本期文章：《柳叶刀》：Online/在线发表

西班牙圣克鲁i圣帕医院Juan Fortea团队分析了唐氏综合征成人阿尔茨海默病临床及生物标志物的变化。2020年6月27日，该研究发表在《柳叶刀》杂志上。

阿尔茨海默病及其并发症是唐氏综合症成年人的主要死亡原因。已有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。研究组表征了唐氏综合症成年人群中阿尔茨海默氏病生物标志物变化的顺序和时机。

研究组使用巴塞罗那（西班牙）基于人群的健康计划以及剑桥（英国）为智障人士提供的服务，对唐氏综合症成年人进行了双中心、横断面研究。唐氏综合症参与者的认知障碍通过剑桥唐氏综合症老年人认知检查（CAMCOG-DS）进行分类。

研究组仅招募轻中度残疾的参与者，他们伴有至少一种阿尔茨海默氏病指标：载脂蛋白E等位基因携带者状态；血浆淀粉样蛋白β肽1-42和1-40的浓度及其比率（Aβ1-42/ 1-40），总tau蛋白和神经丝轻链（NFL）； 脑脊液（CSF）中tau在苏氨酸181（p-tau）和NFL处磷酸化；一种或多种含18F-氟脱氧葡萄糖的PET，含淀粉样示踪剂的PET和MRI。研究组还招募了年龄在75岁以下、无生物标志物异常的认知健康的整倍体人群做对照组。

2013年2月1日至2019年6月28日在巴塞罗那，2009年6月1日至2014年12月31日在剑桥，研究组共招募了388名唐氏综合症患者，其中66%无症状，12％为原发性阿尔茨海默氏病，21％患有阿尔茨海默氏病痴呆。同时还招募了242例整倍体对照。

唐氏综合症患者的CSF Aβ1-42/ 1-40和血浆NFL值早在21-30岁时就发生了变化，淀粉样蛋白PET的摄取在31-40岁时发生变化。18F-氟脱氧葡萄糖PET和CSF p-tau改变发生在31-40岁，之后41-50岁时海马萎缩，认知改变。前驱期阿尔茨海默病的确诊中位年龄为50.2岁，阿尔茨海默病痴呆的确诊中位年龄为53.7岁。唐氏综合症患者的症状性阿尔茨海默氏病患病率随年龄增加而上升，在61-70岁时达到90-100％。

唐氏综合症患者的阿尔茨海默氏病具有长期的临床前阶段，在该阶段中，生物标志物在超过二十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病的相似性以及唐氏综合征的患病率，使该人群成为防治阿尔茨海默病的主要目标。

附：英文原文

Title: Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study

Author: Juan Fortea, Eduard Vilaplana, Maria Carmona-Iragui, Bessy Benejam, Laura Videla, Isabel Barroeta, Susana Fernández, Miren Altuna, Jordi Pegueroles, Víctor Montal, Silvia Valldeneu, Sandra Giménez, Sofía González-Ortiz, Laia Muoz, Teresa Estellés, Ignacio Illán-Gala, Olivia Belbin, Valle Camacho, Liam Reese Wilson, Tiina Annus, Ricardo S Osorio, Sebastián Videla, Sylvain Lehmann, Anthony J Holland, Daniel Alcolea, Jordi Clarimón, Shahid H Zaman, Rafael Blesa, Alberto Lleó

Issue&Volume: 2020/06/27

Abstract: 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 (Aβ1–42/1–40), 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 Aβ1–42/1–40 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.

DOI: 10.1016/S0140-6736(20)30689-9

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30689-9/fulltext