The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease

Objective: To determine the timing of cholinergic loss and reduction of synapses in AD. Background: Decrements in neocortical synapses and cholinergic function occur in AD and correlate with cognitive decline. However, how early in the disease process these changes appear remains unclear. Methods: An autopsy series of 89 demented patients with pathologically confirmed AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria) and 18 normal control subjects (NC). The AD cases were stratified according to their last Mini-Mental State Examination (MMSE) score prior to death as mild (MMSE = 20; n = 14), moderate (MMSE = 10 to 19; n = 20), severe (MMSE = 1 to 9; n = 29), and very severe (MMSE = 0; n = 26). Midfrontal (MF) synapse density was assessed by dot-immunobinding assay for synaptophysin (Syn), and MF choline acetyltransferase (ChAT) activity was determined using standard protocols. Results: Compared with those in NC, neither Syn nor ChAT was appreciably reduced in patients with mild AD at death. Decline of ChAT was significant only in AD patients who died in the late stages of the disease and was maximal in those who had more severely deteriorated. In contrast, decline of Syn was significant and almost maximal in patients in intermediate or moderate stages. Consequently, the last MMSE score prior to death correlated more strongly with ChAT than Syn when the AD cohort included more impaired patients (r = 0.46 versus 0.40). The reverse occurred when only less impaired patients (MMSE = 10) were included in the analyses (r = 0.28 versus 0.64). There was only a modest correlation between Syn and ChAT activity. Conclusions: The results imply an asynchronous pattern of decline of synapses and cholinergic activity, with Syn loss preceding ChAT decrements. However, neither MF synapse reduction nor cholinergic dysfunction appears to be an early event in AD.