A limitation of the NIA AA recommendations

A limitation of the 2011 NIA-AA recommendations was that biomarkers were grouped into just two categories—amyloid and tau-related neurodegeneration. Tauopathy and neurodegeneration were placed into the same biomarker category. In persons with only AD, it is reasonable to assume that neurodegeneration is closely associated with pathologic tau. However, it is increasingly recognized that neurodegeneration/injury, even in classic AD ddhUTP regions, also occurs in non-AD conditions. This is particularly so in elderly individuals where comorbidities are common [92]. AT(N) classification provides a solution to this problem, which is to separate biomarkers that are specific for pathologic tau from those that are nonspecific measures of neurodegeneration/neuronal injury. The AT(N) system was designed with both a CSF and an imaging biomarker in each of the three biomarker groups (Table 1) [16]. Thus, complete AT(N) biomarker characterization of research participants is possible using either imaging or CSF biomarkers alone. However, some research groups may prefer a mixture of imaging and CSF biomarkers for AT(N) characterization. For example, when lumbar puncture and MRI are accessible but PET is not, investigators may choose to use CSF Aβ42 and P-tau as the A and T biomarkers and MRI as the (N) biomarker.
Definition of AD Numerous studies have shown that CU individuals with abnormal amyloid biomarkers have more rapid progression of atrophy, hypometabolism, and clinical/cognitive decline than individuals without biomarker evidence of Aβ deposition [13,33,80,93–99] The proportion of amyloid PET–positive clinically normal individuals by age nearly perfectly parallels the (increasing) age-specific prevalence of individuals clinically diagnosed as AD dementia 15–20 years later [53]. The first biomarkers to become abnormal in carriers of deterministic AD mutations are those of Aβ [9–11,14]. These human data and animal model data [100] suggest a causal upstream role for Aβ in the pathogenesis of AD; and although β-amyloidosis alone is insufficient to cause cognitive deterioration directly, corpus callosum may be sufficient to cause downstream pathologic changes (i.e., tauopathy and neurodegeneration) that ultimately lead to cognitive deterioration. These findings are supported by clinicopathologic studies as well [101,102]. Consequently, a widely held view is that amyloid biomarkers represent the earliest evidence of AD neuropathologic change currently detectable in living persons [9,11,72,103,104]. This suggests that abnormal β-amyloidosis biomarkers alone could serve as the defining signature of AD. However, both Aβ and paired helical filament (PHF) tau deposits are required to fulfill neuropathologic criteria for AD [105,106], which suggests that evidence of abnormalities in both Aβ and pathologic tau biomarkers should be present to apply the label “Alzheimer's disease” in a living person (Fig. 1). With these considerations in mind, the committee agreed on the following definitions. An individual with biomarker evidence of Aβ deposition alone (abnormal amyloid PET scan or low CSF Aβ42 or Aβ42/Aβ40 ratio) with a normal pathologic tau biomarker would be assigned the label “Alzheimer's pathologic change” (Table 2, Fig. 2, Text Box 1). The term “Alzheimer's disease” would be applied if biomarker evidence of both Aβ and pathologic tau was present (Table 2, Fig. 1, Text Box 1). Alzheimer's pathologic change and AD are not regarded as separate entities but earlier and later phases of the “Alzheimer's continuum” (an umbrella term that includes both). These definitions are applied independently from clinical symptoms. They also meet our specifications to function equally well across the disease spectrum: from early- through late-life onset, from presymptomatic through symptomatic phases, and for typical and atypical clinical presentations.
Staging