Early functional disconnection of the basal forebrain-hippocampal system predicts memory impairment in amnestic mild cognitive impairment.

Abstract

While central remodeling in amnestic mild cognitive impairment (aMCI) is well documented, prevailing studies emphasize whole-brain networks or undirected functional connectivity, largely neglecting specific neuromodulatory systems. We therefore investigated structural integrity and directional effective connectivity within the basal forebrain (BF)-hippocampal-cortical axis to elucidate early pathophysiology. Fifty-one aMCI patients and 67 cognitively healthy controls underwent multimodal MRI and comprehensive neuropsychological assessment. Spectral dynamic causal modeling (spDCM) characterized directional BF-hippocampal connectivity, generalized linear modeling (GLM) identified memory-related BF-cortical circuits, and system dynamics modeling (SDM) quantified pathways linking neural architecture, functional coupling, and cognitive performance. Macroscopic BF and hippocampal volumes did not differ significantly between groups. However, spDCM revealed altered effective connectivity patterns in aMCI patients, characterized by reduced negative effective connectivity. GLM demonstrated that BF-cortical modulation, specifically within medial septum/diagonal band (MS/DB) -parietal circuits, significantly interacted with diagnostic status to predict memory scores. Furthermore, SDM indicated that effective connectivity between the nucleus basalis of Meynert (NBM) and frontoparietal regions significantly predicted NBM structural integrity, which in turn was positively associated with hippocampal volume and long-term memory performance. Collectively, directional connectivity alterations within the BF-hippocampal-cortical axis were observed in patients with aMCI in the absence of detectable macroscopic atrophy, highlighting the potential contribution of BF-related network dysfunction to early disease processes.