Work

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

Year: 2026

Type: article

Abstract: 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 $$\ge $$ 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.

Source: Scientific Reports

DOI: 10.1038/s41598-026-79010-2

Authors: Jannis Barking, Sofie Theisen Honoré, Guillaume Azarias, Steven Sison, Søren Brunak, Holger Fröhlich