Longitudinal Alzheimer’s Degeneration Reflects the Spatial Topography of Cholinergic Basal Forebrain Projections

Abstract

Summary: The cholinergic neurons of the basal forebrain (BF) provide virtually all of the brain’s cortical and amygdalar cholinergic input. They are particularly vulnerable to neuropathology in early Alzheimer’s disease (AD) and may trigger the emergence of neuropathology in their cortico-amygdalar projection system through cholinergic denervation and trans-synaptic spreading of misfolded proteins. We examined whether longitudinal degeneration within the BF can explain longitudinal cortico-amygdalar degeneration in older human adults with abnormal cerebrospinal fluid biomarkers of AD neuropathology. We focused on two BF subregions, which are known to innervate cortico-amygdalar regions via two distinct macroscopic cholinergic projections. To further assess whether structural degeneration of these regions in AD reflects cholinergic denervation, we used the [18F] FEOBV radiotracer, which binds to cortico-amygdalar cholinergic terminals. We found that the two BF subregions explain spatially distinct patterns of cortico-amygdalar degeneration, which closely reflect their cholinergic projections, and overlap with [18F] FEOBV indices of cholinergic denervation. : Among older adults in prodromal stages of Alzheimer’s disease, Schmitz et al. show that longitudinal degeneration within sub-regions of the basal forebrain covaries with cortico-amygdalar topographies of both structural degeneration and cholinergic denervation. The findings support the view that loss of cortico-amygdalar cholinergic input is a pivotal event in AD progression. Keywords: basal forebrain, cholinergic system, longitudinal analysis, structural MRI, cerebrospinal fluid biomarker, amyloid beta, tau, [18F] FEOBV PET, Alzheimer’s disease, aging