Plasma p-tau212 identifies cognitively unimpaired individuals with emerging amyloid-β pathology

Plasma phosphorylated-tau (p-tau) biomarkers show high performance as first-in-line tests in the evaluation of patients with cognitive symptoms and have also found utility in clinical trials for anti-amyloid drug therapies for Alzheimer's disease (AD). Plasma p-tau212 is a novel blood biomarker that can discriminate cognitively unimpaired (CU) and subjective cognitive decline patients from mild cognitive impairment (MCI)-AD and AD dementia patients in clinical cohorts. Using Simoa technology, we evaluated plasma p-tau212 for its ability to detect emerging amyloid-beta (Aβ) pathology in CU individuals with brain amyloidosis from CSF Aβ42/40 ratio (n = 317) or Aβ PET scans (n = 277). We benchmarked plasma p-tau212 against p-tau181, p-tau217, and p-tau231 by comparing their accuracies and fold changes for detecting brain amyloidosis. Our results showed that all the plasma p-tau biomarkers are increased in the CU CSF Aβ + participants, with the highest median fold change observed for plasma p-tau212. Discrimination performance of the biomarkers to differentiate amyloid PET-positive from amyloid PET-negative participants differed between plasma p-tau biomarkers, being higher for plasma p-tau217 and p-tau212 compared to plasma p-tau181 and p-tau231. Furthermore, plasma p-tau212 was elevated in participants with low Aβ burden (CSF Aβ-positive, amyloid PET-negative), supporting its potential as a cost-effective, easily implemented biomarker for trial recruitment in early stages. Its further increase in Aβ PET-positive participants suggests additional utility for monitoring anti-amyloid therapies.