Soluble Aβ 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 Aβ, and
bapineuzumab, targeting
amyloid plaques, prompted expert comments that
drug discovery efforts in
Alzheimer's disease should focus on soluble forms of Aβ rather than fibrillar Aβ deposits found in
amyloid plaques. Accumulating scientific data suggest that soluble Aβ oligomers represent the optimal intervention target within the
amyloid manifold. Active
drug discovery approaches include
antibodies that selectively capture soluble Aβ 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 Aβ 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 cytoskeletal degeneration.