Genetic risk score modifies the effect of <i>APOE</i> on risk and age onset of Alzheimer's disease

Shi, Zhuqing; Yu, Hongjie; Wu, Yishuo; Ford, Madison; Perschon, Chelsea; Wang, Chi‐Hsiung; Zheng, S. Lilly; Xu, Jianfeng

doi:10.1111/cge.13479

Cited by 5 publications

(3 citation statements)

References 42 publications

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“…Our PRS builds upon a rich foundation of previous AD PRSs, with nearly twenty studies expressing significant ability of the PRS to discern AD [ 8 , 34 , 35 ]. Four of these studies have also utilized a cohort approach: (1) Chouraki et al used eight prospective cohorts from the IGAP consortia, a mix of varying types of cohort studies including the Rotterdam study; [ 36 ] (2) Tan et al examined the PRS in a clinical cohort; [ 37 ] and (3) finally two studies by Ahmad et al and Van der Lee et al utilized the community-based Rotterdam cohort study [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Prediction of clinical diagnosis of Alzheimer’s disease, vascular, mixed, and all-cause dementia by a polygenic risk score and APOE status in a community-based cohort prospectively followed over 17 years

et al. 2020

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The strongest genetic risk factor for Alzheimer’s disease (AD) is the ε4 allele of Apolipoprotein E (APOE) and recent genome-wide association meta-analyses have confirmed additional associated genetic loci with smaller effects. The aim of this study was to investigate the ability of an AD polygenic risk score (PRS) and APOE status to predict clinical diagnosis of AD, vascular (VD), mixed (MD), and all-cause dementia in a community-based cohort prospectively followed over 17 years and secondarily across age, sex, and education strata. A PRS encompassing genetic variants reaching genome-wide significant associations to AD (excluding APOE) from the most recent genome-wide association meta-analysis data was calculated and APOE status was determined in 5203 participants. During follow-up, 103, 111, 58, and 359 participants were diagnosed with AD, VD, MD, and all-cause dementia, respectively. Prediction ability of AD, VD, MD, and all-cause dementia by the PRS and APOE was assessed by multiple logistic regression and receiver operating characteristic curve analyses. The PRS per standard deviation increase in score and APOE4 positivity (≥1 ε4 allele) were significantly associated with greater odds of AD (OR, 95% CI: PRS: 1.70, 1.45–1.99; APOE4: 3.34, 2.24–4.99) and AD prediction accuracy was significantly improved when adding the PRS to a base model of age, sex, and education (ASE) (c-statistics: ASE, 0.772; ASE + PRS, 0.810). The PRS enriched the ability of APOE to discern AD with stronger associations than to VD, MD, or all-cause dementia in a prospective community-based cohort.

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Section: Discussionmentioning

confidence: 99%

Prediction of clinical diagnosis of Alzheimer’s disease, vascular, mixed, and all-cause dementia by a polygenic risk score and APOE status in a community-based cohort prospectively followed over 17 years

et al. 2020

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“…While the ApoE2 allele reduces the chance to develop LOAD, one copy of the ApoE4 variant elevates the risk for AD up to three-fold, while ApoE4 homozygosity increases this further to a 12 times higher risk [127]. These are population-based values, which may deviate from an individual-level risk one has regarding the cumulative effect of SNPs in a person’s genome [128, 129]. Notwithstanding, the ApoE2 allele keeps getting ascribed with a beneficial/protective effect that may in part be attributed to a recently discovered impact of glial-secreted ApoE on the activation of surface ApoE receptors [130].…”

Section: Alterations Of Endosomal Functions Related To Apoe and Trem2mentioning

confidence: 99%

Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors

Acker

Bretou

Annaert

2019

Mol Neurodegeneration

158

136

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Increasing evidence supports that cellular dysregulations in the degradative routes contribute to the initiation and progression of neurodegenerative diseases, including Alzheimer’s disease. Autophagy and endolysosomal homeostasis need to be maintained throughout life as they are major cellular mechanisms involved in both the production of toxic amyloid peptides and the clearance of misfolded or aggregated proteins. As such, alterations in endolysosomal and autophagic flux, as a measure of degradation activity in these routes or compartments, may directly impact as well on disease-related mechanisms such as amyloid-β clearance through the blood-brain-barrier and the interneuronal spreading of amyloid-β and/or Tau seeds, affecting synaptic function, plasticity and metabolism. The emerging of several genetic risk factors for late-onset Alzheimer’s disease that are functionally related to endocytic transport regulation, including cholesterol metabolism and clearance, supports the notion that in particular the autophagy/lysosomal flux might become more vulnerable during ageing thereby contributing to disease onset. In this review we discuss our current knowledge of the risk genes APOE4, BIN1, CD2AP, PICALM, PLD3 and TREM2 and their impact on endolysosomal (dys)regulations in the light of late-onset Alzheimer’s disease pathology. Electronic supplementary material The online version of this article (10.1186/s13024-019-0323-7) contains supplementary material, which is available to authorized users.

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“…Many risk factors have been reported to be associated with AD such as Aβ and tau [8,9]. The other investigations have found ε4 allele of the apolipoprotein E gene (APOEε4+) as a risk genetic factor for AD dementia and MCI [10][11][12]. However, it was found to be a significant risk factor for AD dementia rather than for MCI [13].…”

Section: Introductionmentioning

confidence: 99%

Exploring APOE Epsilon4 Genotype to Predict MCI-to-AD Dementia: A Meta- Analysis

JuanYang¹,

Zhao²,

Sui

et al. 2020

BJSTR

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Background: APOE4 have been considered as the risk of AD, but the predict value of MCI progressing to AD was not clear. Objective:The aim of the current study was to investigate the predictive-value of APOE4+ in the development of Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD) using a meta-analysis.Methods: At PubMed, Elsevier Science Direct, Scihub and Google Scholar we searched all the previous cohort studies on APOE4+ genotype associated with the risk of MCI-to-AD dementia, published before January 1, 2019. Stata Meta-DiSc (version 1.4) software was used to pool the APOE4+ prognosis data to examine the sensitivity, specificity and the summary receiver operating characteristic curve (SROC) in predicting the risk MCI-to-AD dementia; Stata software, to calculate the relative risk (RR) and 95% CIs.Results: For the meta-analysis were involved 43 previously reported studies, where it was found that in MCI people aged ≥70, who had progressed to AD dementia within 5 years, the APOE4+ predictive sensitivity was 0.71; the specificity, 0.71; and AUC, 0.78. Moreover, the results showed that RR was 1.49 and 1.56, respectively, for MCI people in general and for MCI people aged ≥70 and with the risk of APOE4+-to-AD. Particularly, the RR was 2.24 for the individuals aged ≥70 and with APOE4+ who progressed to AD dementia within 5 years. Conclusion:The findings strongly suggested that it could take less than 5 years for MCI people aged ≥70 and with the gene of APOE4 to progress to AD dementia.

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Genetic risk score modifies the effect of APOE on risk and age onset of Alzheimer's disease

Cited by 5 publications

References 42 publications

Prediction of clinical diagnosis of Alzheimer’s disease, vascular, mixed, and all-cause dementia by a polygenic risk score and APOE status in a community-based cohort prospectively followed over 17 years

Prediction of clinical diagnosis of Alzheimer’s disease, vascular, mixed, and all-cause dementia by a polygenic risk score and APOE status in a community-based cohort prospectively followed over 17 years

Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors

Exploring APOE Epsilon4 Genotype to Predict MCI-to-AD Dementia: A Meta- Analysis

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