Annals of Neurology | January 27, 2022

Meyer PF, Ashton NJ, Karikari TK, Strikwerda-Brown C, Köbe T, Gonneaud J, Pichet Binette A, Ozlen H, Yakoub Y, Simrén J, Pannee J, Lantero-Rodriguez J, Labonté A, Baker SL, Schöll M, Vanmechelen E, Breitner JCS, Zetterberg H, Blennow K, Poirier J and Villeneuve S

Ann Neurol. 2022

https://doi.org/10.1002/ana.26308

Abstract

Objective

To evaluate novel plasma p-tau231, p-tau181 as well as Aβ₄₀ and Aβ₄₂ assays as indicators of tau and Aβ pathologies measured with positron emission tomography (PET), and their association with cognitive change, in cognitively unimpaired older adults.

Methods

In a cohort of 244 older adults at risk of AD owing to a family history of AD dementia, we measured single molecule array (Simoa)-based plasma tau biomarkers (p-tau231, p-tau181), Aβ₄₀ and Aβ₄₂ with immunoprecipitation mass spectrometry, and Simoa NfL. A subset of 129 participants underwent amyloid-β (¹⁸F-NAV4694) and tau (¹⁸F-flortaucipir) PET assessments. We investigated plasma biomarker associations with Aβ and tau PET at the global and voxel level and tested plasma biomarker combinations for improved detection of Aβ-PET positivity. We also investigated associations with 8-year cognitive change.

Results

Plasma p-tau biomarkers correlated with flortaucipir binding in medial temporal, parietal and inferior temporal regions. P-tau231 showed further associations in lateral parietal and occipital cortices. Plasma Aβ_42/40 explained more variance in global Aβ-PET binding than Aβ₄₂ alone. P-tau231 also showed strong and widespread associations with cortical Aβ-PET binding. Combining Aβ_42/40 with p-tau231 or p-tau181 allowed for good distinction between Aβ-negative and -positive participants (AUC range 0.81-0.86). Individuals with low plasma Aβ_42/40 and high p-tau experienced faster cognitive decline.

Interpretation

Plasma p-tau231 showed more robust associations with PET biomarkers than p-tau181 in pre-symptomatic individuals. The combination of p-tau and Aβ_42/40 biomarkers detected early AD pathology and cognitive decline. Such markers could be used as pre-screening tools to reduce the cost of prevention trials.