Abstract
BackgroundAPOE ε4 allele is most common genetic risk factor for Alzheimer’s disease (AD) and cognitive decline. However, it remains poorly understood why only some carriers of APOE ε4 develop AD and how ethnic variabilities in APOE locus contribute to AD risk. Here, to address the role of APOE haplotypes, we reassessed the diversity of APOE locus in major ethnic groups and in Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset on patients with AD, and subjects with mild cognitive impairment (MCI), and control non-demented individuals.ResultsWe performed APOE gene haplotype analysis for a short block of five SNPs across the gene using the ADNI whole genome sequencing dataset. The compilation of ADNI data with 1000 Genomes identified the APOE ε4 linked haplotypes, which appeared to be distant for the Asian, African and European populations. The common European ε4-bearing haplotype is associated with AD but not with MCI, and the Africans lack this haplotype. Haplotypic inference revealed alleles that may confer protection against AD. By assessing the DNA methylation profile of the APOE haplotypes, we found that the AD-associated haplotype features elevated APOE CpG content, implying that this locus can also be regulated by genetic-epigenetic interactions.ConclusionsWe showed that SNP frequency profiles within APOE locus are highly skewed to population-specific haplotypes, suggesting that the ancestral background within different sites at APOE gene may shape the disease phenotype. We propose that our results can be utilized for more specific risk assessment based on population descent of the individuals and on higher specificity of five site haplotypes associated with AD.
Highlights
APOE ε4 allele is most common genetic risk factor for Alzheimer’s disease (AD) and cognitive decline
The primary goal of Alzheimer’s Disease Neuroimaging Initiative (ADNI) was to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer’s disease (AD)
Analysis of Single nucleotide polymorphisms (SNPs) frequencies in APOE gene revealed that only five of them are common in human population with frequency > 5% (Fig. 1, Table 2)
Summary
APOE ε4 allele is most common genetic risk factor for Alzheimer’s disease (AD) and cognitive decline. It remains poorly understood why only some carriers of APOE ε4 develop AD and how ethnic variabilities in APOE locus contribute to AD risk. To address the role of APOE haplotypes, we reassessed the diversity of APOE locus in major ethnic groups and in Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset on patients with AD, and subjects with mild cognitive impairment (MCI), and control non-demented individuals. Alzheimer’s disease (AD) is the most frequent case of dementia worldwide, which is manifested by a progressive decline in cognitive function due to loss of neurons, white matter, and synapses. It was ascertained that sole rs429358 is the most common AD-associated variant
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