Consequence of A immunization on the vasculature of human Alzheimers disease brain

A major feature of Alzheimers disease is the accumulation of amyloid- peptide (A) in the brain both in the form of plaques in the cerebral cortex and in blood vessel as cerebral amyloid angiopathy (CAA). Experimental models and human clinical trials have shown that accumulation of A plaques can be reversed by immunotherapy. In this study, we hypothesized that A in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular A. We have performed a follow up study of Alzheimers disease patients immunized against A42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for A40 and A42 was quantified and compared with that in unimmunized Alzheimers disease controls (n 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing A42 in the cerebral cortex (P0.001) and seven times more in the leptomeninges (P 0.013); among the affected blood vessels in the immunized cases, most of them had full thickness and full circumference involvement of the vessel wall in the cortex (P 0.001), and in the leptomeninges (P 0.015). There was also a significantly higher level of cerebrovascular A40 in the immunized cases than in the unimmunized cases (cortex: P 0.009 and leptomeninges: P 0.002). In addition, the immunized patients showed a higher density of cortical microhaemorrhages and microvascular lesions than the unimmunized controls, though none had major CAA-related intracerebral haemorrhages. The changes in cerebral vascular A load did not appear to substantially influence the structural proteins of the blood vessels. Unlike most of the immunized patients, two of the longest survivors, four to five years after first immunization, had virtually complete absence of both plaques and CAA, raising the possibility that, given time, A is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that A immunization results in solubilization of plaque A42 which, at least in part, exits the brain via the perivascular pathway, causing a transient increase in the severity of CAA. The extent to which these vascular alterations following A immunization in Alzheimers disease are reflected in changes in cognitive function remains to be determined.