Background

Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome.

Methods

We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid β peptides 1–42 and 1–40 and their ratio (Aβ_{1–42/1–40}), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with ¹⁸F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate.

Findings

Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aβ_{1–42/1–40} and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. ¹⁸F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5–54·1), and Alzheimer's disease dementia at 53·7 years (49·5–57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90–100% in the seventh decade of life.

Interpretation

Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments.

Funding

Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.

中文翻译：

---

患有唐氏综合症的成人阿尔茨海默病的临床和生物标志物变化：一项横断面研究。

背景

阿尔茨海默病及其并发症是唐氏综合症成人死亡的主要原因。研究评估了唐氏综合症患者的阿尔茨海默病，但尚未确定唐氏综合症生物标志物变化的自然史。我们描述了患有唐氏综合症的成年人群中阿尔茨海默氏病生物标志物变化的顺序和时间。

方法

我们对通过巴塞罗那（西班牙）人口健康计划和剑桥（英国）智障人士服务招募的患有唐氏综合症的成年人进行了双中心横断面研究。患有唐氏综合症的参与者的认知障碍通过剑桥老年唐氏综合症认知检查 (CAMCOG-DS) 进行分类。仅包括轻度或中度残疾的参与者，他们至少具有以下阿尔茨海默病指标之一：载脂蛋白 E 等位基因携带者状态；淀粉样蛋白 β 肽 1–42 和 1–40 的血浆浓度及其比率 (Aβ _{1–42/1–40} )、总 tau 蛋白和神经丝轻链 (NFL)；tau 在苏氨酸 181 (p-tau) 磷酸化，以及脑脊液 (CSF) 中的 NFL；和一种或多种具有^18F-氟脱氧葡萄糖、带淀粉样蛋白示踪剂的 PET 和 MRI。从 Sant Pau Initiative on Neurodegeneration 招募了年龄不超过 75 岁且没有生物标志物异常的认知健康整倍体对照。我们使用一阶局部估计散点图平滑曲线来确定生物标志物变化开始时的顺序和年龄，并且在适当的情况下还报告了具有 95% CI 的分歧的最低年龄。

发现

2013 年 2 月 1 日至 2019 年 6 月 28 日（巴塞罗那），以及 2009 年 6 月 1 日至 2014 年 12 月 31 日（剑桥），我们纳入了 388 名患有唐氏综合症的参与者（257 [66%] 无症状，48 [12%] ] 前驱阿尔茨海默病，83 [21%] 患有阿尔茨海默病痴呆）和 242 个整倍体对照。唐氏综合症患者的CSF Aβ _{1–42/1–40}和血浆 NFL 值早在生命的第三个十年就发生了变化，淀粉样蛋白 PET 摄取在第四个十年发生了变化。¹⁸F-氟脱氧葡萄糖 PET 和 CSF p-tau 变化发生在生命的第四个十年后期，随后是海马萎缩和生命第五个十年的认知变化。前驱阿尔茨海默病被诊断的中位年龄为 50·2 岁 (IQR 47·5–54·1)，阿尔茨海默病痴呆的中位年龄为 53·7 岁 (49·5–57·2)。有症状的阿尔茨海默病患病率随着唐氏综合症患者年龄的增长而增加，在生命的第七个十年达到 90-100%。

解释

唐氏综合症患者的阿尔茨海默氏病有一个漫长的临床前阶段，在这个阶段，生物标志物在二十多年的时间里遵循可预测的变化顺序。与散发性和常染色体显性遗传性阿尔茨海默氏病的相似性以及唐氏综合症的流行使该人群成为阿尔茨海默氏病预防性治疗的合适目标。

资金

Instituto de Salud Carlos III、Fundació Bancaria La Caixa、Fundació La Marató de TV3、医学研究委员会和国立卫生研究院。