Journal Article

DZNE-2023-00805

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer's disease.

Johnson, E. C. B. ; Bian, S. ; Haque, R. U. ; Carter, E. K. ; Watson, C. M. ; Gordon, B. A. ; Ping, L. ; Duong, D. M. ; Epstein, M. P. ; McDade, E. ; Barthélemy, N. R. ; Karch, C. M. ; Xiong, C. ; Cruchaga, C. ; Perrin, R. J. ; Wingo, A. P. ; Wingo, T. S. ; Chhatwal, J. P. ; Day, G. S. ; Noble, J. M. ; Berman, S. B. ; Martins, R. ; Graff-Radford, N. R. ; Schofield, P. R. ; Ikeuchi, T. ; Mori, H. ; Levin, J.Extern* ; Farlow, M. ; Lah, J. J. ; Haass, C.DZNE* ; Jucker, M.DZNE* ; Morris, J. C. ; Benzinger, T. L. S. ; Roberts, B. R. ; Bateman, R. J. ; Fagan, A. M. ; Seyfried, N. T. ; Levey, A. I. ; Network, D. I. A. (Collaboration Author) ; Noble, J. M. (Contributor) ; Day, G. S. (Contributor) ; Graff-Radford, N. R. (Contributor) ; Voglein, J. (Contributor) ; Allegri, R. (Contributor) ; Mendez, P. C. (Contributor) ; Surace, E. (Contributor) ; Berman, S. B. (Contributor) ; Ikonomovic, S. (Contributor) ; Nadkarni, N. (Contributor) ; Lopera, F. (Contributor) ; Ramirez, L. (Contributor) ; Aguillon, D. (Contributor) ; Leon, Y. (Contributor) ; Ramos, C. (Contributor) ; Alzate, D. (Contributor) ; Baena, A. (Contributor) ; Londono, N. (Contributor) ; Moreno, S. (Contributor) ; Laske, C. (Contributor) ; Kuder-Buletta, E. (Contributor) ; Graber-Sultan, S. (Contributor) ; Preische, O. (Contributor) ; Hofmann, A. (Contributor) ; Ikeuchi, T. (Contributor) ; Kasuga, K. (Contributor) ; Niimi, Y. (Contributor) ; Ishii, K. (Contributor) ; Senda, M. (Contributor) ; Sanchez-Valle, R. (Contributor) ; Rosa-Neto, P. (Contributor) ; Fox, N. (Contributor) ; Cash, D. (Contributor) ; Lee, J.-H. (Contributor) ; Roh, J. H. (Contributor) ; Riddle, M. (Contributor) ; Menard, W. (Contributor) ; Bodge, C. (Contributor) ; Surti, M. (Contributor) ; Takada, L. T. (Contributor) ; Chhatwal, J. P. (Contributor) ; Sanchez-Gonzalez, V. J. (Contributor) ; Orozco-Barajas, M. (Contributor) ; Goate, A. (Contributor) ; Renton, A. (Contributor) ; Esposito, B. (Contributor) ; Karch, C. M. (Contributor) ; Marsh, J. (Contributor) ; Cruchaga, C. (Contributor) ; Fernandez, V. (Contributor) ; Gordon, B. A. (Contributor) ; Fagan, A. M. (Contributor) ; Jerome, G. (Contributor) ; Herries, E. (Contributor) ; Llibre-Guerra, J. (Contributor) ; Johnson, E. C. B. (Contributor) ; Seyfried, N. T. (Contributor) ; Schofield, P. R. (Contributor) ; Brooks, W. (Contributor) ; Bechara, J. (Contributor) ; Bateman, R. J. (Contributor) ; Hassenstab, J. (Contributor) ; Perrin, R. J. (Contributor) ; Franklin, E. (Contributor) ; Benzinger, T. L. S. (Contributor) ; Chen, A. (Contributor) ; Chen, C. (Contributor) ; Flores, S. (Contributor) ; Friedrichsen, N. (Contributor) ; Hantler, N. (Contributor) ; Hornbeck, R. (Contributor) ; Jarman, S. (Contributor) ; Keefe, S. (Contributor) ; Koudelis, D. (Contributor) ; Massoumzadeh, P. (Contributor) ; McCullough, A. (Contributor) ; McKay, N. (Contributor) ; Nicklaus, J. (Contributor) ; Pulizos, C. (Contributor) ; Wang, Q. (Contributor) ; Mishall, S. (Contributor) ; Sabaredzovic, E. (Contributor) ; Deng, E. (Contributor) ; Candela, M. (Contributor) ; Smith, H. (Contributor) ; Hobbs, D. (Contributor) ; Scott, J. (Contributor) ; Levin, J. (Contributor) ; Xiong, C. (Contributor) ; Wang, P. (Contributor) ; Xu, X. (Contributor) ; Li, Y. (Contributor) ; Gremminger, E. (Contributor) ; Ma, Y. (Contributor) ; Bui, R. (Contributor) ; Lu, R. (Contributor) ; Ortiz, A. L. S. (Contributor) ; Daniels, A. (Contributor) ; Courtney, L. (Contributor) ; Supnet-Bell, C. (Contributor) ; Xu, J. (Contributor) ; Ringman, J. (Contributor)

2023
Nature America Inc. New York, NY

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Please use a persistent id in citations: doi:10.1038/s41591-023-02476-4

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.

Keyword(s): Alzheimer Disease: cerebrospinal fluid (MeSH) ; Humans (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Proteomics (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; tau Proteins: metabolism (MeSH) ; Neurofibrillary Tangles: pathology (MeSH) ; Biomarkers: metabolism (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: physiopathology (MeSH) ; Male (MeSH) ; Female (MeSH) ; Adult (MeSH) ; Middle Aged (MeSH) ; Mutation (MeSH) ; Age of Onset (MeSH) ; SMOC1 protein, human ; Amyloid beta-Peptides ; tau Proteins ; Biomarkers

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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)
2. Cell Biology of Neurological Diseases (AG Jucker)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Experiment(s):

1. Longitudinal Study on Dominantly Inherited Alzheimer's Disease

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 80 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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