Document Type
Journal Article
Publication Title
Nature Medicine
Volume
29
Issue
8
First Page
1979
Last Page
1988
PubMed ID
37550416
Publisher
Nature
School
School of Medical and Health Sciences
RAS ID
61866
Funders
https://doi.org/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- (A ) 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 A 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 A 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 A 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 A and tau.
DOI
10.1038/s41591-023-02476-4
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Johnson, E. C. B., Bian, S., Haque, R. U., Carter, E. K., Watson, C. M., Gordon, B. A., . . . Levey, A. I. (2023). Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease. Nature Medicine, 29, 1979-1988. https://doi.org/10.1038/s41591-023-02476-4