APOE, vascular pathology, and the AD brain

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-epsilon 4 vs those who did not. Pairwise rank-order correlations between measures were calculated. The association between APOE epsilon 4 status and measures of vascular and AD pathology, adjusting for age at death, sex, brain weight, and Braak stage, were evaluated. Results: APOE-epsilon 4 was not associated with gross cerebrovascular pathology. Compared to those who were negative, brains from epsilon 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 epsilon 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 epsilon 4 was associated with neuritic SP burden, but not NFT. Conclusion: APOE-epsilon 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 epsilon 4 in some of the microvascular changes commonly found in AD and are consistent with a potential amyloidogenic role for epsilon 4.