Selective effects of the APOE ε4 allele on presynaptic cholinergic markers in the neocortex of Alzheimer's disease

The effects of the APOE ε4 allele on a range of pre- and postsynaptic cholinergic markers were studied in a cohort of community-based Alzheimer's disease (AD) patients. Compared with age-matched controls, the postmortem AD neocortex showed decreased choline acetyltransferase (ChAT) and acetyl cholinesterase activities, lower muscarinic M2, and nicotinic α4β2 receptor densities, as well as reduced M1 receptor coupling to G-proteins. However, the ε4 allele was dose-dependently correlated only with higher losses of ChAT activities. AD patients with two ε4 alleles also had more β-amyloid containing senile plaques in the temporal cortex compared to patients with 0/1 ε4. This study suggests that APOE ε4 selectively affects presynaptic cholinergic function which may contribute to the clinical and neuropathological features of AD.