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 ([(18)F]-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.

Figure 1. Images of clinically normal individuals and participants with AD

Individuals with AD dementia are clinically diagnosed participants in Mayo Alzheimer's Disease Research Center study while clinically normal individuals are participants in the Mayo Clinic Study of Aging. (A) FDG-PET of 75-year-old man with AD dementia. Hypometabolism in medial parietal and lateral temporal-parietal isocortex with relative preservation of frontal metabolism, which is characteristic of typical (multidomain amnestic) AD. (B) FDG-PET of clinically normal 71-year-old man. Uniform FDG uptake is present throughout the isocortex. (C) MRI of 71-year-old man with AD dementia. Atrophy is present in the medial temporal allocortex and the basal-lateral temporal isocortex, which is characteristic of typical (multidomain amnestic) AD. (D) MRI of clinically normal 71-year-old woman without atrophy. (E) Amyloid PET with Pittsburgh compound B of 71-year-old woman with AD dementia. Ligand uptake is seen throughout the isocortex. (F) Amyloid PET of clinically normal 93-year-old man showing no ligand uptake in the isocortex. AD = Alzheimer disease; FDG = [¹⁸F]-fluorodeoxyglucose.

Figure 2. Tau and amyloid PET imaging in AD

A 79-year-old man with a clinical diagnosis of AD dementia. He is a participant in the Mayo Alzheimer's Disease Research Center study. (A, B) Coronal and axial tau PET images (AV1451) superimposed on MRI. (C, D) Coronal and axial Pittsburgh compound B PET images superimposed on MRI. The tau PET images (top) illustrate extensive tracer uptake in basal lateral temporal, parietal, and frontal isocortex with sparing of sensory motor and primary visual cortices. Off-target binding is seen in the basal ganglia, which is characteristic of this tracer. Although areas of spatial overlap between the tau and amyloid tracers are present, abundant amyloid tracer uptake is seen in the frontal lobes, but not with the tau tracer. Conversely, abundant uptake is seen in the medial temporal lobes with the tau ligand but not with the amyloid ligand. AD = Alzheimer disease.