Persistent Cognitive Vulnerability After COVID-19 in Older Adults: Longitudinal Clinical Trajectories and Multi-Cohort Transcriptomic Evidence.

<h4>Background</h4>Older adults frequently experience persistent cognitive impairment after COVID-19, yet the mechanisms underlying impaired recovery and resilience remain poorly understood. Integrating longitudinal clinical trajectories with molecular signatures may clarify why cognitive function fails to recover in this population.<h4>Methods</h4>We conducted a longitudinal study of adults aged ≥60 years hospitalized with COVID- 19, integrating comprehensive geriatric assessments across premorbid, morbid, and postmorbid states with transcriptomic analyses from three independent public cohorts (GSE152641, GSE196822, and GSE157103). Clinical resilience was classified as complete, partial, or absent across geriatric domains. Differential expression analyses, cross-cohort gene integration, and transcriptomic score analyses were performed to identify biological pathways associated with COVID-19 in older adults.<h4>Results</h4>Forty-nine older adults contributed 147 longitudinal observations. Cognitive performance (MoCA) declined significantly during acute COVID-19 compared with the premorbid state (p < 0.001) and remained persistently impaired during follow-up, with no improvement from the morbid state (p = 0.549), indicating absence of cognitive resilience. Depressive symptoms and mobility showed similar patterns of persistent impairment, whereas functional status and nutritional measures demonstrated partial recovery. Age was the only independent predictor of poorer outcomes across multiple geriatric domains (all p < 0.05). Transcriptomic analyses identified 66 genes consistently upregulated across all cohorts, including CDC6, RRM2, CDCA2, DTL, MCM10, and CLSPN. The most reproducible molecular finding was activation of interferon-responsive pathways. The Interferon Response Score was significantly elevated in the pooled meta-analysis (Hedges' g = 1.00, 95% CI 0.14-1.87, p = 0.022), whereas Neuroinflammation and Synaptic Function scores were not significantly altered.<h4>Discussion</h4>Persistent cognitive impairment after COVID-19 was accompanied by a reproducible interferon-associated transcriptional signature across independent cohorts of older adults. The absence of recovery in cognition, together with sustained activation of interferon-responsive pathways, suggests that aging-related immune dysregulation may contribute to impaired resilience following COVID-19. In contrast, broader neuroinflammatory and synaptic transcriptional signatures showed limited reproducibility, highlighting interferon signaling as the most consistent biological correlate of post-COVID vulnerability.<h4>Conclusion</h4>COVID-19 in older adults induces a state of persistent vulnerability characterized by incomplete cognitive recovery and sustained activation of interferon-associated transcriptional programs. The dominant influence of age and the absence of both clinical and molecular resilience suggest that recovery is constrained by aging-related biological processes. These findings identify interferon signaling as a potential therapeutic target for improving long-term outcomes in older COVID-19 survivors.