Long COVID-related blood-brain barrier breakdown and microstructure in older adults are modified by sex and Alzheimer’s disease genetic risk

Long COVID is characterized by lingering symptoms following SARS-CoV-2 infection, which may include neurological and cognitive complaints. Hypothesized mechanisms, including blood-brain barrier (BBB) dysfunction and neuroinflammation, are shared with Alzheimer's disease (AD) and related dementias. To address concern that long COVID may accelerate cognitive decline and neurodegeneration, this study examined neuroimaging-based markers of BBB breakdown and brain microstructure among older adults with long COVID, and modification by AD risk factors. Individuals with persistent cognitive complaints following SARS-CoV-2 infection (neurological long COVID, NLCV) and cognitively normal controls (50-90 years, 61% women) underwent neuropsychological evaluation, genotyping, dynamic contrast-enhanced MRI to measure BBB permeability, and multi-compartment diffusion MRI to measure brain microstructure. Cognitive and brain measures were compared between NLCV and controls using analysis of covariance, and associations among measures were assessed using linear regression. Interaction models probed modification by sex and AD genetic risk, quantified with a polygenic hazard score. Compared to controls, NLCV exhibited cognitive impairment, BBB breakdown, and subcortical microstructural abnormalities. NLCV-related BBB leakage was widespread across the brain and more pronounced among men, whereas white matter and subcortical microstructural differences were stronger among women. AD polygenic hazard score modified associations of BBB permeability with memory and microstructure, such that higher caudate BBB permeability correlated with worse immediate recall, and higher white matter permeability correlated with higher free water only for those with elevated genetic risk. BBB dysfunction and microstructural compromise may contribute to cognitive symptoms of long COVID in older adults. Sex-specific patterns, and more deleterious associations between brain and memory abnormalities among individuals with elevated AD genetic risk, highlight the need for precision medicine diagnostic and therapeutic approaches for long COVID.