Fig. 6.

Hypothesis testing using the research framework. In this figure, we outline various possible mechanistic pathways that involve A, T, (N), and (C). We believe current evidence most strongly supports the “modified amyloid cascade hypothesis” pathway denoted in (A), and this is reflected in the terminology in Table 2. However, we illustrate several alternatives that could be tested using the research framework. These are discussed in the text. This is not intended to represent an exhaustive list of all possible pathways but rather an illustration of some possible mechanistic pathways where A and Tare and are not causal in AD pathogenesis. In each of these models, the final common pathway is (N) → (C), which is based on the assumption that in neurodegenerative diseases, neuronal/ synaptic damage is the histopathologic feature that is most proximate to cognitive impairment. Abbreviation: AD, Alzheimer disease.