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APOE, vascular pathology, and the AD brain

From the Departments of Medicine (Genetics Program) (Drs. Yip, Green, and Farrer), Neurology (Drs. McKee, Green, Wells, and Farrer), and Genetics & Genomics (Dr. Farrer), Boston University School of Medicine; Departments of Epidemiology (Drs. Green and Farrer) and Biostatistics (Drs. Cupples and Farrer), Boston University School of Public Health; and Edith Nourse Rogers Memorial Veterans Hospital (Drs. McKee and Wells, and H. Young), Bedford, MA.

Address correspondence and reprint requests to Dr. Lindsay A. Farrer, Genetics Program, Boston University School of Medicine, 715 Albany Street L-320, Boston, MA 02118; e-mail: farrer{at}bu.edu

Objective: To use neuropathologic data to examine the association between APOE genotype and cerebrovascular lesions commonly found in Alzheimer disease (AD), as well as neuritic senile plaque (SP) and neurofibrillary tangle (NFT) burden.

Methods: The sample comprised brains from 96 men and 3 women who fulfilled NIA-Reagan criteria for intermediate to high likelihood of AD. Region-specific and global measures of gross cerebrovascular disease, arteriolosclerosis, white matter lesions, microinfarcts, amyloid angiopathy, neuritic SP, and NFT burden were compared among those who had at least one APOE-4 vs those who did not. Pairwise rank-order correlations between measures were calculated. The association between APOE 4 status and measures of vascular and AD pathology, adjusting for age at death, sex, brain weight, and Braak stage, were evaluated.

Results: APOE-4 was not associated with gross cerebrovascular pathology. Compared to those who were negative, brains from 4 individuals had a greater degree of small vessel arteriolosclerosis (p = 0.04) and perivascular macrophage infiltration (p = 0.06), but not other markers of small vessel disease or white matter myelin loss. Microinfarcts in the deep nuclei were associated with 4 (p = 0.009), whereas cortical and subcortical microinfarcts were not. There was a trend toward association between APOE genotype and amyloid angiopathy (p = 0.08), and 4 was associated with neuritic SP burden, but not NFT.

Conclusion: APOE-4 is associated with small vessel arteriolosclerosis, microinfarcts of the deep nuclei, neuritic senile plaque density, and amyloid angiopathy in patients with autopsy-proven Alzheimer disease (AD). These results suggest a role for 4 in some of the microvascular changes commonly found in AD and are consistent with a potential amyloidogenic role for 4.

Supported by Alzheimer’s Association grant NIRG-03-5874, a VA Merit Award, and NIH grants P30 AG13846, R01 AG09029, and RO1 HG/AG02213.

Received November 18, 2004. Accepted in final form April 5, 2005.

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