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Impact Of APOE Genotype On Neuropathologic And Neurochemical Markers Of Alzheimer Disease

P. Tiraboschi, L. Hansen, E. Masliah, M. Alford, L. Thal, J. Corey-Bloom
Published 2004 · Psychology, Medicine

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Background: The APOE ε4 allele has emerged as a major genetic factor for Alzheimer disease (AD), and its presence has been associated with an increase in β-amyloid senile plaques (SPs) and neuritic plaques (NPs). Whether it affects neurofibrillary tangle (NFT) accumulation or cholinergic losses in AD remains controversial. In contrast, the ε2 allele has been reported to decrease the risk for AD. However, its effect on neuropathologic and neurochemical markers of disease is unclear. Objective: To investigate the relationship between APOE genotype and both pathologic severity and cholinergic dysfunction in AD. Methods: In an autopsy series of 296 patients with AD, APOE genotype was determined in blood or postmortem brain tissue. NPs and NFTs were counted in the midfrontal (MF), inferior parietal (IP), and superior temporal (ST) cortices and the hippocampus. Choline acetyltransferase (ChAT) activity was assessed in the MF, IP, and ST cortices. Results: Compared with patients with no ε4 alleles, ε4 carriers (patients with either one or two ε4 alleles) did not differ significantly with regard to any pathologic or neurochemical measures, except for increased ST NPs. However, when cases were stratified into three groups according to the number of ε4 alleles, patients with two ε4 alleles had significantly more NPs and NFTs in all neocortical regions than those with either one or no ε4 alleles. The association of the ε4/4 genotype with neocortical pathologic severity remained significant even after adjusting for age at onset or age at death. In contrast, there were no significant group differences with regard to neocortical ChAT activity. When pathologic and neurochemical measures were compared between patients with the ε2 allele and those without, a strong relationship emerged between the ε2 allele and decreased NPs in all neocortical regions. Conclusions: The ε4 allele does not predict cholinergic decline in AD. Although the presence of a single ε4 allele appears to have no effect, the presence of two ε4 alleles is an important determinant of both NP and NFT accumulation. A putative protective role for the ε2 allele in AD may be mediated by reduced plaque burden.
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