The case for soluble Aβ oligomers as a drug target in Alzheimer's disease

Soluble A beta oligomers are now widely recognized as key pathogenic structures in Alzheimer's disease. They inhibit synaptic function, leading to early memory deficits and synaptic degeneration, and they trigger the downstream neuronal signaling responsible for phospho-tau Alzheimer's pathology. The marginal effects observed in recent clinical studies of solanezumab, targeting monomeric A beta, and bapineuzumab, targeting amyloid plaques, prompted expert comments that drug discovery efforts in Alzheimer's disease should focus on soluble forms of A beta rather than fibrillar A beta deposits found in amyloid plaques. Accumulating scientific data suggest that soluble A beta oligomers represent the optimal intervention target within the amyloid manifold. Active drug discovery approaches include antibodies that selectively capture soluble A beta oligomers, selective modifiers of oligomer assembly, and receptor antagonists. The onset of symptomatic clinical benefit is expected to be rapid for such agents, because neuronal memory signaling should normalize on blockage of soluble A beta oligomers. This key feature is not shared by amyloid-lowering therapeutics, and it should translate into streamlined clinical development for oligomer-targeting drugs. Oligomer-targeting drugs should also confer long-term disease modification and slowing of disease progression, because they prevent the downstream signaling responsible for phospho-tau mediated cyto-skeletal degeneration.