Cholinergic Basal Forebrain Atrophy Accelerates Cognitive Decline via Cortical Thinning: The Moderating Role of Amyloid-β Pathology in Preclinical Alzheimer’s Disease

Degeneration of the cholinergic basal forebrain (cBF) is a hallmark of early neurodegeneration in Alzheimer’s disease (AD). While cBF atrophy has been linked to cognitive decline, the extent to which cortical thinning mediates this association, particularly in preclinical AD, remains unclear. Furthermore, the influence of amyloid-β (Aβ) pathology on these relationships warrants further investigation. This study analyzed longitudinal MRI and PIB-PET data from 230 cognitively normal older adults in the Harvard Aging Brain Study, with a mean follow-up of six years. FreeSurfer was used to quantify cBF volume and cortical thickness, while cognitive performance was assessed using the Preclinical Alzheimer Cognitive Composite-5 (PACC5). Linear mixed-effects models evaluated longitudinal associations between cBF atrophy, cortical thinning, and cognitive decline. Mediation analyses assessed whether cortical thinning mediated the relationship between cBF degeneration and cognitive decline, and the moderating effect of Aβ burden was examined. Progressive cortical thinning in multiple cognition-related regions was significantly associated with longitudinal cBF atrophy. Mediation analysis revealed that cortical thinning accounted for approximately 44% of the association between cBF degeneration and cognitive decline. These effects were more pronounced in Aβ-positive individuals, suggesting a synergistic interaction between amyloid pathology and cholinergic degeneration. These findings indicate that cBF atrophy accelerates cognitive decline by driving cortical thinning, with Aβ pathology further exacerbating these effects. This study enhances understanding of the structural mechanisms underlying cognitive decline in preclinical AD and highlights potential early intervention targets.