Documented SARS-CoV-2 infection and risk of neurodegenerative disease diagnosis: a target trial emulation across three real-world cohorts
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 ≥ 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.
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BibTeX
@article{barking2026documented,
title = {{Documented SARS-CoV-2 infection and risk of neurodegenerative disease diagnosis: a target trial emulation across three real-world cohorts}},
author = {Jannis Barking and Sofie Theisen Honoré and Guillaume Azarias and Steven Sison and Søren Brunak and Holger Fröhlich},
journal = {Scientific Reports},
year = {2026},
month = nov,
doi = {10.1038/s41598-026-79010-2},
url = {https://www.nature.com/articles/s41598-026-79010-2},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Documented SARS-CoV-2 infection and risk of neurodegenerative disease diagnosis: a target trial emulation across three real-world cohorts
AU - Jannis Barking
AU - Sofie Theisen Honoré
AU - Guillaume Azarias
AU - Steven Sison
AU - Søren Brunak
AU - Holger Fröhlich
PY - 2026
DA - 2026/11/05
JO - Scientific Reports
DO - 10.1038/s41598-026-79010-2
UR - https://www.nature.com/articles/s41598-026-79010-2
AB - 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.
SN - 2045-2322
ER -