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

Abstract

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‐β 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.

Symptomatic clusters related to amyloid positivity in cognitively unimpaired individuals

“…The advantage of this approach is that longitudinal testing is not required. Replication of our results with a longitudinal criterion of transitional cognitive decline will increase comparability with previous stage 2 operationalization approaches [40,41].…”

Investigating cognition in midlife

“…Recent advances in translating basic discoveries into clinical settings revealed that molecular perturbations of cognitive disorders begin decades prior to the onset of cognitive phenotypes and decline 27 . These findings led to the introduction of biological definitions of cognitive disorders 28 with the aim to further refine our understanding and evaluation of cognitive disorders including their clinical phenotypes 29 …”

“…27 These findings led to the introduction of biological definitions of cognitive disorders 28 with the aim to further refine our understanding and evaluation of cognitive disorders including their clinical phenotypes. 29…”

The impact of conventional versus robust norming on cognitive characterization and clinical classification of MCI and dementia

“…While these samples exclude individuals with current cognitive impairment, they may include some individuals who eventually go on to develop cognitive impairment (Ritchie et al, 2007). The presence of such individuals in a normative group creates the possibility that subtle cognitive impairments are being missed in normative comparisons, as prior research has shown that individuals who go on to develop MCI and dementia typically show preclinical signs of cognitive decline (Dubois et al, 2016; Kiselica & Alzheimer's Disease Neuroimaging Initiative, 2021; Saxton et al, 2004; Thomas et al, 2018).…”