Aβ43 in human Alzheimer's disease: effects of active Aβ42 immunization

Neuropathological follow-up of patients with Alzheimer's disease (AD) who participated in the first clinical trial of Amyloid-beta 42 (A beta 42) immunization (AN1792, Elan Pharmaceuticals) has shown that immunization can induce removal of A beta 42 and A beta 40 from plaques, whereas analysis of the cerebral vessels has shown increased levels of these A beta peptides in cerebral amyloid angiopathy (CAA). A beta 43 has been less frequently studied in AD, but its aggregation propensity and neurotoxic properties suggest it may have an important pathogenic role. In the current study we show by using immunohistochemistry that in unimmunized AD patients A beta 43 is a frequent constituent of plaques (6.0% immunostained area), similar to A beta 42 (3.9% immunostained area). A beta 43 immunostained area was significantly higher than that of A beta 40 (2.3%, p = 0.006). In addition, we show that A beta 43 is only a minor component of CAA in both parenchymal vessels (1.5 A beta 43-positive vessels per cm(2) cortex vs. 5.3 A beta 42-positive vessels, p = 0.03, and 6.2 A beta 40-positive vessels, p = 0.045) and leptomeningeal vessels (5.6% A beta 43-positive vessels vs. 17.3% A beta 42-positive vessels, p = 0.007, and 27.4% A beta 40-positive vessels, p = 0.003). Furthermore, we have shown that A beta 43 is cleared from plaques after A beta immunotherapy, similar to A beta 42 and A beta 40. Cerebrovascular A beta 43 levels did not change after immunotherapy.