Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants.

中文翻译：

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从常见变种到罕见变种：阿尔茨海默氏病的遗传成分。

阿尔茨海默病（AD）是遗传异质性的一个典型例子。APP，PSEN1或PSEN2基因中的极为罕见的变体，或APP基因的重复会导致常染色体显性形式，通常在65岁时具有完全的外显率。无论发病年龄如何，非常染色体显性遗传形式都被认为是具有高遗传成分的复杂疾病。尽管遗传上异质，但AD在所有配置中均由相同的神经病理学标准定义。根据淀粉样蛋白级联假说，在AD脑中聚集的Aβ肽是关键参与者。APP，PSEN1或PSEN2基因突变增加了Aβ肽的更多聚集倾向形式的产生，从而触发了病理过程。关联研究中发现的几种危险因素会影响参与Aβ产生/分泌的基因，聚集，清除或毒性。其中，APOEε4等位基因是常见等位基因的罕见例子，其影响大小很大，杂合子和纯合子携带者的OR分别为4至11-14。此外，全基因组关联研究已鉴定出两个以上的关联弱而显着的基因座，高风险等位基因的OR范围为1.08至1.30。最近，大规模并行测序的使用使得能够以全基因组的方式分析稀有变体。名义上有两种罕见的变体与AD风险或保护有关（TREM2 p.R47H，MAF约为0.002，或约4； APP p.A673T，MAF约为0.0005，或约0.2）。在基因水平上的关联分析确定了罕见的功能丧失和错义，预测的破坏性变异（MAF <0。01）中的SORL1和ABCA7基因与中等相对风险（或分别为约5和约2.8）相关。尽管后者的分析通过折叠使它们揭示了具有中等稀有变体的关联信号，但是检测极其稀有变体命中的基因的能力仍然有限。另一种方法是考虑从头范例，指出从头变异可能会导致散发性患者的AD遗传。在这里，我们批判性地回顾了AD遗传学报告，重点关注稀有变体。另一种方法是考虑从头范例，指出从头变异可能会导致散发性患者的AD遗传。在这里，我们批判性地回顾了AD遗传学报告，重点关注稀有变体。另一种方法是考虑从头范例，指出从头变异可能会导致散发性患者的AD遗传。在这里，我们批判性地回顾了AD遗传学报告，重点关注稀有变体。