Cholinergic dysregulation in prodromal Alzheimer’s disease

Abstract

The cholinergic hypothesis of geriatric memory dysfunction led to the development of FDA-approved anticholinesterase drugs to maintain this system in AD patients. The importance of defining the status of the cholinergic basal forebrain cortical projection system in subjects with prodromal AD who are at risk for developing AD continues to be of great clinical and translational interest. The findings presented are derived from molecular and cellular neuropathologic investigations of people who died with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and Alzheimer's disease (AD) as well as from AD transgenic animal studies. Clinical pathologic investigations revealed that CBF neurons maintain their cholinergic neuronal phenotype despite exhibiting pretangles, which correlate with cognitive impairment and an altered ratio of 3 repeat to 4 repeat tau in the MCI brain. Interestingly, the cortical cholinergic system displays an upregulation of choline acetyltransferease (ChAT) activity in the frontal cortex and hippocampus suggesting early reparative mechanisms during prodromal AD. Moreover, despite the early accumulation of amyloid burden in the precuneus component of the default memory network, cholinergic enzyme activity remains stable in MCI and only declines in clinical AD, when PiB binding and soluble beta-amyloid 42 levels are substantially elevated compared to MCI. Moreover, amyloid deposition failed to induce cholinergic cortical neuronal degeneration in APP and triple transgenic mouse models of AD. Increased cortical levels of proNGF and a decrease in TrkA suggest a shift away from cell survival to apoptotic proNGF signaling. Interestingly, this switch to cell death mechanisms did not occur in the hippocampus during prodromal AD. Together these data suggest that CBF system dysregulation is not uniform, the system is neuroplastic, pretangle pathology plays a key role in cognitive impairment, amyloid deposition may not be toxic early on and there is a shift from cell survival to cell death trophic factor signaling in MCI.