Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

• Type of Material: Article
• Authors: Shijia Bian, Emory University; Rafi U. Haque, Emory University; E. Kathleen Carter, Emory University; Duc M. Duong, Emory University; James Lah, Emory University; Thomas Wingo, Emory University; Aliza Wingo, Emory University; Erik Johnson, Emory University; Michael Epstein, Emory University; Caroline Watson, Emory University; Blaine Roberts, Emory University; Lingyan Ping, Emory University; Nicholas Seyfried, Emory University; Allan Levey, Emory University
• Language: English
• Date: 2023-08-01
• Publisher: Nature Portfolio
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41591-023-02476-4
• Title of Journal or Parent Work: Nature Medicine
• Volume: 29
• Issue: 8
• Start Page: 1979
• End Page: 1988
• Grant/Funding Information: E.C.B.J. was supported by K08AG068604. S.B. and M.P.E. were supported by RF1AG071170. Other support included the Emory Goizueta Alzheimer’s Disease Research Center (P30AG066511, A.I.L.) and the Accelerating Medicines Partnership Program for Alzheimer’s Disease (U01AG061357, A.I.L. and N.T.S.) funded by the National Institute on Aging (NIA), Japan Agency for Medical Research and Development (AMED) JP22dk0207049 (T.I.), AMED 17929884 (H.M.), P30 AG066444, P01AG003991, P01AG026276, U19 AG024904 (J.C.M.), Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198) and a Koselleck Project HA1737/16-1 (C.H.). Sample and data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer Network (DIAN, U19AG032438) funded by the NIA, the Alzheimer’s Association (SG-20-690363-DIAN), the German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, partial support by the Research and Development Grants for Dementia from AMED and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, Spanish Institute of Health Carlos III, Canadian Institutes of Health Research, Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation and Fonds de Recherche du Québec – Santé.
• Keywords: Humans; tau Proteins; Neurofibrillary Tangles; Biomarkers; Amyloid beta-Peptides; Proteomics; Alzheimer Disease
• Research Categories: Psychology, Cognitive; Biology, Neuroscience

Abstract

Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau.