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

Autor: Johnson ECB; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA. erik.johnson@emory.edu.; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA. erik.johnson@emory.edu., Bian S; Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA., Haque RU; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA., Carter EK; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA., Watson CM; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA., Gordon BA; Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, MO, USA., Ping L; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA., Duong DM; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA., Epstein MP; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., McDade E; Department of Neurology, Washington University in St Louis, St Louis, MO, USA., Barthélemy NR; Department of Neurology, Washington University in St Louis, St Louis, MO, USA., Karch CM; Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA., Xiong C; Department of Neurology, Washington University in St Louis, St Louis, MO, USA.; Division of Biostatistics, Washington University in St Louis, St Louis, MO, USA., Cruchaga C; Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA., Perrin RJ; Department of Neurology, Washington University in St Louis, St Louis, MO, USA.; Department of Pathology and Immunology, Washington University in St Louis, St Louis, MO, USA., Wingo AP; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA.; Division of Mental Health, Atlanta VA Medical Center, Atlanta, GA, USA., Wingo TS; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., Chhatwal JP; Massachusetts General and Brigham & Women's Hospitals, Harvard Medical School, Boston, MA, USA., Day GS; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA., Noble JM; Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and GH Sergievsky Center, Columbia University Irving Medical Center, New York, NY, USA., Berman SB; Departments of Neurology and Clinical and Translational Science, Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA., Martins R; Edith Cowan University, Perth, Western Australia, Australia., Graff-Radford NR; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA., Schofield PR; Neuroscience Research Australia, Sydney, New South Wales, Australia.; School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia., Ikeuchi T; Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan., Mori H; Osaka Metropolitan University Medical School, Nagaoka Sutoku University, Nagaoka, Japan., Levin J; Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany., Farlow M; Indiana University, Bloomington, IN, USA., Lah JJ; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA., Haass C; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Metabolic Biochemistry, Biomedical Center (BMC), Ludwig-Maximilians University, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Jucker M; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany., Morris JC; Department of Neurology, Washington University in St Louis, St Louis, MO, USA., Benzinger TLS; Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, MO, USA., Roberts BR; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA., Bateman RJ; Department of Neurology, Washington University in St Louis, St Louis, MO, USA., Fagan AM; Department of Neurology, Washington University in St Louis, St Louis, MO, USA., Seyfried NT; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA., Levey AI; Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2023 Aug; Vol. 29 (8), pp. 1979-1988. Date of Electronic Publication: 2023 Aug 07.
DOI: 10.1038/s41591-023-02476-4
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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