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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02931-w

摘要内容如下：

本研究旨在评估ApoE4纯合子对阿尔茨海默病（AD）的影响，通过检测其临床、病理和生物标志物的变化，以确定ApoE4纯合子是否构成一种独特的、遗传决定的AD形式。我们分析了来自国家阿尔茨海默病协调中心和五个大型队列的AD生物标志物数据。该分析包括病理研究的3，297人和临床研究的10，039人。研究结果显示，与ApoE3纯合子相比，几乎所有的ApoE4纯合子都表现出AD病理，并且从55岁开始具有显著更高水平的AD生物标志物。到65岁时，几乎所有人的脑脊液中淀粉样蛋白水平都异常，75%的人淀粉样蛋白扫描阳性，这些标记物的患病率随着年龄的增长而增加，表明ApoE4纯合子中AD生物学几乎完全外显。ApoE4纯合子的发病年龄较早，为65.1岁，95%预测区间较ApoE3纯合子窄。在ApoE4纯合子中，症状发作的可预测性和生物标志物变化的顺序反映了常染色体显性AD和唐氏综合征。然而，在痴呆阶段，尽管早期的临床和生物标志物发生了变化，但不同单倍型的淀粉样蛋白或Tau正电子发射断层扫描没有差异。该研究的结论是，ApoE4纯合子代表了AD的一种遗传形式，提示需要个体化的预防策略、临床试验和治疗。

英文原文如下：

Abstracts

This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer's disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer's Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.

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