Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease
Authors: Johnson Erik C. B. , Bian Shijia , Haque Rafi U. , Carter E. Kathleen , Watson Caroline M. , Gordon Brian A. , Ping Lingyan , Duong Duc M. , Epstein Michael P. , McDade Eric , Barthélemy Nicolas R. , Karch Celeste M. , Xiong Chengjie , Cruchaga Carlos , Perrin Richard J. , Wingo Aliza P. , Wingo Thomas S. , Chhatwal Jasmeer P. , Day Gregory S. , Noble James M. , Berman Sarah B. , Martins Ralph , Graff-Radford Neill R. , Schofield Peter R. , Ikeuchi Takeshi , Mori Hiroshi , Levin Johannes , Farlow Martin , Lah James J. , Haass Christian , Jucker Mathias , Morris John C. , Benzinger Tammie L. S. , Roberts Blaine R. , Bateman Randall J. , Fagan Anne M. , Seyfried Nicholas T. , Levey Allan I. ,   the Dominantly Inherited Alzheimer Network, Vöglein Jonathan , Allegri Ricardo , Mendez Patricio Chrem , Surace Ezequiel , Berman Sarah B. , Ikonomovic Snezana , Nadkarni Neelesh , Lopera Francisco , Ramirez Laura , Aguillon David , Leon Yudy , Ramos Claudia , Alzate Diana , Baena Ana , Londono Natalia , Moreno Sonia , Laske Christoph , Kuder-Buletta Elke , Graber-Sultan Susanne , Preische Oliver , Hofmann Anna , Kasuga Kensaku , Niimi Yoshiki , Ishii Kenji , Senda Michio , Sanchez-Valle Raquel , Rosa-Neto Pedro , Fox Nick , Cash Dave , Lee Jae-Hong , Roh Jee Hoon , Riddle Meghan , Menard William , Bodge Courtney , Surti Mustafa , Takada Leonel Tadao , Sanchez-Gonzalez V. J. , Orozco-Barajas Maribel , Goate Alison , Renton Alan , Esposito Bianca , Marsh Jacob , Cruchaga Carlos , Fernandez Victoria , Jerome Gina , Herries Elizabeth , Llibre-Guerra Jorge , Brooks William , Bechara Jacob , Hassenstab Jason , Franklin Erin , Chen Allison , Chen Charles , Flores Shaney , Friedrichsen Nelly , Hantler Nancy , Hornbeck Russ , Jarman Steve , Keefe Sarah , Koudelis Deborah , Massoumzadeh Parinaz , McCullough Austin , McKay Nicole , Nicklaus Joyce , Pulizos Christine , Wang Qing , Mishall Sheetal , Sabaredzovic Edita , Deng Emily , Candela Madison , Smith Hunter , Hobbs Diana , Scott Jalen , Wang Peter , Xu Xiong , Li Yan , Gremminger Emily , Ma Yinjiao , Bui Ryan , Lu Ruijin , Ortiz Ana Luisa Sosa , Daniels Alisha , Courtney Laura , Supnet-Bell Charlene , Xu Jinbin , Ringman John 
Published: August 2023

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.