Abstract
INTRODUCTION: The independent contributions of baseline and longitudinal tau positron emission tomography (PET) and magnetic resonance imaging (MRI) to cognitive decline remain unclear. METHODS: We included n = 761 amyloid-positive individuals from the Swedish BioFINDER-2 study with [(18)F]RO948-tau-PET, 3-Tesla structural-MRI, and cognition (n = 322 with longitudinal imaging data). Linear-mixed-models with random-intercepts and -slopes or linear-regressions were adjusted for age, sex, education, diagnosis, and other-imaging-modality. RESULTS: Tau-PET showed stronger associations with cognitive decline than MRI, showing the strongest associations in a neocortical-composite-region with a cognitive composite (β = -0.25 ± 0.02, p < 0.001) for baseline and longitudinal tau-PET (β = -0.62 ± 0.05, p < 0.001). Baseline tau-PET explained the largest proportion of cognitive decline (54.0%-94.0%), with modest mediation effects for longitudinal tau-PET or MRI pathways (2.0%-15.0%). Simulated reductions of tau-PET-slopes (up to 100%) were associated with marginally altered cognitive trajectories. DISCUSSION: The strong associations between baseline tau-PET and longitudinal cognition, with marginal contributions of longitudinal tau-PET and MRI, emphasize the importance of baseline tau aggregates for prognostics and treatments in Alzheimer's disease (AD). HIGHLIGHTS: Baseline and longitudinal regional tau-PET uptake were more closely associated than structural MRI with longitudinal cognitive decline. Baseline tau-PET was a stronger determinant of longitudinal cognitive decline than longitudinal tau-PET. Simulated reductions of tau-PET accumulation showed limited alterations of cognitive trajectories, with potential implications for tau-targeting therapies.