Sex-Specific Association Between Acute COVID-19 Systemic Inflammation and Persistent White Matter Pathology and Cognition in Survivors

Six years into the COVID-19 pandemic, evidence is increasingly clear that long COVID affects women disproportionately, with higher rates of persistent cognitive and neurological symptoms. Yet, the biological mechanisms underlying this sex-dimorphic impact remain elusive. We investigated whether the immune storm of acute COVID-19 leaves a silent yet sex-specific scar on white matter integrity that shapes long-term cognitive health. In 60 previously hospitalized COVID-19 survivors, we combined an inflammatory snapshot at admission proxied by the systemic immune-inflammation index (SII) with 3T diffusion MRI and a comprehensive cognitive battery (BACS) acquired three months after recovery. Sex reshaped the inflammation–brain relationship: a higher SII predicted a diffuse alteration pattern within core associative and inter-hemispheric fibres in females only, sparing the male architecture despite a comparable inflammatory burden. In women, white matter damage coupled with poorer psychomotor coordination, and mean diffusivity fully mediated the link, unveiling a female-specific pathway from systemic inflammation to cognitive slowdown. COVID-19 inflammation imprints a durable, sex-sensitive footprint on white matter that selectively undermines psychomotor coordination in female survivors, despite a clinical recovery. This work positions women’s white matter as a critical target of post-COVID neuroinflammation and argues for sex-informed monitoring and interventions that explicitly tackle immune–brain crosstalk in long COVID.