唐氏综合征和临床前阿尔茨海默病中β-淀粉样蛋白和tau病理的联合空间关联：与早期认知障碍的横断面关联

Joint spatial associations of amyloid beta and tau pathology in Down syndrome and preclinical Alzheimer's disease: Cross-sectional associations with early cognitive impairments.

作者信息

Fu Jessie Fanglu, Garimella Arun, Lapointe Alex, Aye William W T, Chen Charles D, Lee Joseph H, Krinsky-McHale Sharon J, Zaman Shahid, Lott Ira T, Hom Christy, Ances Beau, Head Elizabeth, Mapstone Mark, Lai Florence, Handen Benjamin L, Laymon Charles M, Hartley Sigan L, Christian Bradley T, Rentz Dorene M, Johnson Keith A, Rosas H Diana, Price Julie C

机构信息

Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.

Departments of Neurology and Epidemiology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA.

出版信息

Alzheimers Dement. 2025 Jul;21(7):e70424. doi: 10.1002/alz.70424.

DOI:10.1002/alz.70424

PMID:40588723

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12208798/

Abstract

INTRODUCTION

Individuals with Down syndrome (DS) have elevated risks for Alzheimer's disease (AD) due to amyloid beta (Aβ) precursor protein overexpression, with nearly all developing AD pathology by age 40 at autopsy. This study examined spatial associations between Aβ and tau burden in DS and neurotypical aging.

METHODS

Data included 145 DS (25-67 years) and 191 neurotypical aging individuals (63-89 years). Regional Aβ and tau positron emission tomography outcomes were analyzed using multiset canonical correlation analysis to identify joint Aβ/tau spatial patterns, with regression models assessing associations with age and cognition.

RESULTS

For a given Aβ burden, cognitively stable DS individuals exhibited relatively higher tau burden than neurotypical aging, while DS mild cognitive impairment/AD individuals exhibited more widespread pathology. Joint Aβ/tau patterns were associated with episodic memory impairment in DS and, as the disease progresses, executive dysfunction.

DISCUSSION

DS exhibits overlapping and distinct AD-related neuropathology features, emphasizing the importance of biomarkers for early detection and intervention.

HIGHLIGHTS

There are distinct amyloid beta (Aβ) and tau spatial patterns in Down syndrome (DS): For a given level of Aβ burden, individuals with DS exhibited greater and more widespread tau burden compared to neurotypical aging, even before a clinical diagnosis of dementia. Aβ-associated tau burden was linked to episodic memory impairment in DS prior to dementia, with executive dysfunction emerging as the disease progressed, highlighting the sequential impact of pathology on cognition. The unique pattern of early striatal Aβ accumulation in DS supports its use as a potential biomarker for tracking disease progression and guiding clinical trial inclusion criteria for Alzheimer's disease interventions in DS.

摘要

引言

由于淀粉样β（Aβ）前体蛋白过度表达，唐氏综合征（DS）患者患阿尔茨海默病（AD）的风险升高，几乎所有患者在尸检时40岁前都会出现AD病理特征。本研究调查了DS患者中Aβ和tau蛋白沉积的空间关联以及典型神经老化情况。

方法

数据包括145名DS患者（25 - 67岁）和191名典型神经老化个体（63 - 89岁）。使用多集典型相关分析来分析区域Aβ和tau正电子发射断层扫描结果，以识别联合Aβ/tau空间模式，并通过回归模型评估与年龄和认知的关联。

结果

对于给定的Aβ沉积量，认知稳定的DS患者比典型神经老化个体表现出相对更高的tau蛋白沉积量，而DS轻度认知障碍/AD患者表现出更广泛的病理特征。联合Aβ/tau模式与DS患者的情景记忆障碍相关，并且随着疾病进展，与执行功能障碍相关。

讨论

DS表现出与AD相关的重叠且独特的神经病理特征，强调了生物标志物对于早期检测和干预的重要性。

要点

唐氏综合征（DS）存在独特的淀粉样β（Aβ）和tau空间模式：对于给定水平的Aβ沉积量，与典型神经老化相比，DS患者即使在临床诊断为痴呆之前，也表现出更大且更广泛的tau蛋白沉积量。在痴呆发生之前，DS患者中与Aβ相关的tau蛋白沉积量与情景记忆障碍相关，随着疾病进展出现执行功能障碍，突出了病理对认知的顺序性影响。DS患者早期纹状体Aβ积累的独特模式支持其作为追踪疾病进展和指导DS患者AD干预临床试验纳入标准的潜在生物标志物。