Continuum of Core 1 Biomarkers in Preclinical Alzheimers Disease

Background and Objectives: 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 ptau-217 and amyloid-PET) within Biological Stage A, the earliest biological stage of AD, predicts progression of downstream biomarkers and cognition. Methods: We used baseline plasma ptau-217 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 continuous baseline levels of plasma p-tau217 and amyloid-PET burden with longitudinal regional tau-PET, atrophy, and cognition. We additionally evaluated whether continuous ptau217 and amyloid-PET burden within this group was 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, continuous baseline plasma p-tau217 and amyloid-PET burden were independently associated with faster tau-PET accumulation and atrophy in AD-relevant regions (mean follow-up time for both tau-PET and MRI: 4.2 years), as well as faster cognitive decline (mean follow-up time for PACC: 5.7 years) (all p<0.05). Plasma p-tau217 and amyloid-PET burden were independently associated with higher risk of progression to Biological Stage B+. Discussion: In CU individuals, early changing AD biomarkers during the initial stage of AD (Biological Stage A) provide prognostic information of downstream markers of disease. Evaluation of the utility of these continuous measures in a real-world setting is warranted. Clinical Trial Information: The A4 study was submitted for registration to clinicaltrials.gov on December 6th, 2023. The study is registered with ID NCT02008357 . Screening and data collection for the study began in April 2014.