Immunotherapy for Alzheimer's disease

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.

Figure 1

Opsonization and Phagocytosis. Anti-Aβ antibodies bind to Aβ aggregates within the CNS. The immune complex then stimulates phagocytosis by Fc-gamma receptor bearing macrophages. The ingested Aβ is then digested and/or exported from the CNS. Reprinted from Ugen, K. and Morgan, D. DNA and Cell Biology 20:677–678

Figure 2

Peripheral Sink. Circulating anti-Aβ antibodies bind free Aβ in the blood and increase the efflux of Aβ down its concentration gradient and/or block the influx of Aβ from the circulation and back into the brain. Reprinted from Ugen, K. and Morgan, D. DNA and Cell Biology 20:677–678

Figure 3

Catalytic Modification of Conformation. Antibody binds Aβ and modifies the secondary structure to one which minimizes the formation of aggregates. Reprinted from Ugen, K. and Morgan, D. DNA and Cell Biology 20:677–678