title: The case for soluble Aβ oligomers as a drug target in Alzheimer's disease.
abstract: 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.
authors.affiliation: Acumen Pharmaceuticals Inc., 4435 North First St, Livermore, CA 94551, USA. fhefti@acumenpharm.com
authors.forename: Franz
authors.initials: F
authors.lastname: Hefti
authors.forename: William F
authors.initials: WF
authors.lastname: Goure
authors.forename: Jasna
authors.initials: J
authors.lastname: Jerecic
authors.forename: Kent S
authors.initials: KS
authors.lastname: Iverson
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Walicke
authors.forename: Grant A
authors.initials: GA
authors.lastname: Krafft
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides