No abstract

Key Points Question How well does plasma amyloid-β 42/40 (Aβ42/40), measured using 8 different assays, detect brain Aβ pathology in the early stages of Alzheimer disease? Findings In this study, including 408 participants from 2 independent cohorts (BioFINDER and Alzheimer Disease Neuroimaging Initiative), plasma Aβ42/40 quantified using certain mass spectrometry–based methods showed better discriminative accuracy than immunoassays when identifying individuals with abnormal intracerebral Aβ status according to cerebrospinal fluid Aβ42/40 levels and Aβ positron emission tomography. Meaning Certain mass spectrometry–based plasma tests might have sufficient performance to detect brain Aβ pathology in Alzheimer disease.

Code availabilityAll code for data cleaning and analysis associated with the current submission is available upon request to the corresponding author and is provided as part of the replication package.

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β status and predict future progression to Alzheimer's dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aβ-status (i.e., abnormal CSF Aβ42/40) at baseline; and 45 of these Aβ-positive participants progressed to Alzheimer's dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aβ status (AUC = 0.947; pdiff < 0.015) or progression to Alzheimer's dementia (AUC = 0.932; pdiff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886-0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange, 0.835-0.872; pdiff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji, and p-tau181Splex (AUCrange, 0.642-0.813; pdiff ≤0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; pdiff = 0.003 vs p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange, 0.320-0.669). In conclusion, the findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aβ or those who will subsequently progress to Alzheimer's dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx, and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aβ-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer's dementia in the future.

The Dominantly Inherited Alzheimer Network (DIAN) is a collaborative effort of international Alzheimer disease (AD) centers that are conducting a multifaceted prospective biomarker study in individuals at-risk for autosomal dominant AD (ADAD). DIAN collects comprehensive information and tissue in accordance with standard protocols from asymptomatic and symptomatic ADAD mutation carriers and their non-carrier family members to determine the pathochronology of clinical, cognitive, neuroimaging, and fluid biomarkers of AD. This article describes the structure, implementation, and underlying principles of DIAN, as well as the demographic features of the initial DIAN cohort.