Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels.

Numerous studies have established a pivotal role for A␤42 in Alzheimer's disease (AD) pathogenesis. In contrast, although A␤40 is the predominant form of amyloid ␤ (A␤) produced and accumulates to a variable degree in the human AD brain, its role in AD pathogenesis has not been established. It has generally been assumed that an increase in A␤40 would accelerate amyloid plaque formation in vivo. We have crossed BRI-A␤40 mice that selectively express high levels of A␤40 with both Tg2576 (APPswe, K670NϩM671L) mice and BRI-A␤42A mice expressing A␤42 selectively and analyzed parenchymal and cerebrovascular A␤ deposition in the bitransgenic mice compared with their singly transgenic littermates. In the bitransgenic mice, the increased steady-state levels of A␤40 decreased A␤ deposition by 60 -90%. These results demonstrate that A␤42 and A␤40 have opposing effects on amyloid deposition: A␤42 promotes amyloid deposition but A␤40 inhibits it. In addition, increasing A␤40 levels protected BRI-A␤40/Tg2576 mice from the premature-death phenotype observed in Tg2576 mice. The protective properties of A␤40 with respect to amyloid deposition suggest that strategies that preferentially target A␤40 may actually worsen the disease course and that selective increases in A␤40 levels may actually reduce the risk for development of AD.