A cognitive architecture for Long COVID: the interplay of brain fog, fatigue, attention and memory

Abstract The cognitive mechanisms underlying post-acute COVID-19 sequelae (“Long COVID”) remain poorly defined. While deficits in memory and executive function are well-documented, it is unclear whether these arise from primary neural dysfunction or are secondary consequences of fatigue related factors. Here, we addressed this in a community cohort (N = 24,095) using a custom cognitive battery to dissect the interplay between sustained attention, fatigue, and memory. Among this subset, 11,925 participants had previously tested positive for COVID-19, and 548 reported ongoing symptoms consistent with Long COVID. Path analysis (structural equation modelling) was used to evaluate competing mechanistic models linking COVID-19-related features (e.g., duration of symptoms, severity of illness) with objective performance and subjective cognitive symptoms. Participants with persistent symptoms post COVID-19 (unresolved beyond 12 weeks) showed significant deficits in sustained attention compared to non-infected individuals. Path models revealed complex relationships underlying these deficits. Unlike models of mental health disorders and general ageing, where cognitive performance was largely mediated by relationships to fatigue, the final Long COVID model represented a hybrid mechanism: COVID-19 features were associated with direct, independent effects on attention and memory, while simultaneously relating lower cognitive performance to on-task fatigue buildup. Findings also suggest that 'brain fog' reflects a distinct neurocognitive vulnerability associated with fatigue and reduced performance on sustained attention and memory tasks. These findings accord with the hypothesis that Long COVID has a heterogeneous, multi-faceted impact on cognitive function, with higher-order processes such as memory being particularly vulnerable due to their dependence on foundational attention and motivation processes.