阿尔茨海默病中的保护性变异体。
Protective Variants in Alzheimer's Disease.
作者信息
Andrews Shea J, Fulton-Howard Brian, Goate Alison
机构信息
Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Equal first author.
出版信息
Curr Genet Med Rep. 2019 Mar;7(1):1-12. doi: 10.1007/s40142-019-0156-2. Epub 2019 Jan 24.
Abstract
PURPOSE OF REVIEW
Over the last decade over 40 loci have been associated with risk of Alzheimer's disease (AD). However, most studies have either focused on identifying risk loci or performing unbiased screens without a focus on protective variation in AD. Here, we provide a review of known protective variants in AD and their putative mechanisms of action. Additionally, we recommend strategies for finding new protective variants.
RECENT FINDINGS
Recent Genome-Wide Association Studies have identified both common and rare protective variants associated with AD. These include variants in or near , , and .
SUMMARY
There are very few protective variants with functional evidence and a derived allele with a frequency below 20%. Additional fine mapping and multi-omic studies are needed to further validate and characterize known variants as well as specialized genome-wide scans to identify novel variants.
摘要
综述目的
在过去十年中，超过40个基因座与阿尔茨海默病（AD）风险相关。然而，大多数研究要么专注于识别风险基因座，要么进行无偏筛选，而没有关注AD中的保护性变异。在此，我们对AD中已知的保护性变异及其假定作用机制进行综述。此外，我们推荐寻找新的保护性变异的策略。
最新发现
最近的全基因组关联研究已经鉴定出与AD相关的常见和罕见保护性变异。这些包括位于 、 及 内或附近的变异。
总结
具有功能证据且衍生等位基因频率低于20%的保护性变异非常少。需要进一步的精细定位和多组学研究来进一步验证和表征已知变异，以及进行专门的全基因组扫描以识别新变异。
相似文献
1
Protective Variants in Alzheimer's Disease.阿尔茨海默病中的保护性变异体。
Curr Genet Med Rep. 2019 Mar;7(1):1-12. doi: 10.1007/s40142-019-0156-2. Epub 2019 Jan 24.
2
Genetics of Alzheimer's disease.阿尔茨海默病的遗传学
Adv Genet. 2014;87:245-94. doi: 10.1016/B978-0-12-800149-3.00005-6.
3
Late-Onset Alzheimer's Disease Genes and the Potentially Implicated Pathways.迟发性阿尔茨海默病基因及潜在相关通路
Curr Genet Med Rep. 2014 Mar 22;2(2):85-101. doi: 10.1007/s40142-014-0034-x. eCollection 2014.
4
Alzheimer's disease risk genes and mechanisms of disease pathogenesis.阿尔茨海默病风险基因与疾病发病机制
Biol Psychiatry. 2015 Jan 1;77(1):43-51. doi: 10.1016/j.biopsych.2014.05.006. Epub 2014 May 17.
5
ABCA7 p.G215S as potential protective factor for Alzheimer's disease.ABCA7基因p.G215S位点作为阿尔茨海默病的潜在保护因素。
Neurobiol Aging. 2016 Oct;46:235.e1-9. doi: 10.1016/j.neurobiolaging.2016.04.004. Epub 2016 Apr 20.
6
Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome.唐氏综合征成年患者中sortilin相关受体1（SORL1）基因变异与阿尔茨海默病之间的关联。
Neurosci Lett. 2007 Sep 25;425(2):105-9. doi: 10.1016/j.neulet.2007.08.042. Epub 2007 Aug 25.
7
A novel Alzheimer disease locus located near the gene encoding tau protein.一个位于编码tau蛋白基因附近的新型阿尔茨海默病基因座。
Mol Psychiatry. 2016 Jan;21(1):108-17. doi: 10.1038/mp.2015.23. Epub 2015 Mar 17.
8
Investigating APOE, APP-Aβ metabolism genes and Alzheimer's disease GWAS hits in brain small vessel ischemic disease.探讨载脂蛋白 E（APOE）、淀粉样前体蛋白（APP）-β 代谢基因与脑小血管缺血性疾病阿尔茨海默病全基因组关联研究（GWAS）研究热点的关系。
Sci Rep. 2020 Apr 28;10(1):7103. doi: 10.1038/s41598-020-63183-5.
9
Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy.与阿尔茨海默病相关的致病性SORL1基因变异的特征分析：一种临床解读策略。
Eur J Hum Genet. 2017 Aug;25(8):973-981. doi: 10.1038/ejhg.2017.87. Epub 2017 May 24.
10
Association of GWAS-linked loci with late-onset Alzheimer's disease in a northern Han Chinese population.GWAS 连锁位点与北方汉族人群晚发性阿尔茨海默病的关联。
Alzheimers Dement. 2013 Sep;9(5):546-53. doi: 10.1016/j.jalz.2012.08.007. Epub 2012 Dec 8.
引用本文的文献
1
Biobank-scale genetic characterization of Alzheimer's disease and related dementias across diverse ancestries.阿尔茨海默病及相关痴呆症在不同种族中的生物样本库规模基因特征分析。
Nat Commun. 2025 Aug 14;16(1):7554. doi: 10.1038/s41467-025-62108-y.
2
Driving research on successful aging and neuroprotection in Latin America: Insights from the inaugural symposium on brain resilience and healthy longevity.推动拉丁美洲成功老龄化与神经保护研究：首届脑韧性与健康长寿研讨会的见解
Alzheimers Dement. 2025 Mar;21(3):e70037. doi: 10.1002/alz.70037.
3
A comprehensive interpretable machine learning framework for mild cognitive impairment and Alzheimer's disease diagnosis.用于轻度认知障碍和阿尔茨海默病诊断的综合可解释机器学习框架。
Sci Rep. 2025 Mar 11;15(1):8410. doi: 10.1038/s41598-025-92577-6.
