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

Celeste M Karch,Amanda T Jeng,Janet Cady,Alison M Goate,Carlos Cruchaga,Petra Nowotny,Stephen D Ginsberg

doi:10.1371/journal.pone.0050976

Celeste M Karch, Amanda T Jeng + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0050976

Copy DOI

Journal: PloS one	Publication Date: Nov 30, 2012
Citations: 327	License type: CC BY 4.0

Affiliation: Hope Center for Neurological Disorders

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.

Highlights

Late onset Alzheimer’s disease (LOAD) is the most common form of dementia
In recent efforts to identify additional genetic risk factors for LOAD, large-scale genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP) in 10 genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A4E, and PICALM [5,6,7,8,9,10]. These genes fall into several functional pathways that are affected in AD: immune response (CLU, CR1, ABCA7, MS4A family, CD33, and EPHA1), cholesterol metabolism (CLU and ABCA7), and synaptic function (PICALM, BIN1, CD33, CD2AP, and EPHA1)
ABCA7 expression was associated with clinical dementia rating (CDR) (p = 0.0304), where higher expression levels are correlated with elevated CDR (Table 2)

Summary

Introduction

Late onset Alzheimer’s disease (LOAD) is the most common form of dementia. AD is pathologically defined by extensive neuronal loss and the accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain. In recent efforts to identify additional genetic risk factors for LOAD, large-scale genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP) in 10 genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A4E, and PICALM [5,6,7,8,9,10]. These genes fall into several functional pathways that are affected in AD: immune response (CLU, CR1, ABCA7, MS4A family, CD33, and EPHA1), cholesterol metabolism (CLU and ABCA7), and synaptic function (PICALM, BIN1, CD33, CD2AP, and EPHA1)

Methods

Results

Conclusion