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Two pathological processes\u2014aggregation of the amyloid-\u03b2 (A\u03b2) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)\u2014are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of A\u03b2 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\u03b2 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\u03b2 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\u03b2 and tau.<\/jats:p>","DOI":"10.1038\/s41591-023-02476-4","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T12:02:17Z","timestamp":1691409737000},"page":"1979-1988","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":184,"title":["Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0604-2944","authenticated-orcid":false,"given":"Erik C. 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