We next developed a system

We next developed a system for staging severity. Our guiding principles were the following. Two types of information about the research participant are staged independently from each other: (1) grading disease severity using biomarkers and (2) grading the severity of cognitive impairment. Measures used to define AD must be specific for the disease, whereas measures used to stage severity need not be. Thus, different measures have different roles (Text Box 2). Aβ biomarkers determine whether or not an individual is in the Alzheimer's continuum. Pathologic tau biomarkers determine if someone who Diosmetin is in the Alzheimer's continuum has AD because both Aβ and tau are required for a neuropathologic diagnosis of the disease. Neurodegenerative/neuronal injury biomarkers and cognitive symptoms, neither of which is specific for AD, are used only to stage severity not to define the presence of the Alzheimer's continuum.
Biomarker profiles and categories The addition of a normal/abnormal cut point for each AT(N) biomarker group results in eight different AT(N) “biomarker profiles” (Table 2, Text Box 1): A+T−(N)−, A+T+(N)+, etc. Based on the definitions of Alzheimer's pathologic change and AD outlined earlier, the ATN biomarker system assigns every individual to one of three “biomarker categories” (Table 2, Text Box 1): (1) individuals with normal AD biomarkers; (2) those in the Alzheimer's continuum (subdivided into Alzheimer's pathologic change and AD); and (3) those with a normal amyloid biomarker but with abnormal T or (N), or both. This latter biomarker profile implies evidence of one or more neuropathologic processes other than AD [35,40,107] and has been labeled “suspected non-Alzheimer's pathophysiology” (or SNAP) [38]. It is worthwhile emphasizing that, like the 2012 NIA-AA classification system for AD neuropathic change [105,106], AT(N) scoring of biomarkers is independent from clinical symptoms. Although the term “stage” is more familiar, we use the term “biomarker profile” (Table 2) because the term “stage” implies a sequence, that is, stage 1 always precedes stage 2, etc. The AT(N) biomarker system does not imply a specific order of events nor does it imply causality. It is a system for grouping biomarkers and classifying research participants on the basis of biomarker profiles. A−T−(N)− represents a state without evidence of pathologic change that is detectable by AT(N) biomarkers, whereas A+T+(N)+ represents an advanced pathologic state. Staging can be accomplished by combining information from each of the three biomarker groups; the more biomarker groups that are abnormal, the more advanced the pathologic stage. The rate of cognitive decline is significantly greater for cognitively impaired and CU individuals who have abnormalities in both an amyloid biomarker and a second biomarker type (which could be CSF T-tau or P-tau, atrophy, or hypometabolism) in comparison to individuals who have neither or only one of these biomarker abnormalities [30–35,39,40,42–45]. These data firmly establish that more advanced disease defined by biomarkers predicts greater likelihood of and more rapid cognitive decline. Thus, a solid evidence base exists proving that combinations of biomarker abnormalities are useful for staging the Alzheimer's continuum.
Characteristics and limitations of biomarkers
Cognitive staging Like biomarkers, cognitive performance exists on a continuum. An obvious approach to cognitive staging therefore is to use continuous cognitive instruments, which may be the preferred outcome measure in many modern clinical trials [175]. While recognizing that cognition does exist on a continuum, the committee felt it was also appropriate to outline categorical cognitive staging schemes. In the 2011 NIA-AA guidelines, cognitive staging was implicit rather than explicit. Three different documents were published describing preclinical AD, MCI, and dementia; however, these categories have at times been interpreted to indicate three distinct entities. In the research framework, we avoid the notion of separate entities and instead refer to the “cognitive continuum”.