APOE, vascular pathology, and the AD brain

Abstract

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-ε4 vs those who did not. Pairwise rank-order correlations between measures were calculated. The association between APOE ε4 status and measures of vascular and AD pathology, adjusting for age at death, sex, brain weight, and Braak stage, were evaluated.

Results: APOE-ε4 was not associated with gross cerebrovascular pathology. Compared to those who were negative, brains from ε4 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 ε4 (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 ε4 was associated with neuritic SP burden, but not NFT.

Conclusion: APOE-ε4 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 ε4 in some of the microvascular changes commonly found in AD and are consistent with a potential amyloidogenic role for ε4.