Documented SARS-CoV-2 infection and risk of neurodegenerative disease diagnosis: a target trial emulation across three real-world cohorts

Electronic health record studies have reported increased incidence of Neurodegenerative Diseases (NDD) following SARS-CoV-2 infection, but causal interpretation is complicated by differences between infected and uninfected individuals, differential follow-up, incomplete infection ascertainment and competing mortality. We emulated target trials using Danish national health registries, the US TriNetX network, and UK Biobank data, including individuals aged ≥ 70 years without a previous diagnosis of Alzheimer’s disease, Parkinson’s disease, or unspecified dementia. Historical pre-pandemic and contemporary test-negative control designs were evaluated. Cause-specific cumulative incidence functions were estimated using cross-fitted targeted maximum likelihood estimation (TMLE), accounting for measured baseline confounding, dependent censoring, and death as a competing event. We estimated marginal effects for the diagnoses of Alzheimer’s disease, Parkinson’s disease, unspecified dementia, and a composite endpoint, and explored heterogeneity among clinically relevant subgroups. Across cohorts, control-group designs, outcomes, and follow-up horizons, documented SARS-CoV-2 infection was not associated with a consistent increase in average risk for NDD diagnosis. Exploratory analyses nevertheless suggested higher risks among older individuals and among those with established dementia-related risk factors, including type 2 diabetes, cardiovascular disease, depression, and hearing impairment. These patterns were observed across several analyses, although their magnitude and consistency varied between cohorts and outcomes, and require further confirmation in independent studies.