A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers

Abstract

Biomarkers have become an essential component of Alzheimer disease (AD) research and because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. A number of current issues suggest that an unbiased descriptive classification scheme for these biomarkers would be useful. We propose the “A/T/N” system in which 7 major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology that each measures. “A” refers to the value of a β-amyloid biomarker (amyloid PET or CSF Aβ42); “T,” the value of a tau biomarker (CSF phospho tau, or tau PET); and “N,” biomarkers of neurodegeneration or neuronal injury ([18F]-fluorodeoxyglucose–PET, structural MRI, or CSF total tau). Each biomarker category is rated as positive or negative. An individual score might appear as A+/T+/N−, or A+/T−/N−, etc. The A/T/N system includes the new modality tau PET. It is agnostic to the temporal ordering of mechanisms underlying AD pathogenesis. It includes all individuals in any population regardless of the mix of biomarker findings and therefore is suited to population studies of cognitive aging. It does not specify disease labels and thus is not a diagnostic classification system. It is a descriptive system for categorizing multidomain biomarker findings at the individual person level in a format that is easy to understand and use. Given the present lack of consensus among AD specialists on terminology across the clinically normal to dementia spectrum, a biomarker classification scheme will have broadest acceptance if it is independent from any one clinically defined diagnostic scheme.

Differentiating cognitive impairment due to corticobasal degeneration and Alzheimer disease

“…In contrast, AD biomarkers are increasingly used in research and clinical settings to determine individual risk of AD pathology and support clinical diagnoses. 37 It may be challenging to use AD biomarkers to differentiate individuals with cognitive impairment due to CBD and AD because AD copathology was present in the majority of individuals with CBD (10 of 17, 59%) in this cohort (previously reported in 13%-27% 2,9 ). Given the high prevalence of AD copathology, some individuals with CBD may test positive for AD-specific biomarkers, leading to misplaced confidence in the clinical diagnosis.…”

Update on Alzheimer's Disease Therapy and Prevention Strategies

“…Recently, Jack et al (102) proposed a descriptive classification scheme to be used as a framework whereby patients are classified based on the presence or absence of three key factors: Aβ (A), NFTs (T), and neurodegeneration (N), to be complemented by cognitive evaluation. The A/T/N classification system is not an individual diagnostic tool, but rather a biomarker classification scheme that allows the description and characterization of a wide range of patients, based on specific biomarkers.…”

Amyloidosis and neurodegeneration result in distinct structural connectivity patterns in mild cognitive impairment

“…This may have led to reduced statistical power to detect differences between groups, and it is possible that additional alterations would be discovered within a larger cohort. Another limitation is that our biomarker-based stratification model did not use the very recently published unbiased A/T/N classification scheme incorporating tau biomarkers (T) (Jack et al, 2016a). We did not incorporate tau biomarkers in our classification because tau PET imaging was not available in our dataset, and CSF tau was available only in a small fraction of the patients.…”