4
Biobank-scale characterization of Alzheimer's disease and related dementias identifies potential disease-causing variants, risk factors, and genetic modifiers across diverse ancestries.阿尔茨海默病及相关痴呆症的生物样本库规模特征分析确定了不同血统中潜在的致病变异、风险因素和基因修饰因子。
medRxiv. 2024 Nov 17:2024.11.03.24313587. doi: 10.1101/2024.11.03.24313587.
5
Genetic-based patient stratification in Alzheimer's disease.基于遗传的阿尔茨海默病患者分层。
Sci Rep. 2024 Apr 30;14(1):9970. doi: 10.1038/s41598-024-60707-1.
6
The LRRK2 kinase substrates RAB8a and RAB10 contribute complementary but distinct disease-relevant phenotypes in human neurons.富含亮氨酸重复激酶2（LRRK2）的激酶底物RAB8a和RAB10在人类神经元中呈现出互补但不同的疾病相关表型。
Stem Cell Reports. 2024 Feb 13;19(2):163-173. doi: 10.1016/j.stemcr.2024.01.001. Epub 2024 Feb 1.
7
Alzheimer's Disease: Models and Molecular Mechanisms Informing Disease and Treatments.阿尔茨海默病：为疾病与治疗提供信息的模型和分子机制
Bioengineering (Basel). 2024 Jan 1;11(1):45. doi: 10.3390/bioengineering11010045.
8
Biomarker Genes Discovery of Alzheimer's Disease by Multi-Omics-Based Gene Regulatory Network Construction of Microglia.基于小胶质细胞多组学基因调控网络构建的阿尔茨海默病生物标志物基因发现
Brain Sci. 2022 Sep 5;12(9):1196. doi: 10.3390/brainsci12091196.
9
Strategies to gain novel Alzheimer's disease diagnostics and therapeutics using modulators of ABCA transporters.利用ABCA转运蛋白调节剂获取新型阿尔茨海默病诊断方法和治疗手段的策略。
Free Neuropathol. 2021;2:33. doi: 10.17879/freeneuropathology-2021-3528. Epub 2021 Dec 13.
10
Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics.用于预测新型阿尔茨海默病治疗药物的ABCA7结合模式分析
Comput Struct Biotechnol J. 2021 Nov 27;19:6490-6504. doi: 10.1016/j.csbj.2021.11.035. eCollection 2021.
本文引用的文献
1
Alzheimer's disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph.阿尔茨海默病磷脂酶 C-γ-2 (PLCG2) 保护性变体是一种功能超变体。
Alzheimers Res Ther. 2019 Feb 2;11(1):16. doi: 10.1186/s13195-019-0469-0.
2
A Brief Synopsis on the Genetics of Alzheimer's Disease.阿尔茨海默病遗传学简述
Curr Genet Med Rep. 2018;6(4):133-135. doi: 10.1007/s40142-018-0155-8. Epub 2018 Oct 30.
3
Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer's disease.配对免疫球蛋白样受体 2 型α G78R 变体改变配体结合并赋予阿尔茨海默病保护作用。
PLoS Genet. 2018 Nov 2;14(11):e1007427. doi: 10.1371/journal.pgen.1007427. eCollection 2018 Nov.
4
Neuroprotective effect of naturally occurring RXR agonists isolated from Sophora tonkinensis Gagnep. on amyloid-β-induced cytotoxicity in PC12 cells.从苦参中分离出的天然 RXR 激动剂对 PC12 细胞中淀粉样β诱导的细胞毒性的神经保护作用。
J Nat Med. 2019 Jan;73(1):154-162. doi: 10.1007/s11418-018-1257-z. Epub 2018 Oct 30.
5
Clinical phenotype, atrophy, and small vessel disease in ε2 carriers with Alzheimer disease.阿尔茨海默病 ε2 携带者的临床表型、萎缩和小血管疾病。
Neurology. 2018 Nov 13;91(20):e1851-e1859. doi: 10.1212/WNL.0000000000006503. Epub 2018 Oct 19.
6
Role of Rab GTPases in Alzheimer's Disease.Rab GTPases 在阿尔茨海默病中的作用。
ACS Chem Neurosci. 2019 Feb 20;10(2):828-838. doi: 10.1021/acschemneuro.8b00387. Epub 2018 Oct 11.
7
Regulatory roles of vertebrate Nocturnin: insights and remaining mysteries.脊椎动物 Nocturnin 的调控作用：研究进展与未解之谜
RNA Biol. 2018;15(10):1255-1267. doi: 10.1080/15476286.2018.1526541. Epub 2018 Oct 9.
8
Association of the Polymorphisms and Plasma Level of CHI3L1 with Alzheimer's Disease in the Chinese Han Population: A Case-Control Study.中国汉族人群 CHI3L1 多态性与阿尔茨海默病的关联：病例对照研究。
Neuropsychobiology. 2019;77(1):29-37. doi: 10.1159/000492536. Epub 2018 Sep 17.
9
Absolute 10-year risk of dementia by age, sex and genotype: a population-based cohort study.基于人群的队列研究：按年龄、性别和基因型划分的痴呆绝对 10 年风险。
CMAJ. 2018 Sep 4;190(35):E1033-E1041. doi: 10.1503/cmaj.180066.
10
Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.全外显子组测序研究鉴定出新型罕见和常见的与阿尔茨海默病相关的变异，这些变异参与免疫反应和转录调控。
Mol Psychiatry. 2020 Aug;25(8):1859-1875. doi: 10.1038/s41380-018-0112-7. Epub 2018 Aug 14.
Zotero 插件