Aß immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy.

ABSTRACT

Aß immunotherapy for Alzheimer's disease (AD) results in the removal of Aß plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aß transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aß immunotherapy. 12 Aß42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aß42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aß immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aß42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %, P < 0.001), but smooth muscle cell abnormalities did not differ. The findings suggest that apoE is involved in the removal of plaques and transport of Aß to the cerebral vasculature induced by Aß immunotherapy. Immunotherapy was not associated with CAA-related vascular smooth muscle damage, but was accompanied by increased splitting of the vessel wall, perhaps reflecting enhanced deposition and subsequent removal of Aß. ARIA occurring in some current trials of Aß immunotherapy may reflect an extreme form of these vascular changes.