Empirically defining the preclinical stages of the Alzheimer's continuum in the Alzheimer's Disease Neuroimaging Initiative

Aim The National Institute on Aging and the Alzheimer's Association published new research criteria defining the Alzheimer's continuum (AC) by the presence of positive amyloid-beta biomarkers. Symptom severity of those on the AC is staged across six levels, including two preclinical stages (stages 1 and 2). AC stage 2 is defined by the presence of at least one of the following: (i) transitional cognitive decline; (ii) subjective cognitive decline; or (iii) neurobehavioural symptoms. In contrast, AC stage 1 is defined by the absence of symptoms. Methods Initial empirical definitions for each symptom class were developed. These empirical criteria were then applied in a sample of 285 cognitively normal, amyloid-positive individuals from the Alzheimer's Disease Neuroimaging Initiative for purposes of AC stage 1 and 2 classification. Results In this sample, 56.10% of participants were asymptomatic and classified as AC stage 1. In contrast, 42.46% of individuals were positive for at least one symptom class: 22.11% for transitional cognitive decline, 20.35% for subjective cognitive decline, and 14.74% for neurobehavioural symptoms. AC stage was a predictor of cognitive/functional decline over 4 years of follow up in a longitudinal growth model (B = 0.33, P < 0.001). Conclusions Results provide a methodology to operationalize the National Institute on Aging and the Alzheimer's Association AC stage 1 and 2 criteria and include preliminary evidence of the validity of this approach. The methods outlined in this manuscript can be used to test hypotheses regarding prodromal Alzheimer's disease, as well as implemented in clinical trial selection procedures.