Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease
Erik C. B. Johnson, Shijia Bian, Rafi U. Haque, Kathleen Carter, Caroline M Watson, Brian A. Gordon, Lingyan Ping, Duc M. Duong, Michael P. Epstein, Eric McDade, Nicolas R. Barthélemy, Celeste M. Karch, Chengjie Xiong, Carlos Cruchaga, Richard J. Perrin, Aliza P. Wingo, Thomas S. Wingo, Jasmeer P. Chhatwal, Gregory S. Day, James M. Noble, Sarah Berman, Ralph N. Martins, Neill R. Graff‐Radford, Peter R. Schofield, Takeshi Ikeuchi, Hiroshi Mori, Johannes Levin, Martin R. Farlow, James J. Lah, Christian Haass, Mathias Jucker, John C. Morris, Tammie L.S. Benzinger, Blaine R. Roberts, Randall J. Bateman, Anne M. Fagan, Nicholas T. Seyfried, Allan I. Levey, the Dominantly Inherited Alzheimer Network, Jonathan Vöglein, Ricardo Allegri, Patricio Chrem Méndez, Ezequiel Surace, Sarah Berman, Snežana Ikonomović, Neelesh K. Nadkarni, Francisco Lopera, Laura Ramírez, David Aguillón, Yudy Milena Leon, Cláudia Ramos, Diana Alzate, Ana Baena, Natalia Londono, Sonia Moreno, Christoph Laske, Elke Kuder-Buletta, Susanne Gräber‐Sultan, Oliver Preische, Anna Hofmann, Kensaku Kasuga, Yoshiki Niimi, Kenji Ishii, Michio Senda, Raquel Sánchez‐Valle, Pedro Rosa‐Neto, Nick C. Fox, David M. Cash, Jae‐Hong Lee, Jee Hoon Roh, Meghan Riddle, William Menard, Courtney Bodge, Mustafa Surti, Leonel Tadao Takada, Víctor Javier Sánchez-González, Maribel Orozco-Barajas, Alison Goate, Alan E. Renton, Bianca Esposito, Jacob Marsh, Carlos Cruchaga, María Victoria Fernández, Gina Jerome, Elizabeth Herries, Jorge J. Llibre‐Guerra, William S. Brooks, Jacob Bechara, Jason Hassenstab, Erin Franklin, Allison Chen, Charles D. Chen, Shaney Flores, Nelly Friedrichsen, Nancy Hantler, Russ C. Hornbeck, Steve Jarman, Sarah Keefe, Deborah Koudelis, Parinaz Massoumzadeh
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.