COVID-19 Related Brain MRI Changes and Anticipated Long-Term Dementia Risk: A Front-Door-Criterion-Inspired Approach.

PURPOSE Evaluating long-term effects of COVID-19 is challenging due to confounding and lack of comparable unexposed groups. The front-door criterion for causal inference identifies causal effects operating via specific pathways, even if unmeasured confounding occurs. We leverage the front-door criterion to estimate effects of COVID-19 on long-term dementia risk mediated by short-term brain magnetic resonance imaging (MRI) changes.

METHODS UK Biobank participants (n=37,426) aged 55+ without prevalent dementia completed brain MRIs. Mediators were defined based on 31 MRI-derived variables previously shown to change due to COVID-19. We evaluated associations of these brain variables with incident all-cause dementia using confounder-adjusted Cox proportional-hazards models and combined results to infer effects of COVID-19 on dementia risk mediated via brain changes.

RESULTS Over 4.7 years (SD, 1.5) of follow-up, 112 incident dementia cases occurred. Of the 31 brain MRI-derived variables previously linked to COVID-19, 29 were associated with higher dementia incidence. Brain MRI changes of the magnitude induced on average by COVID-19 were associated with 9% higher dementia hazard (HR: 1.09 [95% CI, 1.06-1.12]).

CONCLUSIONS Front-door-criterion-inspired approaches can circumvent nearly intractable confounding and evaluate effects mediated by short-term physiologic changes. We find that MRI-based structural brain changes attributable to COVID-19 modestly increase dementia risk.