title: Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer's disease immunotherapeutics.
abstract: Levels of amyloid-beta monomer and deposited amyloid-beta in the Alzheimer's disease brain are orders of magnitude greater than soluble amyloid-beta oligomer levels. Monomeric amyloid-beta has no known direct toxicity. Insoluble fibrillar amyloid-beta has been proposed to be an in vivo mechanism for removal of soluble amyloid-beta and exhibits relatively low toxicity. In contrast, soluble amyloid-beta oligomers are widely reported to be the most toxic amyloid-beta form, both causing acute synaptotoxicity and inducing neurodegenerative processes. None of the amyloid-beta immunotherapies currently in clinical development selectively target soluble amyloid-beta oligomers, and their lack of efficacy is not unexpected considering their selectivity for monomeric or fibrillar amyloid-beta (or both) rather than soluble amyloid-beta oligomers. Because they exhibit acute, memory-compromising synaptic toxicity and induce chronic neurodegenerative toxicity and because they exist at very low in vivo levels in the Alzheimer's disease brain, soluble amyloid-beta oligomers constitute an optimal immunotherapeutic target that should be pursued more aggressively.
authors.affiliation: Acumen Pharmaceuticals, Inc., 4453 North First Street, #360, Livermore, CA 94551, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Goure
authors.affiliation: Acumen Pharmaceuticals, Inc., 4453 North First Street, #360, Livermore, CA 94551, USA.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Krafft
authors.affiliation: Acumen Pharmaceuticals, Inc., 4453 North First Street, #360, Livermore, CA 94551, USA.
authors.forename: Jasna
authors.initials: J
authors.lastname: Jerecic
authors.affiliation: Acumen Pharmaceuticals, Inc., 4453 North First Street, #360, Livermore, CA 94551, USA.
authors.forename: Franz
authors.initials: F
authors.lastname: Hefti