Cholinergic basal forebrain atrophy accelerates cognitive decline via cortical thinning: The moderating role of amyloid-β pathology in preclinical Alzheimer’s disease - 31/10/25
, Fan Yang f, 1, ⁎ , Wencai Ding a, b, 1, ⁎ on behalf of the Harvard Aging Brain Study (HABS)
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Highlights |
• | Basal forebrain atrophy predicts cortical thinning and cognitive decline. |
• | Cortical thinning mediates ∼44 % of the association between cBF atrophy and cognition. |
• | Amyloid-β pathology strengthens the link between cBF atrophy and cortical thinning. |
• | Cholinergic system degeneration may be an early target for AD interventions. |
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.
Le texte complet de cet article est disponible en PDF.Keywords : Cholinergic basal forebrain, Cognitive decline, Cortical thinning, Amyloid-β Pathology, Preclinical Alzheimer’s Disease
Plan
| Data used in preparation of this article were obtained from the Harvard Aging Brain Study (HABS), As such, the investigators within the HABS contributed to the design and implementation of HABS and/or provided data but did not participate in analysis or writing of this report. |
Vol 12 - N° 10
Article 100315- décembre 2025 Retour au numéro
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