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

From the Department of Neurosciences (Drs. Corey-Bloom, Hansen, Sabbagh, Masliah, and Thal, and M. Alford), University of California, San Diego, La Jolla; the Neurology Service (Drs. Corey-Bloom, Schoos, Sabbagh, and Thal), San Diego VA Medical Center, San Diego, CA; and the Neurologia Prima (Dr. Tiraboschi), Ospedali Riuniti, Bergamo, Italy.

Address correspondence and reprint requests to Dr. Jody Corey-Bloom, Neurology Service (9127), VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161; e-mail: jcoreybl{at}vapop.ucsd.edu

OBJECTIVE: To investigate the relationship between apolipoprotein E (APOE) genotype and both cholinergic dysfunction and synapse loss in AD.

BACKGROUND: A reduction in neocortical synapses and marked losses in the cholinergic system occur in AD. It has been suggested that the number of APOE 4 alleles is inversely related to choline acetyltransferase (ChAT) activity, thereby influencing cholinergic function. Whether APOE genotype may influence neocortical synapse loss remains unclear.

METHODS: An autopsy series of 182 patients with AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer’s Disease criteria) and 16 normal controls (NC). APOE genotype was determined in blood samples or in postmortem brain tissue. Midfrontal synapse counts (AU/µg) were quantified by a dot-immunobinding assay for synaptophysin (Syn). Midfrontal ChAT activity (nmol/h/100 mg) was assessed using standard assays.

RESULTS: Mean midfrontal ChAT activity and Syn were both significantly reduced in patients with AD compared with NC. The relationship between ChAT activity and number of 4 allele copies in AD was complex, with ChAT activity lower in patients with either two or no 4 alleles compared with those with one 4 allele. There was no relationship between APOE genotype and synapse loss in AD. Syn density was almost identical across the three genotypes.

CONCLUSIONS: Unlike other studies, we failed to detect a linear relationship between ChAT activity and number of 4 allele copies in the midfrontal cortex of this large sample of patients with AD. Our data also show that the presence of 4 allele does not influence midfrontal synapse loss in AD. This suggests that factors other than APOE genotype may be operative in the decline in midfrontal cholinergic function and synapses seen in AD.

Key words: Choline acetyltransferase—Synaptophysin—APOE genotype—AD

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