Objective We assessed the association of apolipoprotein E (APOE) genotype with cerebrovascular disease (CVD) in a large neuropathological database maintained by the National Alzheimer’s Coordinating Center (NACC). Such a comprehensive investigation of APOE and CVD pathology has not heretofore been conducted. We focused on APOE e2, an established neuroprotective genetic variant against Alzheimer’s disease.

Methods To implement these objectives APOE associations in the NACC database of 1275 brains with 11 CVD pathologies, including old and recent infarcts, haemorrhages, cerebral amyloid angiopathy (CAA) and arteriosclerosis, were examined. These pathologies were uniformly and semiquantitatively measured across 39 Alzheimer’s Disease Center sites. We used χ2 statistics and ordinal regression to assess the significance of associations and Bonferroni corrected for multiple comparisons.

Results Of the cases, 98 were e2/e3 or e2/e2 genotypes (‘e2’ carriers), 621 were e3 homozygotes (‘e3’ group), and 556 were e4/e3 (442) or e4/e4 (114) genotypes (‘e4’ group). Results indicated that the APOE e4 allele significantly increased risk for CAA. After stratification by CAA presence/absence, we found that in those cases in which CAA was present, APOE e2 significantly increased risk for gross haemorrhage. All other associations were negative.

Conclusions In this, the largest study of APOE e2 effects on pathologically verified CVD, e2 was not protective against any CVD pathology compared with e3 homozygotes, including CAA. Regarding the latter pathology, e4 was associated with increases in its severity. Furthermore, and perhaps unexpectedly, e2 significantly increased risk of acute/subacute gross haemorrhage in the presence of CAA. Thus, there were limits to e2 neuroprotection against amyloidosis, despite its known and large protective effects against diffuse and neuritic amyloid plaques compared with e3/e3 and e4 carriers in this very collection.