Consequence of Aβ immunization on the vasculature of human Alzheimer's disease brain

A major feature of Alzheimer's disease is the accumulation of amyloid-β peptide (Aβ) 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 Aβ plaques can be reversed by immunotherapy. In this study, we hypothesized that Aβ in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular Aβ. We have performed a follow up study of Alzheimer's disease patients immunized against Aβ42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for Aβ40 and Aβ42 was quantified and compared with that in unimmunized Alzheimer's disease controls (n = 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing Aβ42 in the cerebral cortex (P<0.001) 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 Aβ40 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 Aβ 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, Aβ is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that Aβ immunization results in solubilization of plaque Aβ42 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 Aβ immunization in Alzheimer's disease are reflected in changes in cognitive function remains to be determined.