The specific amyloid-beta (Aβ) species or other amyloid-precursor protein cleavage products that are most directly related to human neurodegeneration and clinical dementia of the Alzheimer’s type have not yet been directly identified. Without a clear understanding of the most relevant species, it is difficult to determine whether therapeutic candidates successfully engaged the correct target(s). Here, we review some of the controversies regarding soluble Aβ aggregates (also termed oligomers, dimers, trimers, Aβ56, amylospheroids, etc.) and propose experiments designed to move forward towards new therapeutic approaches. Specifically, we review the increasing evidence for the relevance of non-canonical forms of Aβ, the much more potent toxicity attributable to native species than to synthetic Aβ, and the evidence implicating the ratio of soluble Aβ aggregates to plaques in differentiating demented patients from non-demented high Aβ plaque pathology controls. To move forward, we propose four related directions. 1) Narrowing the focus to species derived from human Alzheimer’s disease (AD) brain tissue, as opposed to synthetic Aβ, cell culture-derived species, or species primarily present in animal models. 2) Careful study of differences between patients with dementia of the Alzheimer’s type vs. non-demented controls with high Aβ plaque pathology. This will involve testing the hypothesis that, under some circumstances, plaques may buffer soluble toxic species, but later release them into the surrounding milieu. 3) Investigations of other protein constituents of soluble Aβ aggregates in addition to Aβ itself. Our initial data based on chemical cleavage experiments indicate that other proteins do appear to be part of the human brain soluble Aβ aggregates. 4) Multimodal experimental assessments of toxicity, including longer term effects on synapse loss, related deleterious cellular responses, and degeneration in human-derived neuron-like cells. Overall, the goal is to identify specific Aβ species, other amyloid precursor protein cleavage products, or other key proteins in aggregates present in human AD brains, less abundant in non-demented high pathology control brains, and robustly toxic in a wide variety of relevant assays. These species themselves, the enzymatic or cellular processes involved in their production, and their routes of clearance would be highly relevant therapeutic targets for dementia of the Alzheimer’s type. © 2017 The Author(s).