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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.

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Alzheimer's disease, senile dementia, atherosclerosis, senile dementia of the Alzheimer's type, NINCDS-ADRDA probable Alzheimer's disease, IWG prodromal Alzheimer's disease, NIA-AA preclinical Alzheimer's disease, IWG2 at risk for Alzheimer's disease... This disease has been in dynamic re-definition for the past 115 years. Biomarkers of AD pathology have allowed to perform an "in vivo neuropathology" and demonstrate the presence of brain pathology long before any sign of cognitive deterioration, and possibly even in persons who will never develop cognitive deterioration. In persons with cognitive impairment, this has provided the unprecedented opportunity of an accurate molecular diagnosis and paved the way to personalised pathology-based interventions. In persons with no cognitive impairment, the detection of pathology is not accompanied by the prediction of when, and even if, cognitive impairment will develop. This uncertainty must be sorted out for biomarkers to be used appropriately and safely in this population and for the very concept of Alzheimer's disease to be fleshed out once and for all.