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Objective: To test the hypothesis that among cognitively healthy individuals, distinct groups exist in terms of amyloid and phosphorylated-tau accumulation rates; that if rapid accumulator groups exist, their membership can be predicted by Alzheimer's disease (AD) risk factors, and that time points of significant increase in AD protein accumulation will be evident. Methods: The analysis reports data from 263 individuals from the BIOCARD and 184 individuals from the Baltimore Longitudinal Study of Aging with repeated cerebrospinal fluid (CSF) and positron emission tomography (PET) sampling, respectively. We used latent class mixed-effect models to identify distinct classes of amyloid (CSF and PET) and p-Tau (CSF) accumulation rates and generalized additive modeling to investigate non-linear changes to AD biomarkers. Results: For both amyloid and p-Tau latent class models we confirmed the existence of two separate classes: accumulators and non-accumulators. The accumulator and non-accumulator groups differed significantly in terms of baseline AD protein levels and slope of change. APOE ε4 carrier status and episodic memory predicted amyloid class membership. Non-linear models revealed time points of significant increase in the rate of amyloid and p-Tau accumulation whereby APOE ε4 carrier status associated with earlier age at onset of rapid accumulation. Conclusions: The current analysis demonstrates the existence of distinct classes of amyloid and p-Tau accumulators. Predictors of class membership were identified but the overall accuracy of the models was modest, highlighting the need for additional biomarkers that are sensitive to early disease phenotypes.

Original publication




Journal article


Alzheimers Dement (Amst)

Publication Date





CSF, amyloid, emerging Alzheimer's disease pathology, phosphorylated tau, positron emission tomography