The prognostic value of ATN Alzheimer biomarker profiles in cognitively normal individuals

Alzheimer disease (AD) is characterized by a long preclinical stage, in which the presence of progressively increasing AD pathology is not yet accompanied by clinical symptoms. In this preclinical stage, biomarkers of amyloid pathology and neurodegeneration have prognostic value with regard to cognitive outcome.^1,2 The newly proposed ATN classification framework aims to further refine the pathophysiology and staging of AD, by differentiating between several neurodegeneration markers (T and N). In the ATN classification, A stands for β-amyloid (Aβ) pathology (CSF or PET), T for tau pathology (CSF phosphorylated tau [p-tau] or tau PET), and N for other nonspecific biomarkers of neurodegeneration, such as hippocampal volume, CSF total tau (t-tau), and FDG-PET. The framework includes 8 possible subgroups, ranging from a group in which all biomarkers are negative (A−T−N−) to one in which all are positive (A+T+N+). This framework provides a mechanism to operationalize the recent National Institute of Aging and Alzheimer's Association research criteria for AD, which state that both Aβ and tau pathology are required for classification as AD, regardless of the presence of clinical symptoms.³ The frequencies of ATN biomarker groups change with age among cognitively normal individuals, from age 50 onwards, such that the A−T−N− prevalence declines while A+T+N+ prevalence increases with age⁴; in this cross-sectional study, greater positivity in these ATN biomarker profiles was associated with lower cognitive performance, although the prognostic import of these biomarkers was not evident.