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

Jul 30, 2025The journal of prevention of Alzheimer's disease

Loss of brain cells that support thinking speeds up mental decline through brain surface shrinking, influenced by early Alzheimer's protein buildup

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Abstract

Progressive cortical thinning in multiple cognition-related regions is significantly associated with cBF atrophy.

Cortical thinning may account for approximately 44% of the relationship between cBF degeneration and cognitive decline.
The association between cBF atrophy and cognitive decline is more pronounced in individuals with elevated amyloid-β (Aβ) levels.
Cholinergic basal forebrain (cBF) degeneration could accelerate cognitive decline through its impact on cortical thickness.
The findings suggest that cBF and cortical thinning may serve as early biomarkers for preclinical Alzheimer's disease.

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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.

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

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