INTRODUCTION To address an urgent need for a scalable, accurate blood test for brain amyloid pathology that provides a conclusive result for the greatest number of patients, we developed a multi-analyte algorithmic test combining p-Tau 217 with four other biomarkers.

METHODS Multiplexed digital immunoassays measured p-Tau 217, Aβ42/40, GFAP, and NfL in 730 individuals to establish an algorithm with cutoffs, then in 1,082 individuals with cognitive symptoms from three independent cohorts to identify brain amyloid pathology.

RESULTS The test’s algorithmic risk score AUC was 0.92, yielding 90% agreement with amyloid PET and CSF. Positive predictive value was 92% at 55% amyloid prevalence. The multi-marker algorithm reduced the intermediate zone 3-fold to 12% vs. p-Tau 217 alone. Diagnostic performance was similar by race, ethnicity, sex, age, and apoE4 status.

DISCUSSION The LucentAD Complete multi-analyte blood test demonstrated high clinical validity for brain amyloid pathology detection while substantially reducing inconclusive intermediate results.

Charlotte E. Teunissen performed contract research for Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vivoryon. Charlotte E. Teunissen is editor in chief of Alzheimer Research and Therapy, and serves on editorial boards of Medidact Neurologie/Springer, and Neurology: Neuroimmunology & Neuroinflammation. Inge Verberk received a speaker honorarium from Quanterix, which was paid directly to her institution. David Wilson, Meenakshi Khare, Michele Wolfe, Patrick Sheehy, Ann-Jeanette Vasko, and Mike Miller are employees of Quanterix. Karen Copeland and Lyndal Hesterberg are contractors of Quanterix.

Charlotte E. Teunissen is a recipient of TAP-dementia (www.tap-dementia.nl) receiving funding from ZonMw (#10510032120003) in the context of Onderzoeks programma Dementie part of the Dutch National Dementia Strategy and ABOARD which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). Alzheimer NederlandInge. Prof. Teunissen further received grants of the European Commission (Marie Curie International Training Network grant agreement No 860197 (MIRIADE) Innovative Medicines Initiatives 3TR (Horizon 2020 grant no 831434) EPND (IMI 2 Joint Undertaking (JU) grant No. 101034344) and JPND (bPRIDE) National MS Society (Progressive MS Alliance) Alzheimer Drug Discovery Foundation Alzheimer Association Health Holland the Dutch Research Council (ZonMW) the Selfridges Group Foundation and Alzheimer Netherlands. M.W. Verberk is supported by grants of the Alzheimers Association Health∼Holland and Amsterdam UMC.

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All Amsterdam Dementia Cohort participants provided written informed consent to use medical data and biomaterials for research purposes. The study is approved by the medical ethical committee of the VU University Medical Center (Ref: 2016.061, Ref: 2017.315), and is conducted in accordance with the Helsinki Declaration of 1975. The BioHermes study and informed consent was reviewed and approved by Advarra, 6100 Merriweather Dr., Suite 600 Columbia, MD 21044. The Alzheimer's Disease Neuroimaging Initiative (ADNI) study procedures were approved by the institutional review boards (IRBs) of all participating centers, and written informed consent was obtained from all participants or their authorized representatives.

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