The proportion of Alzheimer disease attributable to apolipoprotein E
The proportion of Alzheimer disease attributable to apolipoprotein E
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载脂蛋白 E 导致阿尔茨海默病的比例
DOI：
10.1101/2023.11.16.23298475
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Williams D
中科院分区：
文献类型：
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作者：
Williams D
目的在三项独立队列研究和一项病例对照研究中，估计APOE基因设计中常见风险等位基因ε3和ε4导致的阿尔茨海默病（AD）和全因痴呆负担的比例。（UK Biobank，FinnGen）; A4研究（一项多国随机临床试验）的干预前受试者队列; AD病例对照样本来自美国阿尔茨海默病基因组学联盟（ADGC），年龄≥60岁的队列来自英国生物银行（n= 171，128）和FinnGen（n= 279，036）。在A4中招募了具有基线神经影像学的认知正常的试验招募者，年龄为65至85岁（n= 4，415）。ADGC中死亡的AD病例和对照（平均年龄<82岁; n= 5，007）主要结局临床诊断为AD和全因痴呆，主要或完全通过健康记录联系确定（UK Biobank，FinnGen）;通过正电子发射断层扫描神经成像确定的脑淀粉样变性（A4）;尸检时神经病理学证实的AD（ADGC）。（95%可信区间：37.3%~ 89.0%）的AD和37.8%（9.1%~ 57.4%）的全因痴呆可归因于ε3和ε4携带的组合。在FinnGen中，AD的估计值为64.4%（45.1%至76.6%），全因痴呆的估计值为42.4%（25.0%至55.4%）。在A4研究中，85.1%（19.2%-93.9%）的脑淀粉样变性可归因于ε3和ε4。在ADGC数据中，92.7%（81.4%~ 96.5%）的AD可归因于ε3和ε4，其中ε4占56.9%（36.0%~ 63.0%），ε3占35.8%（22.1%~ 58.3%）。载脂蛋白E（apoE）是晚发性AD的主要病因。鉴于apoE作为AD预防和治疗靶点的巨大潜力，应优先考虑对apoE的研究。研究摘要关于该主题的已知内容AD预防和治疗的治疗策略尚不清楚，最近的疾病修饰疗法的疗效不确定APOE的变异是AD的一个公认决定因素，然而，在过去的流行病学研究中，它对人群疾病负担的贡献被错误地计算，并且仍然知之甚少。通过干预载脂蛋白E的表达或功能，可以在多大程度上预防这种疾病。这项研究补充说：我们表明，大多数AD可归因于APOEA的ε3和ε4等位基因，大部分AD是由ε3特异性引起的。减轻载脂蛋白E的有害作用将预防大多数AD和大部分全因痴呆。研究人员和资助者应该优先考虑实现这一目标。
ObjectiveTo estimate the proportions of Alzheimer’s disease (AD) and all-cause dementia burden attributable to the common risk alleles ε3 and ε4 in theAPOEgeneDesignGenetic association analyses in three independent cohort studies and one case-control studySettingsNational cohorts in the UK and Finland (UK Biobank, FinnGen); a pre-intervention cohort of participants in the A4 Study, a multi-national randomised clinical trial; AD case-control samples from the Alzheimer’s Disease Genomics Consortium (ADGC) in the U.S.ParticipantsCohorts aged ≥60 years in UK Biobank (n=171,128) and FinnGen (n=279,036). Cognitively normal trial recruits with baseline neuroimaging aged 65 to 85 years in A4 (n=4,415). Deceased AD cases and controls in ADGC (mean age ∼ 82 years; n=5,007)Main outcomesClinically diagnosed AD and all-cause dementia, principally or exclusively ascertained through health record linkages (UK Biobank, FinnGen); Cerebral amyloidosis ascertained through Positron Emission Tomography neuroimaging (A4); AD neuropathologically confirmed at autopsy (ADGC).ResultsIn UKB, 73.9% (95% confidence interval: 37.3% to 89.0%) of AD and 37.8% (9.1% to 57.4%) of all-cause dementia were attributable to a combination of ε3 and ε4 carriage. In FinnGen, estimates were 64.4% (45.1% to 76.6%) for AD and 42.4% (25.0% to 55.4%) for all-cause dementia. In the A4 study, 85.1% (19.2% to 93.9%) of cerebral amyloidosis was attributable to ε3 and ε4. In the ADGC data, 92.7% (81.4% to 96.5%) of neuropathologically confirmed AD was attributable to ε3 and ε4, with ε4 accounting for 56.9% (36.0% to 63.0%) and ε3 for 35.8% (22.1% to 58.3%).ConclusionsWithout the strong risk-increasing effects of bothAPOEε3 and ε4, most AD would not occur. Apolipoprotein E (apoE) predominates late-onset AD’s causes. Research into apoE should be prioritised given its major potential as a target for AD prevention and treatment.Research SummaryWhat is already known on this topicTherapeutic strategies for AD prevention and treatment are unclear, with the efficacy of recent disease-modifying therapeutics uncertainVariation inAPOEis a well-established determinant of AD, yet its contribution to disease burden in populations has been miscalculated in past epidemiological studies and remains poorly understood.Quantifying how much AD is caused by ε3 and ε4 indicates the full extent to which the disease could be preventable through intervening on apolipoprotein E’s expression or functionWhat this study addsWe show that most AD is attributable to the ε3 and ε4 alleles ofAPOEA large proportion of AD is caused by ε3 specificallyMitigating the detrimental effects of apolipoprotein E would prevent most AD and a large fraction of all-cause dementia. Realising this aim should be prioritised by researchers and funders.