6/25/2023 0 Comments Install xlstat biomed![]() Recently, the APOE isoforms are shown to differentially modulate the cellular uptake of Aβ mediated by sortilin related receptor 1 (LR11/SorLA). In contrast, the APOE ε2 allele appears to decrease AD risk. Possession of the APOE ε4 allele, the strong genetic factor for AD, facilitates the Aβ deposition from the presymptomatic stage of AD in a gene-dosage-dependent manner. The APOE isoforms, E2, E3 and E4, are metabolically distinct and differ in their affinity for lipoprotein particles and low-density lipoprotein receptors. The biological activity of APOE can be altered by modification of its structure. Apolipolipoprotein E maintains affinity for receptors involved in the clearance of remnants of very low density lipoproteins. Notably, it was ascertained that sole rs429358 is the most common AD-associated variant.ĪPOE gene encodes a plasma apolipoprotein protein E that plays a prominent role in lipid metabolism and cholesterol transport in human tissues. In particular, APOE ε2 represents the major rs429358 variant and minor rs7412 variant (TT haplotype, correspondingly), while APOE ε3 is presented by (TC) and APOE ε4 by (CC) haplotypes. rs429358 at codon 112 and rs7412 at codon 158, determine the genotype of APOE for ε2, ε3, and ε4 protein isoforms. ![]() Two missense nucleotide polymorphisms (SNPs) of APOE, i.e. Since 1993, the highly significant association of AD with APOE ε4 allele has been demonstrated for various ethnic populations. Importantly, the whole genome sequencing (WGS) has also been performed for > 800 subjects in ADNI cohort, including AD-patients, individuals with Mild Cognitive Impairment (MCI) and healthy control individuals (CT) (Materials and methods). To date, the significant progress has been made for neuroimaging of the ADNI subjects and in identifying potentially predictive biomarkers for AD. Since its conception in 2004, Alzheimer’s Disease Neuroimaging Initiative (ADNI, ) has been searching for associations between MRI brain profiles, biomarkers and clinical symptoms. ![]() Although it is thought to be caused by progressive accumulation of diffuse and neuritic extracellular amyloid plaques and intracellular neurofibrillary tangles in the brains of AD patients, the etiological mechanisms underlying the neurodegeneration process remain unclear. ![]() 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.Īlzheimer’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. We 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. 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. Haplotypic inference revealed alleles that may confer protection against AD. The common European ε4-bearing haplotype is associated with AD but not with MCI, and the Africans lack this haplotype. 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. We performed APOE gene haplotype analysis for a short block of five SNPs across the gene using the ADNI whole genome sequencing dataset. 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. 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. APOE ε4 allele is most common genetic risk factor for Alzheimer’s disease (AD) and cognitive decline.
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