Continuum of Core 1 biomarkers in preclinical Alzheimer’s disease

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BACKGROUND: Biological Staging for Alzheimer’s disease (AD) in clinically unimpaired (CU) individuals is critical for early detection efforts. In this study, we evaluated whether Core 1 biomarkers (plasma p-tau217 and amyloid-PET) within Biological Stage A, the earliest biological stage of AD, predict progression of downstream biomarkers and cognition. METHODS: We used baseline plasma p-tau217 and amyloid-PET, and longitudinal tau-PET, atrophy, and cognition data from the recently completed Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study. PET data were used to identify participants within AD Biological Stage A (amyloid-PET positive and medial temporal tau-PET negative). Within these Stage A participants, linear mixed effects models were used to examine associations between baseline levels of plasma p-tau217 and amyloid-PET burden with longitudinal regional tau-PET, atrophy, and cognition. We additionally evaluated whether p-tau217 and amyloid-PET burden within this group were associated with higher risk of progression to Biological Stage B+ (tau-PET positive in the medial temporal lobe). In our statistical models, we included covariates for age, sex, and APOE4 carriage. RESULTS: Of 335 A4 participants with complete biomarker data, 222 were identified as being in Biological Stage A. Among Biological Stage A CU, baseline plasma p-tau217 and amyloid-PET burden were associated with faster tau-PET accumulation and atrophy in AD-relevant regions (mean [SD] follow-up time for tau-PET: 4.2 [2.1] years and MRI: 4.2 [1.9] years), as well as faster cognitive decline (mean [SD] follow-up time for PACC: 5.7 [1.6] years) (all p < 0.05). Plasma p-tau217 and amyloid-PET burden were also associated with higher risk of progression to Biological Stage B+. DISCUSSION: In CU individuals in the initial stage of AD (Biological Stage A), early changing AD biomarkers provide prognostic information of downstream markers of disease. Evaluation of the utility of these measures in a real-world setting is warranted. TRIAL REGISTRATION: The A4 study was submitted for registration to clinicaltrials.gov on December 6th, 2013. The study is registered with ID NCT02008357. Screening and data collection for the study began in April 2014.

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