Importance Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ɛ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce. Objective To investigate the association of the APOE ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS. Design, Setting, and Participants This dual-center cohort study recruited adults with DS in Barcelona, Spain, and in Cambridge, UK, between June 1, 2009, and February 28, 2020. Included individuals had been genotyped for APOE and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either APOE ɛ4 allele carriers or noncarriers. Main Outcomes and Measures Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: Aβ1-42, Aβ1-40, phosphorylated tau 181 (pTau181) and neurofilament light chain (NfL) in cerebrospinal fluid (CSF), pTau181, and NfL in plasma; amyloid positron emission tomography (PET); fluorine 18-labeled-fluorodeoxyglucose PET; and/or magnetic resonance imaging. Age at symptom onset was compared between APOE ɛ4 allele carriers and noncarriers, and within-group local regression models were used to compare the association of biomarkers with age. Voxelwise analyses were performed to assess topographical differences in gray matter metabolism and volume. Results Of the 464 adults with DS included in the study, 97 (20.9%) were APOE ɛ4 allele carriers and 367 (79.1%) were noncarriers. No differences between the 2 groups were found by age (median [interquartile range], 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P = .56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]). APOE ɛ4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; P = .02) and showed earlier cognitive decline. Locally estimated scatterplot smoothing curves further showed between-group differences in biomarker trajectories with age as reflected by nonoverlapping CIs. Specifically, carriers showed lower levels of the CSF Aβ1-42 to Aβ1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma pTau181, and earlier loss of cortical metabolism and hippocampal volume. No differences were found in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE ɛ4 allele carriers. Conclusions and Relevance In this study, the APOE ɛ4 allele was associated with earlier clinical and biomarker changes of AD in DS. These results provide insights into the mechanisms by which APOE increases the risk of AD, emphasizing the importance of APOE genotype for future clinical trials in DS.

中文翻译：

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载脂蛋白 E ɛ4 等位基因与唐氏综合症成人阿尔茨海默病临床和多模式生物标志物变化的关联。

重要性 阿尔茨海默病 (AD) 是导致唐氏综合症 (DS) 患者死亡的主要原因。以前的研究表明，APOE ɛ4 等位基因在 DS 痴呆发病的风险和年龄中发挥作用。然而，体内生物标志物的数据仍然稀缺。目的探讨 APOE ɛ4 等位基因与 DS 成人 AD 临床和多模式生物标志物的关系。设计、设置和参与者这项双中心队列研究在 2009 年 6 月 1 日至 2020 年 2 月 28 日期间在西班牙巴塞罗那和英国剑桥招募了患有 DS 的成年人。纳入的个体已经过 APOE 基因分型，并且至少有1 次临床或 AD 生物标志物测量；由于没有 21 三体，2 人被排除在外。参与者是 APOE ɛ4 等位基因携带者或非携带者。主要结果和措施 参与者接受了神经学和神经心理学评估。一部分参与者进行了生物标志物测量：脑脊液 (CSF) 中的 Aβ1-42、Aβ1-40、磷酸化 tau 181 (pTau181) 和神经丝轻链 (NfL)、pTau181 和血浆中的 NfL；淀粉样蛋白正电子发射断层扫描（PET）；氟18标记的氟脱氧葡萄糖PET；和/或磁共振成像。比较 APOE ɛ4 等位基因携带者和非携带者的症状发作年龄，并使用组内局部回归模型比较生物标志物与年龄的关联。进行体素分析以评估灰质代谢和体积的地形差异。结果 纳入研究的 464 名 DS 成人中，97 人（20.9%）为 APOE ɛ4 等位基因携带者，367 人（79.1%）为非携带者。在年龄（中位数[四分位距]，45.9 [36.4-50.2] 岁 vs 43.7 [34.9-50.2] 岁；P = .56）或性别（51 名男性携带者 [52.6%] vs 199男性非携带者 [54.2%]）。与非携带者相比，APOE ɛ4 等位基因携带者在较年轻时出现 AD 症状（平均 [SD] 年龄，50.7 [4.4] 岁 vs 52.7 [5.8] 岁；P = .02）并表现出较早的认知能力下降。局部估计的散点图平滑曲线进一步显示了生物标志物轨迹随年龄的组间差异，如非重叠 CI 所反映的那样。具体来说，携带者在 40 岁之前表现出较低水平的 CSF Aβ1-42 与 Aβ1-40 比率，淀粉样蛋白 PET 和血浆 pTau181 的早期增加，以及皮质代谢和海马体积的早期损失。NfL 生物标志物或 CSF 总 tau 和 pTau181 没有发现差异。Voxelwise 分析显示，APOE ɛ4 等位基因携带者皮质下和顶枕结构的代谢较低，内侧颞叶体积较低。结论和相关性 在这项研究中，APOE ɛ4 等位基因与 DS 中 AD 的早期临床和生物标志物变化相关。这些结果提供了对 APOE 增加 AD 风险的机制的见解，强调了 APOE 基因型对未来 DS 临床试验的重要性。