E4 allele dosage does not predict cholinergic activity or synapse loss in Alzheimer's disease

Objective: To investigate the relationship between apolipoprotein E (APOE) genotype and both cholinergic dysfunction and synapse loss in AD. Backgroun d: A reduction in neocortical synapses and marked losses in the cholinergic system occur in AD. It has been suggested that the number of APOE epsilon 4 alleles is inversely related to choline acetyltransferase (ChAT) activity , thereby influencing cholinergic function. Whether APOE genotype may influ ence neocortical synapse loss remains unclear. Methods: An autopsy series o f 182 patients with AD (National Institute on Aging and Consortium to Estab lish a Registry for Alzheimer's Disease criteria) and 16 normal controls (N C). APOE genotype was determined in blood samples or in postmortem brain ti ssue. Midfrontal synapse counts (AU/mu g) were quantified by a dot-immunobi nding assay for synaptophysin (Syn). Midfrontal ChAT activity (nmol/h/100 m g) was assessed using standard assays. Results: Mean midfrontal ChAT activi ty and Syn were both significantly reduced in patients with AD compared wit h NC. The relationship between ChAT activity and number of epsilon 4 allele copies in AD was complex, with ChAT activity lower in patients with either two or no epsilon 4 alleles compared with those with one epsilon 4 allele. There was no relationship between APOE genotype and synapse loss in AD. Sy n density was almost identical across the three genotypes. Conclusions: Unl ike other studies, we failed to detect a linear relationship between ChAT a ctivity and number of epsilon 4 allele copies in the midfrontal cortex of t his large sample of patients with AD. Our data also show that the presence of epsilon 4 allele does not influence midfrontal synapse loss in AD. This suggests that factors other than APOE genotype may be operative in the decl ine in midfrontal cholinergic function and synapses seen in AD.