Association between polymorphisms in the promoter region of the apolipoprotein E (APOE) gene and Alzheimer’s disease: a meta-analysis

Xiao, Haibo; Gao, Yuan; Liu, Lei; Li, Yan

doi:10.17179/excli2017-289

Cited by 9 publications

(2 citation statements)

References 61 publications

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“…The rs439401 variant considered in the current study has previously been investigated with regard to AD risk in different contexts and using variable strategies and study designs [ 8 – 11 , 13 ]. Our analyses however considered a substantially larger sample size, essentially incorporating most European ancestry AD cohorts included in prior studies, specifically focused on evaluating effects stratified to respective APOE genotypes, and tested only directly genotyped variants.…”

Section: Discussionmentioning

confidence: 99%

Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping

et al. 2022

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Background Genetic variants within the APOE locus may modulate Alzheimer’s disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE. Methods We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches. Results Using more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost. Conclusions We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.

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Section: Discussionmentioning

confidence: 99%

Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping

et al. 2022

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“…These modifications can exacerbate or mitigate AD pathology by regulating the transcriptional activity of genes implicated in Aβ deposition and tau pathology. Furthermore, genetic factors, such as polymorphisms in the apolipoprotein E (APOE) gene, have been well-documented to affect the risk of developing AD[ 145 ]. The APOE E4 allele is the strongest genetic risk factor for sporadic AD, influencing Aβ aggregation and clearance.…”

Section: Molecular Mechanisms Linking Ir To Admentioning

confidence: 99%

Insulin resistance as the molecular link between diabetes and Alzheimer's disease

Abdalla

2024

World J Diabetes

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Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies have indicated a possible link between DM and an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays a vital role in protecting brain functions. Insulin resistance (IR), especially prevalent in type 2 diabetes, is believed to play a significant role in AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various brain functions, making individuals more susceptible to AD's defining features, such as the buildup of beta-amyloid plaques and tau protein tangles. Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD. This review aims to explore the rela-tionship between DM and AD, with a focus on the role of IR. It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR. Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.

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A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward

Belloy

Napolioni

Greicius

2019

Neuron

408

354

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Alzheimer's disease (AD) is considered a polygenic disorder. This view is clouded, however, by lingering uncertainty over how to treat the quasi ''monogenic'' role of apolipoprotein E (APOE). The APOE4 allele is not only the strongest genetic risk factor for AD, it also affects risk for cardiovascular disease, stroke, and other neurodegenerative disorders. This review, based mostly on data from human studies, ranges across a variety of APOE-related pathologies, touching on evolutionary genetics and risk mitigation by ethnicity and sex. The authors also address one of the most fundamental question pertaining to APOE4 and AD: does APOE4 increase AD risk via a loss or gain of function? The answer will be of the utmost importance in guiding future research in AD. (A) The three main APOE isoforms APOE2, APOE3, and APOE4, respectively, encoded by the Apolipoprotein E2, E3, and E4 alleles, are the result of non-synonymous polymorphisms that cause amino acid changes at position 112 and 158 of the APOE protein (Rall et al., 1982; Weisgraber et al., 1981). APOE3 is the most common variant in the general population. The APOE4 variant is a major genetic risk factor for AD, while APOE2 is protective (Farrer et al., 1997). (B) Structural models of lipid-free APOE are shown for each major isoform, based on X-ray crystallography, structure prediction, and circular dichroism spectroscopy (Zhong and Weisgraber, 2009). The N-terminal domain contains APOE's low-density lipoprotein receptor (LDLR) region at amino acid residues 134-150, while the C-terminal holds the lipid-binding region at residues 244-272. Amino acid substitutions in APOE4 promote a salt bridge between Arg61 and Glu255, which, compared to the APOE2 and APOE3 variants, drives increased domain interaction between the N-and C-terminal domains. In (A), APOE allele frequencies are obtained, with permission, from American

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Association between polymorphisms in the promoter region of the apolipoprotein E (APOE) gene and Alzheimer’s disease: a meta-analysis

Cited by 9 publications

References 61 publications

Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping

Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping

Insulin resistance as the molecular link between diabetes and Alzheimer's disease

A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward

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