Defining the natural history of Alzheimer’s disease by longitudinal cerebrospinal fluid proteomics.
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Defining the molecular natural history of Alzheimer’s disease (AD) is essential for earlier diagnosis and effective therapeutical interventions. Using longitudinal cerebrospinal fluid proteomics from 191 individuals across the AD spectrum, with up to 15 years of follow-up, we identified protein changes that preceded and tracked with development of amyloid-β (Aβ) and/or p-tau181 abnormality over 2.8–6.1 years. Early alterations included SMOC1 and YWHAZ and were enriched for glycolytic, synaptic, and axonal guidance pathways, which remained consistently altered across advancing disease stages. After Aβ and p-tau181 abnormality, 185 proteins progressively decreased with disease worsening, of which a subset of synaptic and axonal proteins including NPTX2, EPHA10 also tracked cognitive decline. Together, our findings can support clinical trial design through accurate effect size estimates, and enable biomarker guided therapeutic targeting across the full pre-amyloid-to-dementia disease continuum.
