Expression of Novel Alzheimer’s Disease Risk Genes in Control and Alzheimer’s Disease Brains

Abstract

Late onset Alzheimer’s disease (LOAD) etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS) for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs) and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR), with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains.

Factors involved in the cisplatin resistance of KCP-4 human epidermoid carcinoma cells

“…ABCA7 is reported to be associated with phospholipid transport, similar to ABCA1 (40), and is linked to Alzheimer's disease (41,42). However, to date, no report has demonstrated the association of ABCA7 with antitumor drug resistance.…”

The Evolving Biology of Microglia in Alzheimer's Disease

“…CD33 function in the CNS, however, was not well studied until a series of genome-wide association studies identified CD33 variants that modified risk for developing AD [116][117][118]. It was later shown that CD33 expression levels correlate with cognitive decline in AD patients [119], and that the protective CD33 variant reduces CD33 expression [120]. Taken together, these data suggest that CD33 promotes AD pathogenesis.…”

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

“…In addition, the effect of the 5XFAD transgene significantly altered the expression of genes known to be misregulated in AD, particularly Bin1, Cd33, Clu (Karch et al, 2012), Trem2 (Piccio et al, 2016), and C1qa (Hong et al, 2016), Figure 1F. However, the impact of causal FAD mutations on cognitive performance and risk gene expression varied widely depending on the specific background strain evaluated.…”