Biofluid phospho‐tau with subthreshold tau‐PET predicts higher rates of tau accumulation: implications for secondary prevention trials

Abstract

AbstractBackgroundAn important end‐point for disease‐modifying treatments is to target the accumulation of tau. This highlights the need to determine which individuals are most likely to accumulate tau in the future. Different biomarkers of tau become abnormal at different stages of Alzheimer’s disease and capturing the evolution of tau pathology in its entirety will rely on multi‐modal assessments. Here, we examine longitudinal changes in tau accumulation associated with elevated CSF p‐tau and tau‐PET biomarkers.MethodA total of 231 amyloid‐positive (A+) individuals from the BioFINDER‐2 study were categorised into groups based on cut‐offs for abnormal CSF p‐tau217 (P) and [18F]RO948 tau‐PET (T), yielding groups of tau‐concordant‐negative (A+P‐T‐;n = 30), tau‐discordant (A+P+T‐;n = 48) and tau‐concordant‐positive (A+P+T+;n = 18) individuals. In addition, 135 amyloid‐β‐negative, unimpaired individuals served as controls. Differences in regional tau‐PET between groups were assessed using general‐linear models, adjusted for age, sex, clinical‐diagnosis and (for cognitive measures) education. We additionally assessed the effects on cortical thickness and cognition. Mean follow‐up time was ∼2 years.ResultIn the A+P+T‐ group, even though below the threshold for positivity, tau‐PET was higher at baseline than in the control and A+P‐T‐ groups, while cortical thickness and cognition were not different between these groups. For the A+P+T+ group, tau‐PET was higher, and cortical thickness, and cognition were lower at baseline than for controls, A+P‐T‐ and A+P+T‐. Longitudinal increase in tau‐PET was faster in the A+P+T‐ group than in controls and A+P‐T‐, primarily in the medial‐temporal lobe. The A+P+T+ group showed a faster rate of tau‐PET compared to controls and A+P‐T‐ (across the entire brain), and compared to A+P+T‐ (primarily neocortex). There were no differences in cortical thinning or cognitive decline between controls, A+P+T‐ and A+P‐T‐. The A+P+T+ group showed faster cortical thinning and cognitive decline compared to controls, A+P‐T‐ and A+P+T‐.ConclusionThe A+P+T‐ group only shows tau accumulation and no cortical thinning or cognitive decline, and therefore represents an interesting population for early intervention in the AD pathological process, preventing downstream effects. The A+P+T+ group shows fast and widespread tau accumulation and will, therefore, show the greatest beneficial effect of tau‐targeted treatment but already shows cortical thinning and cognitive decline at baseline.