Plasma multi-omics profiling reveals unique precursors of post-COVID cognitive decline during clinical recovery in older patients

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Older patients with coronavirus disease 2019 (COVID-19) face substantial challenges from post-COVID cognitive decline (PCCD); however, the early clinical recovery phase of these sequelae remains poorly understood. To address this gap, we conducted a prospective cohort study of 47 older patients with COVID-19 aged ≥ 75 years. Plasma samples collected during hospitalization were subjected to proteomic, metabolomic, and lipidomic analyses using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cognitive function was assessed at baseline and 10–12 months post-infection, to identify early recovery-phase molecular features associated with later cognitive outcomes. The results indicated that despite viral clearance, older individuals exhibited persistent alterations in plasma molecular features related to immune processes and neurovascular unit (NVU) function. Further follow-up at 10–12 months identified aging-specific early factors closely associated with long-term PCCD, including coordinated alterations in immune and inflammatory processes, extensive plasma exposure of markers indicative of NVU and skin epithelial barrier, and metabolic perturbations. Lipidomic and clinical data further corroborated these observations. A multilayer feature selection framework identified candidate biomarkers across multi-omics and clinical layers, and exploratory predictive models demonstrated discriminative performance for cognitive outcomes at 10–12 months. Cross-cohort comparison revealed partially consistent pathway-level alterations. In addition, a set of “prognostic-cognitive decline” molecules exhibiting cross-stage expression patterns was identified, suggesting persistent molecular perturbations associated with disease progression. Our findings provide systematic multi-omics insights into the early identification and underlying molecular mechanisms of cognitive sequelae in older patients with COVID-19.