Comparison of the amyloid and adaptive response hypotheses. A. Amyloid Hypothesis Cognitive tests and amyloid imaging separate the total population into four distinct groups (1). These groups are: Normal Cognition (NC; 4), NC with Aβ accumulation (NC-Aβ; 2), Neurodegeneration-First AD (NDF-AD; 3), and Amyloid-First AD (AF-AD; 5). Under this hypothesis, only the AF-AD and NC groups (4,5) are going to be studied moving forward in EXPEDITION 3 as disease state and control, whereas the NC-Aβ and NDF-AD groups (2,3) are ignored, as they cannot be explained and do not fit the paradigm. B. Adaptive Response Hypothesis The total population (1) is differentiated by a set of stress variables (2) which may include, but are not limited to, oxidative stress, metabolism dysregulation (cholesterol homeostasis, insulin resistance, etc.), genetic factors, and inflammation response. These variables elicit an adaptive response in the brain and, depending on the nature and intensity of such response, the population falls into two groups, either Normal Cognition (NC) (3) or AD (4), both of which contain Aβ positive and negative subpopulations.