Dear Editor,

Research in Alzheimer’s disease (AD) has greatly benefited from the genetic studies of rare autosomal dominant mutations.¹ In a recent case study of the world’s largest early onset AD pedigree with presenilin 1 (PSEN1) mutation, an individual was identified to have a high amyloid burden but low tau measurements, and an unusually delayed onset of cognitive impairment.² Whole-exome sequencing revealed an additional rare homozygous mutation of APOE3 Christchurch (APOE3ch, R136S) as the potential protective factor for AD. APOE3 is one of variants in the Apolipoprotein E (APOE) gene, which has been extensively studied for its association with sporadic AD.³ APOE has three variants, ε2, ε3 and ε4; and APOE ε4 (APOE4) allele confers significantly increased risk for developing AD, relative to the common APOE ε3 (APOE3) allele. Exactly how different variants of APOE alter amyloid-β (Aβ) and tau pathology and neurodegeneration is an active area of research.⁴ While the identification of APOE3ch mutation opens a door for new investigations, the rarity of the APOE3ch makes it hard to study its underlying mechanisms in humans. Further, whether the APOE3ch mutation affects neuronal death and other AD pathophysiology such as neuroinflammation remains to be demonstrated.

 亲爱的编辑，

阿尔茨海默病 (AD) 的研究极大地受益于罕见常染色体显性突变的遗传学研究。 ¹最近对世界上最大的早老性阿尔茨海默病家系进行的一项案例研究中，该家系患有早老素 1 ( PSEN1 ) 突变，该个体被鉴定为淀粉样蛋白负荷高，但 tau 测量值低，并且认知障碍的发病异常延迟。 ²全外显子组测序揭示了APOE3 Christchurch 的另一个罕见纯合突变（ APOE3ch、 R136S）是 AD 的潜在保护因素。 APOE3是载脂蛋白 E ( APOE ) 基因的变体之一，该基因与散发性 AD 的关联已被广泛研究。 ³ APOE有三个变体，ε2、ε3和ε4；相对于常见的APOE ε3 ( APOE3 ) 等位基因， APOE ε4 ( APOE4 ) 等位基因显着增加患 AD 的风险。 APOE 的不同变体究竟如何改变β淀粉样蛋白 (Aβ) 和 tau 蛋白病理学以及神经退行性疾病是一个活跃的研究领域。 ⁴虽然APOE3ch突变的鉴定为新的研究打开了大门，但 APOE3ch 的稀有性使得研究其在人类中的潜在机制变得困难。此外， APOE3ch突变是否影响神经元死亡和其他 AD 病理生理学（例如神经炎症）仍有待证明。