Abstract
Genome-wide associations studies (GWAS) are detecting new variants associated with late-onset of Alzheimer’s disease (LOAD), a multifactorial neurodegenerative disorder. The variants rs744373 BIN1, rs11136000 CLU and rs3764650 ABCA7 uncovered by GWAS led to different AD pathways, such as metabolism, trafficking and endocytosis of lipids and inflammation. However, most of the association studies did not replicate these variants with significance. This could be due to a small power effect evident when these variants are tested independently with LOAD. Therefore, we aimed to investigate whether the combination of different variants would additively modify the risk of association with LOAD that is observed in GWAS. We performed an association study testing pairwise variants in metabolism, trafficking and endocytosis of lipid (rs429358 and rs7412 APOE, rs744373 BIN1, rs3764650 ABCA7 and rs11136000 CLU) pathways with LOAD in samples from southeastern Brazil. Our data suggest a risk effect for LOAD between APOE with CLU and APOE with BIN1 genes.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease that affects millions of elders globally (Prince et al, 2016)
No association was observed for late-onset AD (LOAD) for the G allele in ATP-binding cassette transporter A7 (ABCA7), the T allele in CLU and the C allele in Bridging integrator 1 (BIN1) genes
The presence of the e4 allele in apolipoprotein E (APOE) alone was associated with LOAD in the absence of the minor G allele ABCA7 (p < 0.001), the absence of the minor C allele in BIN1 (p < 0.001) and the T allele in CLU (p=0.030), after p-value adjustment
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease that affects millions of elders globally (Prince et al, 2016). Early-onset AD (EOAD), accounts for 2% of AD cases and occurs before 65 years. EOAD has Mendelian patterns of inheritance, with mutations in APP (amyloid precursor protein), PSEN1 (presenilin 1) and PSEN2 (presenilin 2) genes (Bertram et al, 2010; Holtzman et al, 2011). Unlike EOAD, late-onset AD (LOAD) has a multifactorial pattern, with influence of genetic and environmental factors. It occurs after 65 years and accounts for 98% of AD cases (Yu et al, 2014). The e4 allele in the apolipoprotein E (APOE) gene is considered a major risk factor for LOAD worldwide (Lambert and Amouyel, 2011)
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