In cognitively unimpaired individuals with amyloid-beta pathology, discordant biomarker profiles (elevated plasma p-tau217 without tau-PET positivity or vice versa) are associated with significantly slower rates of tau accumulation, neurodegeneration, and cognitive decline compared to concordant positivity, indicating these profiles represent earlier or less advanced stages of Alzheimer’s pathophysiology.

Amyloid buildup in the brain triggers tau proteins to become abnormally phosphorylated, which causes them to detach from their normal structure and spread between neurons. These soluble abnormal tau proteins enter the bloodstream and can be detected before they clump into visible tangles inside brain cells. Once enough tau tangles form in key brain regions, they destroy nerve cell connections and kill cells, leading to brain shrinkage and memory loss. People with only the early soluble tau signal but no visible tangles still have slow progression because the destructive clumping has not yet reached a critical threshold.