LAUSR

Background Autopsy and early PET data suggest that cognition is more closely associated with tau than with amyloid pathology, including in clinically normal (CN) older adults. Recently acquired serial tau-PET data allowed us to assess the association between cognition, tau, and amyloid, over a two-year follow-up. We hypothesized that the rate of tau accumulation in the temporal lobe would best predict the rate of cognitive decline. Methods Sixty CN (age = 55–90) from the Harvard Aging Brain Study (Boston, USA) had baseline evaluations within a three-month period [0.0–0.7 y]: Cognitive assessment included the Preclinical Alzheimer Cognitive Composite (PACC); Flortaucipir-PET SUVr assessed tau; and PiB-PET SUVr assessed amyloid. Subsequently, participants had annual cognitive evaluations [follow-up duration: 1.9–4.2y] and repeated tau [1.1–3.0 y] and PiB-PET [1.4–4.1 y]. Tau was measured in bilateral inferior temporal gyri and amyloid in a large cortical aggregate. Data were z-transformed to allow fair comparison between biomarkers. We correlated the slope of PACC decline to baseline PET measures, and to the rate of PET changes. We computed a model in which PET predictors were competing to determine which had the closest association with cognitive decline, adjusting for age, sex, and education. Results All measures (tau, amyloid, cognition) changed during the follow-up ( P 2  = 0.06, P  = 0.07) and amyloid (R 2  = 0.02, P  = 0.24) were not significantly associated with cognition. Baseline tau (R 2  = 0.12, P  = 0.008) and amyloid (R 2  = 0.13, P  = 0.006) predicted subsequent cognitive decline. Faster rates of change in tau predicted faster cognitive decline (R 2  = 0.22, P  = 0.0003). In contrast, faster rates of changes in amyloid did not (R 2  = 0.04, P  = 0.15). When baseline and change measures in amyloid and tau competed in the same model, change in tau predicted change in cognition (semi-partial R 2  = 0.13, P  = 0.001), while baseline tau (semi-partial R 2  = 2.9%, P  = 0.12) and amyloid (semi-partial R 2  = 2.4%, P  = 0.15) were no longer significant predictors. Conclusions Cognitive decline in CN is associated with tau accumulation in the temporal lobe. Tau-PET signal changes faster than cognition or amyloid, which makes it a promising marker to track disease progression and evaluate the efficacy of potential new drugs.