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

Objective: To determine the timing of cholinergic loss and reduction of syn apses in AD. Background: Decrements in neocortical synapses and cholinergic function occur in AD and correlate with cognitive decline. However, how ea rly in the disease process these changes appear remains unclear. Methods: A n autopsy series of 89 demented patients with pathologically confirmed AD ( National Institute on Aging and Consortium to Establish a Registry for Alzh eimer's Disease criteria) and 18 normal control subjects (NC). The AD cases were stratified according to their last Mini-Mental State Examination (MMS E) 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 as say for synaptophysin (Syn), and MF choline acetyltransferase (ChAT) activi ty 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 t he late stages of the disease and was maximal in those who had more severel y deteriorated. In contrast, decline of Syn was significant and almost maxi mal 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 r everse 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 asynchron ous pattern of decline of synapses and cholinergic activity, with Syn loss preceding ChAT decrements. However, neither MF synapse reduction nor cholin ergic dysfunction appears to be an early event in AD.