TY  - JOUR
AU  - Johnson, Erik C B
AU  - Bian, Shijia
AU  - Haque, Rafi U
AU  - Carter, E Kathleen
AU  - Watson, Caroline M
AU  - Gordon, Brian A
AU  - Ping, Lingyan
AU  - Duong, Duc M
AU  - Epstein, Michael P
AU  - McDade, Eric
AU  - Barthélemy, Nicolas R
AU  - Karch, Celeste M
AU  - Xiong, Chengjie
AU  - Cruchaga, Carlos
AU  - Perrin, Richard J
AU  - Wingo, Aliza P
AU  - Wingo, Thomas S
AU  - Chhatwal, Jasmeer P
AU  - Day, Gregory S
AU  - Noble, James M
AU  - Berman, Sarah B
AU  - Martins, Ralph
AU  - Graff-Radford, Neill R
AU  - Schofield, Peter R
AU  - Ikeuchi, Takeshi
AU  - Mori, Hiroshi
AU  - Levin, Johannes
AU  - Farlow, Martin
AU  - Lah, James J
AU  - Haass, Christian
AU  - Jucker, Mathias
AU  - Morris, John C
AU  - Benzinger, Tammie L S
AU  - Roberts, Blaine R
AU  - Bateman, Randall J
AU  - Fagan, Anne M
AU  - Seyfried, Nicholas T
AU  - Levey, Allan I
TI  - Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer's disease.
JO  - Nature medicine
VL  - 29
IS  - 8
SN  - 1078-8956
CY  - New York, NY
PB  - Nature America Inc.
M1  - DZNE-2023-00805
SP  - 1979 - 1988
PY  - 2023
AB  - 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.
KW  - Alzheimer Disease: cerebrospinal fluid
KW  - Humans
KW  - Alzheimer Disease: pathology
KW  - Proteomics
KW  - Amyloid beta-Peptides: metabolism
KW  - tau Proteins: metabolism
KW  - Neurofibrillary Tangles: pathology
KW  - Biomarkers: metabolism
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: physiopathology
KW  - Male
KW  - Female
KW  - Adult
KW  - Middle Aged
KW  - Mutation
KW  - Age of Onset
KW  - SMOC1 protein, human (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37550416
C2  - pmc:PMC10427428
DO  - DOI:10.1038/s41591-023-02476-4
UR  - https://pub.dzne.de/record/259941
ER  -