The cholinergic neurons of the basal forebrain (BFCNs) are known to degenerate early in Alzheimer’s disease. Their functional loss underpins aspects of cognitive decline and is coincident with amyloid beta (Aβ) plaque deposition. Studies using Alzheimer’s disease mice models of amyloid deposition in which BFCNs are activated or inhibited result in reduced or enhanced amyloid plaque deposition respectively, indicative of a possible causal relationship.

There are several mechanisms by which Aβ can be removed from the brain, including clearance through the hypothesized perivascular glymphatic system. Animal studies have demonstrated that cholinergic activity in the brain controls artery dilation modulating the blood oxygen level-dependent (BOLD) signal, and providing a mechanism to change the perivascular space that could promote cerebral spinal fluid (CSF) exchange.

We hypothesize that BFCNs can control glymphatic flow and thus clearance of soluble amyloid from the brain.

BFCNs in mice were manipulated by lesioning using the toxin p75-saporin. To measure glymphatic flux, a gadolinium contrast agent was injected into the cisterna magma of mice and longitudinal MRI including imaging sequences for BOLD, arterial pulsation, and spin labeling was undertaken. We have also undertaken analyzed human MRI scans of people living with dementia who have also undergone cholinergic PET tracer FEOVB imaging.

Our results support the hypothesis that BFCNs can control glymphatic flow. The implication is that in situations of reduced cholinergic function such as aging, the resultant reduced glymphatic flux could contribute to Aβ accumulation and deposition, hastening the development of Alzheimer’s dementia.