Abstract
In the year 1999, a vaccine approach was found to reduce amyloid deposits in transgenic mice overproducing the amyloid precursor protein. This was followed closely by demonstrations that vaccines or passive immunotherapy could rescue memory deficits in these mice. Initial human clinical trials revealed apparent autoimmune reactions in a subset of patients, but also some cases of cognitive benefit and amyloid clearance. Further work with passive immunotherapy in mouse models confirmed exceptional clearing abilities of anti-amyloid antibodies even in older mice. However, in parallel with parenchymal amyloid clearance was the appearance of microhaemorrhages and increased vascular amyloid deposition. Additional clinical trials with passive immunotherapy confirmed occasional appearance of microhaemorrhage and occurrence of vasogenic oedema in some patients, particularly those with the apolipoprotein E4 genotype. Recent data with positron emission tomography demonstrates trial participants passively immunized with anti-Aß antibodies have reduced signals with amyloid binding ligands after 18 months of therapy. Several anti-Aß immunotherapies have reached phase 3 testing, and immunotherapy is likely to be the first test of the amyloid hypothesis of Alzheimer's disease. Identifying antibody variants that retain amyloid clearance with fewer adverse reactions remains a major focus of translational research in this area.