearing both the Swedish (K670N/M671L) and Indiana (V717F) familial AD mutations.
In total, we identified 78 potentially damaging rare variants (frequency <1%), including ABCA7p.L400V in a family with Alzheimer's disease and LRRK2 p.R1514Q in 6 of 98 patients with Parkinson's disease (6.1%).
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.
We found that loss-of-function variants in ABCA7 confer risk of Alzheimer's disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10(-13)) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10(-15)).
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.