Molecular Cholinergic Dysfunction in the Presymptomatic Stages of Alzheimer's Disease

Plain Language Summary: Cholinergic neurons are a type of cell in the brain. Research suggests that cholinergic dysfunction is an early sign of Alzheimer's disease. However, there is currently no method for measuring cholinergic function. This project evaluated a new tool for imaging cholinergic function. Using the tool, we found that individuals at risk for disease exhibit cholinergic dysfunction. Background:

Alzheimer's disease (AD) staging models suggest that amyloid and tau pathologies do not emerge throughout the brain all at once. Rather, specific neurons exhibit early changes in function, which potentiate downstream pathophysiological events (Braak & Braak, 1991). The cholinergic neurons of the basal forebrain (BE) are among the first cell-types to exhibit pathology in AD (Schmitz et al., 2016). However, the lack of a cholinergic biomarker has prevented the evaluation of cholinergic function in early disease stages. PET imaging with [18F]FEOBV overcomes this obstacle (Mulholland et al., 1998). FEOBV targets VAChT, a protein found in cholinergic nerve terminals, making it well-suited for measuring changes in cholinergic function. Using FEOBV, we demonstrate the first molecular imaging evidence for cholinergic dysfunction in cognitively normal (CN) humans at-risk for AD. Methods:

We collected longitudinal MRI, cross-sectional FEOBV, and plasma ptaul81 data in 64 CN older adults atrisk for AD. Results:

Individuals were clustered into risk groups according to their longitudinal decline in B F volume: normal, low, and high-risk groups. Using FEOBV, we found that high-risk individuals exhibited greater molecular cholinergic dysfunction compared to low and normal risk groups. Increased cholinergic degeneration and dysfunction was also found to be associated with increased levels of plasma ptaul81. Conclusions:

We present the first evidence for molecular cholinergic dysfunction in CN humans at-risk for AD, highlighting the utility of FEOBV imaging for detecting at-risk individuals for preventative drug treatments. treatments.