In cognitively unimpaired older adults with confirmed amyloid-beta pathology, the presence of both elevated plasma p-tau217 levels (≥0.28 U/mL) and visually positive tau-PET scans is associated with the fastest rate of neocortical tau accumulation, accelerated gray matter atrophy in fronto-temporo-parietal regions, and the most rapid cognitive decline over five years.

Amyloid buildup in the brain causes tau proteins to become abnormally phosphorylated and spread from deep brain regions to the outer cortex. As these abnormal tau proteins clump into tangles inside neurons, they damage the cells' internal structure, kill neurons, and shrink brain tissue in areas responsible for memory and thinking. The amount of abnormal tau in the blood rises early, signaling this process is active, and when enough tangles form in the cortex, they become visible on brain scans. People with both high blood tau and visible brain tangles lose brain tissue and cognitive function fastest.