Plasma Aβ <sub>42</sub> /Aβ <sub>40</sub> is sensitive to early cerebral amyloid accumulation and predicts risk of cognitive decline across the Alzheimer's disease spectrum
Alexandra N. Trelle, Christina B. Young, Hillary Vossler, Javier Ramos Benitez, Karly Alex Cody, Jaime Mendiola, Michelle S. Swarovski, Yann Le Guen, Igor Feinstein, Robert R. Butler, Divya Channappa, America Romero, Jennifer Park, Marian Shahid, Nicole K. Corso, Kelly Chau, Amanda Smith, Irina A. Skylar-Scott, Maya Yutsis, Carolyn Fredericks, Lü Tian, Kyan Younes, Geoffrey A. Kerchner, Gayle K. Deutsch, Guido Davidzon, Sharon J. Sha, Victor W. Henderson, Frank M. Longo, Michael D. Greicius, Tony Wyss‐Coray, Katrin I. Andreasson, Kathleen L. Poston, Anthony D. Wagner, Elizabeth C. Mormino, Edward N. Wilson
Abstract
Abstract INTRODUCTION The availability of amyloid beta (Aβ) targeting therapies for Alzheimer's disease (AD) is increasing the demand for scalable biomarkers that are sensitive to early cerebral Aβ accumulation. METHODS We evaluated fully‐automated Lumipulse plasma Aβ 42 /Aβ 40 immunoassays for detecting cerebral Aβ in 457 clinically unimpaired (CU) and clinically impaired (CI) Stanford Alzheimer's Disease Research Center (Stanford ADRC) participants and 186 CU in the Stanford Aging and Memory Study (SAMS). Longitudinal change in ADRC plasma Aβ 42 /Aβ 40 and cognition and cross‐sectional associations with SAMS memory and tau positron emission tomography (PET) were examined. RESULTS Plasma Aβ 42 /Aβ 40 exhibited high performance in detecting amyloid positivity defined by PET (area under the curve [AUC]: 0.885, 95% confidence interval [CI]: 0.816–0.955). Once abnomal, plasma Aβ 42 /Aβ 40 remained low and predicted cognitive decline in both CU and CI individuals. Among SAMS CU, plasma Aβ 42 /Aβ 40 was associated with poorer hippocampal‐dependent memory and elevated tau accumulation. DISCUSSION Lumipulse plasma Aβ 42 /Aβ 40 is a scalable assay for detection of cerebral Aβ and prediction of risk for cognitive decline across the AD continuum. Highlights Lumipulse plasma amyloid beta (Aβ) 42 /Aβ 40 exhibited high accuracy in detecting amyloid positivity. Plasma amyloid‐positive (Aβ+) individuals exhibited stability of Aβ 42 /Aβ 40 over time. Plasma Aβ 42 /Aβ 40 predicted future cognitive decline across the Alzheimer's disease (AD) spectrum. Plasma Aβ 42 /Aβ 40 was sensitive to memory and tau burden in clinically unimpaired older adults.