Preclinical Alzheimer's or asymptomatic at-risk?

In the latest NIA-AA criteria, AD diagnosis is centered exclusively around a biomarker definition of disease according to ATN status. This proposal moved AD to a purely biological condition dissociated from a clinical phenotype. However, evidence suggest that the presence of tau and amyloid positivity is insufficient to definitively predict the invariable occurrence of symptoms or progression to dementia in those without clinical findings. Longitudinal molecular neuro-imaging studies are also inconsistent in predicting a reliable outcome at an individual level for those who are amyloid and tau positive and cognitively unimpaired, even after long-term follow-up. In addition, cross-sectional data from both post-mortem and in vivo studies demonstrate an overlap between AD neuropathologic changes observed in cognitively normal subjects and in patients with AD dementia. In clinical practice, the limitation of a biological definition of AD will be centered for the foreseeable future on the preclinical stage of the disease. Given the inability to predict reliable clinical trajectories of those who are asymptomatic with biomarker positive status, the following statements are proposed for the clinical setting: 1) the diagnosis of AD is clinical-biological: it requires the presence of both a specific clinical phenotype of AD and biomarker evidence of AD pathology (A + T+); 2) biomarker positive cognitively unimpaired individuals should not be considered as preclinical AD but “at-risk for progression” (ARP) to prodromal AD; 2) measures of pathophysiological markers are not recommended in cognitively unimpaired individuals, in the absence of therapies or prevention programs showing efficacy on delaying onset of disease.