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


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.

SUBMITTER: Johnson ECB 

PROVIDER: S-EPMC10427428 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Johnson Erik C B ECB   Bian Shijia S   Haque Rafi U RU   Carter E Kathleen EK   Watson Caroline M CM   Gordon Brian A BA   Ping Lingyan L   Duong Duc M DM   Epstein Michael P MP   McDade Eric E   Barthélemy Nicolas R NR   Karch Celeste M CM   Xiong Chengjie C   Cruchaga Carlos C   Perrin Richard J RJ   Wingo Aliza P AP   Wingo Thomas S TS   Chhatwal Jasmeer P JP   Day Gregory S GS   Noble James M JM   Berman Sarah B SB   Martins Ralph R   Graff-Radford Neill R NR   Schofield Peter R PR   Ikeuchi Takeshi T   Mori Hiroshi H   Levin Johannes J   Farlow Martin M   Lah James J JJ   Haass Christian C   Jucker Mathias M   Morris John C JC   Benzinger Tammie L S TLS   Roberts Blaine R BR   Bateman Randall J RJ   Fagan Anne M AM   Seyfried Nicholas T NT   Levey Allan I AI  

Nature medicine 20230807 8


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 tha  ...[more]

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