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From the Dipartimento di Scienze Neurologiche (Dr. Tiraboschi), Ospedale Niguarda Ca’ Granda, Milano, Italy; and Department of Neurosciences (Drs. Tiraboschi, Hansen, Masliah, Alford, Thal, and Corey-Bloom), University of California, San Diego, La Jolla, and Neurology Service (Drs. Thal and Corey-Bloom), VA San Diego Healthcare System, San Diego, CA.
Address correspondence and reprint requests to Dr. J. Corey-Bloom, Neurology Service (9127), San Diego VA Medical Center, 3350 La Jolla Village Dr., San Diego, CA 92161-3064; e-mail: jcoreybl{at}vapop.ucsd.edu
Background: The APOE 
4 allele has emerged as a major genetic factor for Alzheimer disease (AD), and its presence has been associated with an increase in ß-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 2 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 4 alleles, 4 carriers (patients with either one or two 4 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 4 alleles, patients with two 4 alleles had significantly more NPs and NFTs in all neocortical regions than those with either one or no 4 alleles. The association of the 4/4 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 2 allele and those without, a strong relationship emerged between the 2 allele and decreased NPs in all neocortical regions.
Conclusions: The 4 allele does not predict cholinergic decline in AD. Although the presence of a single 4 allele appears to have no effect, the presence of two 4 alleles is an important determinant of both NP and NFT accumulation. A putative protective role for the 2 allele in AD may be mediated by reduced plaque burden.
Received July 24, 2003. Accepted in final form January 29, 2004.
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