PREVALENCE AND LONGITUDINAL CLINICAL OUTCOMES OF ALZHEIMER’S ATN BIOMARKER PROFILES: A LONGITUDINAL STUDY

Abstract

In 2018, the National Institute on Aging and Alzheimer's Association created a research framework to define Alzheimer's Disease (AD) biologically by ATN biomarkers (β-amyloid deposition [A], pathologic tau [T], and neurodegeneration [N]), and treat cognitive impairment as a symptom/sign of the disease. We aimed to estimate the prevalence of each ATN profile in different clinical diagnosis groups and to assess the potential clinical utility of applying the research framework in a large longitudinal cohort. Cognitively normal (CN) participants, mild cognitive impairment (MCI), and AD patients were included from the ADNI, and were assessed at enrolment and every 6 months from August 23, 2005 to March 15, 2017. Longitudinal change in clinical outcomes and conversion risk of ATN profiles are also assessed using linear mixed effects models and multivariate Cox proportional hazard models, respectively. In CN group, the proportions of biomarker profiles were 19.2% A-T-N-, 7.6% A+T-N-, 30.3% A+T+N-, 1% A+T-N+, 2.5% A+T+N+ and 39.4% suspected non-Alzheimer's pathophysiology (SNAP). Among mild cognitive impairment (MCI) patients, the proportions were 26.8% A-T-N-, 3.2% A+T-N-, 32.9% A+T+N-, 2.3% A+T-N+, 30.3% A+T+N+ and 17.4% SNAP. In AD dementia patients, the proportions were 1.5% A-T-N-, 4.4% A+T+N-, 2.9% A+T-N+, 87.6% A+T+N+ and 3.6% SNAP. A+T+N+ showed the fastest clinical progression than the remaining three groups and A+T+N- showed faster clinical progression than A-T-N-, no matter in CN or MCI group. A faster clinical progression was observed in female versus male and APOE ε4 carriers versus APOE ε4 non-carriers in amyloid positive groups. Compared with A-T-N-, participants with A+T+N± had an increased risk of conversion from CN to incident prodromal stage of AD (CDR≥0.5) and from MCI to incident AD dementia. A+T+N+ showed an increased conversion risk when compared with A+T±N-. The Research Framework is valuable to clinical research, and may provide prognostic information of clinical change and progression among non-demented elders which can contribute to clinical care. It may also be useful for targeted recruitment of AD participants into clinical trials, both pharmaceutical and non-pharmaceutical.