Estimating the time between amyloid and tau‐pet positivity: implications for Alzheimer’s disease prevention trials

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is characterized by a preclinical stage in which abnormal accumulation of amyloid‐ß (Aß) leads to phosphorylated tau aggregation. This sequence of events represents the transition between “AD pathologic change” (A+T‐) to the much riskier full AD neuropathology (A+T+, Jack et al. Alzheimers Dement. 2018). Thus, to understand the clinical relevance of the A+T‐ stage in the long term, it is important to understand the temporal course of Aß and tau. In this study, we used longitudinal Aß‐ and tau‐positron emission tomography (PET) to estimate the expected time gap between Aß‐ and tau‐PET positivity, and explored factors that influenced this gap.MethodWe estimated the natural history of amyloid accumulation in AD using longitudinal Aß‐PET data from 1690 AD‐continuum subjects from the ADNI. Specifically, we fitted a non‐linear mixed effects model (3‐knot spline) and modelled the subject‐specific “age of Aß positivity” as random effects (Figure 1). An interval‐censored time‐to‐event analysis using “time to amyloid positivity” as time variable was performed on 318 Aß+ ADNI participants who had available tau‐PET ([18F]flortaucipir) visual reads. Cox proportional hazards regression was used to assess whether age of onset of amyloid positivity, sex, APOE status, and cognitive impairment at follow‐up influenced the onset of tau‐PET positivity relative to Aß‐positivity.ResultAfter ∼11 years from Aß positivity, 50% of the CU individuals progressed to tau‐PET positivity, while only ∼17% remained tau‐PET negative after 20 years (Figure 2). Among the studied factors, only the presence of cognitive impairment accelerated the onset of visual tau‐PET positivity (HR = 2.52, p<0.001, median tau‐free survival difference ∼6 years) (Figure 3). Both female sex (HR = 1.44, p = 0.16, median tau‐free survival difference∼2.5 years) and presence of the APOE‐e4 allele (HR = 1.44, p = 0.15, median tau‐free survival difference∼2.5 years) were trend‐level associated to faster onset of tau‐PET positivity.ConclusionThe time gap between Aß‐ and tau‐PET positivity typically spans a decade and is highly variable across individuals. This long gap implies that a significant fraction of A+T‐ CU older individuals will never develop tau‐PET positivity and subsequent symptoms in their lifespan, which suggests that these subjects may not benefit from current disease‐modifying therapies for AD.