Biomarker evidence for uncoupling of amyloid build‐up and toxicity in Alzheimer's disease

Certain preparations of Alzheimer‐associated amyloid beta (Aβ) exhibit rapid (within minutes) synaptotoxicity when applied to hippocampal slices or neuronal cell cultures, or when injected into the central nervous system of rodents. In addition, it is well known that some elderly people have brain amyloidosis without showing signs of cognitive impairment or neurodegeneration beyond the age norm. Biomarkers, reviewed extensively in a recent Perspectives article in Alzheimer's & Dementia , suggest that amyloid‐positive individuals are at higher risk of Alzheimer's disease than similarly aged individuals without evidence of brain amyloidosis, provided they live long enough. But how can the brain resist amyloid pathology for many years? Here, we expand on recent biomarker studies suggesting that Aβ build‐up and toxicity may occur in two phases. We hypothesize that the first phase may involve an autocatalytic build‐up of a nontoxic Aβ reservoir, tentatively named the Aβ Cat pool, and that gain of toxicity may require brain incubation of Aβ in the water‐deprived plaque milieu over years to produce modified forms of the protein that are truly neurotoxic (Aβ Tox ). We argue for the need to describe the molecular natures of Aβ Cat and Aβ Tox in greater detail as a means to gain success in anti‐Aβ disease‐modifying drug development.