Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain; Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases, Madrid, Spain.
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases, Madrid, Spain.
Lancet. 2020 Jun 27;395(10242):1988-1997. doi: 10.1016/S0140-6736(20)30689-9.
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.
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), 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 F-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.
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 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. F-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.
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.
Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.
阿尔茨海默病及其并发症是唐氏综合征患者死亡的主要原因。已有研究评估了唐氏综合征患者的阿尔茨海默病，但唐氏综合征患者的生物标志物变化的自然史尚未建立。我们描述了唐氏综合征患者人群中阿尔茨海默病生物标志物变化的顺序和时间。
我们在巴塞罗那（西班牙）的一项基于人群的健康计划和剑桥（英国）的智障人士服务机构中进行了一项唐氏综合征成年人的双中心横断面研究。唐氏综合征患者的认知障碍使用剑桥老年唐氏综合征认知评估（CAMCOG-DS）进行分类。仅纳入有以下阿尔茨海默病措施之一的轻度或中度残疾患者：载脂蛋白 E 等位基因携带者状态；血浆浓度β淀粉样蛋白 1-42 和 1-40 及其比值（Aβ）、总tau 蛋白和神经丝轻链（NFL）；tau 蛋白在苏氨酸 181 位磷酸化（p-tau）和脑脊液（CSF）中的 NFL；以及 F-氟脱氧葡萄糖的正电子发射断层扫描（PET）、淀粉样蛋白示踪剂的 PET 和 MRI 中的一项或多项。我们从圣保罗马神经退行性变倡议中招募了年龄不超过 75 岁、无生物标志物异常的认知健康的二倍体对照者。我们使用一阶局部估计散点平滑曲线来确定生物标志物变化的顺序和发病年龄，并且在适当的情况下还报告了与 95%置信区间的最低年龄差异。
在 2013 年 2 月 1 日至 2019 年 6 月 28 日（巴塞罗那）和 2009 年 6 月 1 日至 2014 年 12 月 31 日（剑桥）之间，我们纳入了 388 名唐氏综合征患者（257 名[66%]无症状，48 名[12%]有前驱期阿尔茨海默病，83 名[21%]有阿尔茨海默病痴呆）和 242 名二倍体对照者。唐氏综合征患者的 CSF Aβ 和血浆 NFL 值早在第三个十年就发生了变化，而淀粉样 PET 摄取则在第四个十年发生了变化。F-氟脱氧葡萄糖 PET 和 CSF p-tau 的变化发生在第四个十年后期，随后是海马萎缩和第五个十年的认知变化。前驱期阿尔茨海默病的中位诊断年龄为 50.2 岁（IQR 47.5-54.1），阿尔茨海默病痴呆的中位诊断年龄为 53.7 岁（49.5-57.2）。唐氏综合征患者的症状性阿尔茨海默病患病率随年龄增长而增加，在第七个十年达到 90-100%。
唐氏综合征患者的阿尔茨海默病在有临床症状前有一个很长的潜伏期，在此期间，生物标志物在超过二十年的时间里按照可预测的顺序发生变化。与散发性和常染色体显性阿尔茨海默病的相似性以及唐氏综合征的患病率使该人群成为阿尔茨海默病预防治疗的合适目标。
西班牙卡洛斯三世健康研究所、La Caixa 银行基金会、TV3 马拉松基金会、英国医学研究理事会和美国国立卫生研究院。
