To investigate the role of the cholinergic basal forebrain (CBFB) and structural network topology in strategic lesions in mild cognitive impairment (MCI).

Alzheimer’s pathology leads to redistribution of processing, which is reflected in reorganization of the structural connectome. This might affect its vulnerability to structural damage. Cortical acetylcholine allows favorable adaptation to pathology within the memory circuit. However, it remains unclear if it acts on a broader scale, affecting reconfiguration of whole-brain networks.

Twenty patients with MCI and 20 healthy elderly controls underwent structural and diffusion-weighted MRI. Whole-brain tractograms were represented as network graphs. Lesions of individual nodes were simulated by removing a node and its connections from the graph. The impact of simulated lesions was quantified as the proportional change in global efficiency after node removal. Relationships between subregional CBFB volumes (Ch1-2, Ch4), global efficiency of intact connectomes and impacts of individual simulated lesions of network nodes were assessed.

In MCI but not controls, global efficiency was correlated with Ch4 volume. Additionally, higher Ch4 volume was related to reduced impact of lesions of the entorhinal cortex and the thalamus, while preserved Ch1-2 volume was associated with reduced impact of hippocampal and entorhinal lesions. The link between CBFB and the impact of simulated lesions was not observed for other subcortical or cortical nodes. Controls exhibited no relationship between CBFB structure and the impact of simulated lesions.

In MCI, integrity of the CBFB is associated with efficient network topology. Preserved CBFB volumes have a protective effect against global impact of simulated strategic lesions. Our results conform to the anatomy of cholinergic projections: regions Ch1-2 project to medial temporal lobes, whereas Ch4 has diffuse cortical and entorhinal projections. This suggests that the cholinergic system shapes the configuration of the connectome, thereby reducing the impact of localized structural or vascular damage in MCI.