Spatial patterns of tau accumulation across the Alzheimer's disease spectrum

INTRODUCTION The spatial progression of longitudinal tau pathology has been inferred using cross‐sectional data, but longitudinal voxel‐wise analyses allow these patterns to be established without inference. METHODS We pooled 1426 flortaucipir (FTP) positron emission tomography (PET) scans from 583 participants across the aging and Alzheimer's disease (AD) spectrum from four studies. Using longitudinal tau‐PET slope maps, we examined tau accumulation by clinical group and its associations with participant characteristics, baseline beta‐amyloid (Aβ), and tau. RESULTS Tau accumulation was limited to temporoparietal cortices in unimpaired participants but widespread in patients. Baseline Aβ, entorhinal, and inferior temporal tau predicted progressively more severe tau accumulation patterns. Age, sex, and apolipoprotein E (APOE) ε4 had modest moderating effects. Aβ and early tau interactions showed synergistic effects. Greater tau accumulation was linked to worse follow‐up cognition than baseline. DISCUSSION While Aβ influences early tau progression, baseline tau drives later progression. These results may guide future trials targeting tau accumulation at different disease stages. Highlights Faster tau spread from temporal to frontal lobes was linked to clinical impairment. Global beta‐amyloid (Aβ), entorhinal, and inferior temporal gyrus (ITG) tau predicted progressively worse tau accumulation. Age, sex, and apolipoprotein E (APOE) had minimal effects on tau accumulation. Aβ and early tau burden interact synergistically to drive tau accumulation. More severe tau accumulation was linked to worse cognition at follow‐up than baseline.