High performance plasma amyloid-β biomarkers for Alzheimer’s disease

Authors

Akinori Nakamura
Naoki Kaneko
Victor L. Villemagne
Takashi Kato
James Doecke
Vincent Dore
Chris Fowler
Qiao-Xin Li
Ralph Martins, Edith Cowan UniversityFollow
Christopher Rowe
Taisuke Tomita
Katsumi Matsuzaki
Kenji Ishii
Kazunari Ishii
Yutaka Arahata
Shinichi Iwamonto
Kengo Ito
Koichi Tanaka
Colin L. Masters
Katsuhiko Yanagisawa

Document Type

Journal Article

Publication Title

Nature

Publisher

Nature Publishing Group

School

School of Medical and Health Sciences

RAS ID

28023

Comments

Nakamura, A., Kaneko, N., Villemagne, V. L., Kato, T., Doecke, J., Doré, V., ... & Tomita, T. (2018). High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature, 554(7691), 249-254. doi:10.1038/nature25456

Available here.

Abstract

To facilitate clinical trials of disease-modifying therapies for Alzheimer’s disease, which are expected to be most efficacious at the earliest and mildest stages of the disease^1,2, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain—the earliest pathological signature of Alzheimer’s disease—are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable^3,4. Despite much effort^3,4,5,6,7, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)_669–711/amyloid-β (Aβ)_1–42 and Aβ_1–40/Aβ_1–42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using ¹¹C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer’s disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ_1–42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost–benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

DOI

10.1038/nature25456

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