ABSTRACT: We have previously demonstrated that the capillary vascular basement membrane (VBM) is pathologically altered in Alzheimer's disease (AD). This microangiopathy is highlighted by the immunocytochemical localization of the three principal intrinsic VBM components: heparan sulfate proteoglycan, collagen type IV, and laminin. These three VBM components also immunolabel amyloid deposits and senile plaque-associated glial processes. The present study examines the ultrastructure of the VBM in one brain region severely affected (temporal gyrus) and one relatively spared (cerebellum) from the lesions of AD in both AD and neurological control cases. The cross-sectional area as well as the width of the VBM were found to be greater in AD cortical capillaries. In addition, we found ultrastructural evidence for the activation of microglial-related perivascular cells, and their apparent extravasation through the VBM, findings consistent with the hypothesis that these cells are being recruited as part of a disease-related immune response. The recruitment of these “resting” microglial-like cells from their intra-VBM location to plaques and tangles in AD may explain (1) the thickening and vacuolization of the VBM; (2) the specificity of this VBM alteration to brain regions where there are plaques and tangles; and (3) the source of some of the large number of activated microglia in these affected areas. Thus, while VBM alterations may not be specific to AD, these changes appear to be specifically related to the disease process.