胆碱能基底前脑萎缩通过皮质变薄加速认知衰退：淀粉样蛋白β病理在临床前阿尔茨海默病中的调节作用。

Cholinergic basal forebrain atrophy accelerates cognitive decline via cortical thinning: The moderating role of amyloid-β pathology in preclinical Alzheimer's disease.

作者信息

Cen Si, Wang Lijuan, Qiu Meiling, Xu Zhongqiang, Xu Li, Bao Rui, Tang Xiaolei, Gong Juanyu, Wu Jinting, Shao Zhiding, Zhang Tonghua, Yang Fan, Ding Wencai

机构信息

The Second Affiliated Hospital of Wannan Medical College, Wuhu 241000, China; Department of Neurology, The Second Affiliated Hospital of Wannan Medical College, Wuhu 241000, China.

The Second Affiliated Hospital of Wannan Medical College, Wuhu 241000, China; Department of Neurology, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China.

出版信息

J Prev Alzheimers Dis. 2025 Jul 28:100315. doi: 10.1016/j.tjpad.2025.100315.

DOI:10.1016/j.tjpad.2025.100315

PMID:40731233

Abstract

BACKGROUND

Cholinergic basal forebrain (cBF) atrophy is a critical early marker of neurodegeneration in Alzheimer's disease (AD). While cBF degeneration is linked to cognitive decline, the role of cortical thinning in this process, especially during the preclinical phase of AD, remains underexplored. Additionally, the impact of amyloid-β (Aβ) pathology on these relationships warrants further examination.

METHODS

We analyzed longitudinal structural MRI and PIB-PET data from 230 cognitively normal older adults enrolled in the Harvard Aging Brain Study, with a mean follow-up of six years. cBF volume and cortical thickness were quantified using FreeSurfer. Cognitive performance was assessed with the Preclinical Alzheimer Cognitive Composite-5 (PACC5). Linear mixed-effects models were used to investigate the longitudinal associations between cBF atrophy, cortical thinning, and cognitive decline. Mediation analyses explored whether cortical thinning mediated the relationship between cBF degeneration and cognitive decline, and the moderating role of Aβ burden was examined.

RESULTS

Progressive cortical thinning in multiple cognition-related regions was significantly associated with cBF atrophy. Mediation analysis revealed that cortical thinning accounted for approximately 44 % of the relationship between cBF degeneration and cognitive decline. These associations were more pronounced in individuals with elevated Aβ, suggesting a synergistic interaction between amyloid pathology and cholinergic system degeneration.

CONCLUSIONS

Our findings suggest that cBF atrophy accelerates cognitive decline through its impact on cortical thinning, with Aβ pathology further exacerbating these effects. These results highlight the potential of cBF and cortical thinning as early biomarkers for preclinical AD and underscore the importance of targeting cholinergic dysfunction in early intervention strategies.

摘要

背景

胆碱能基底前脑（cBF）萎缩是阿尔茨海默病（AD）神经退行性变的关键早期标志物。虽然cBF变性与认知衰退有关，但皮质变薄在这一过程中的作用，尤其是在AD临床前期，仍未得到充分研究。此外，淀粉样β蛋白（Aβ）病理对这些关系的影响值得进一步研究。

方法

我们分析了来自参与哈佛衰老大脑研究的230名认知正常的老年人的纵向结构MRI和PIB-PET数据，平均随访6年。使用FreeSurfer对cBF体积和皮质厚度进行量化。用临床前阿尔茨海默病认知综合量表-5（PACC5）评估认知表现。采用线性混合效应模型研究cBF萎缩、皮质变薄与认知衰退之间的纵向关联。中介分析探讨皮质变薄是否介导了cBF变性与认知衰退之间的关系，并检验了Aβ负担的调节作用。