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NEUROLOGY / RESEARCH PAPER
Causal Associations between Sleep Apnea and Dementia: A Two-Sample Mendelian Randomization Study
1
Huadong Hospital Affiliated to Fudan University, China
These authors had equal contribution to this work
Submission date: 2025-07-14
Final revision date: 2025-09-25
Acceptance date: 2025-11-09
Online publication date: 2025-11-28
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Observational studies suggest a link between sleep apnea and dementia, but causality and directionality are unclear. This study investigated bidirectional causal relationships between sleep apnea and various dementia types using two-sample Mendelian randomization (MR).
Material and methods:
This study utilized summary-level data from genome-wide association studies (GWAS). Sleep apnea (including obstructive sleep apnea (OSA) and generalized sleep apnea) exposure data were from a European ancestry study. Dementia (general, Alzheimer's, vascular, etc.) outcome/exposure data were from the Finnish FinnGen consortium. The inverse variance weighted (IVW) method was used as the primary analysis, supplemented by multiple analyses (MR-Egger, weighted median, weighted mode). Robustness was assessed using several sensitivity analyses, including MR-PRESSO, Cochran's Q test, and leave-one-out analysis.
Results:
Forward analysis, after MR-PRESSO outlier correction, showed OSA associated with reduced unspecified dementia risk (IVW, OR=0.830, 95%CI=0.700-0.970). Reverse analysis, post-outlier removal, linked general dementia with reduced OSA risk (IVW, OR=0.9399, 95%CI=0.9187-0.9615) and generalized sleep apnea risk (IVW, OR=0.9141, 95%CI=0.8863-0.9427). Alzheimer's dementia was also associated with reduced OSA and generalized sleep apnea risk. Sensitivity analyses did not reveal significant horizontal pleiotropy for the main findings, and heterogeneity was generally within acceptable limits.
Conclusions:
This MR study reveals complex, bidirectional genetic associations between sleep apnea and dementia subtypes. These findings offer new genetic insights into the complex sleep apnea-dementia interplay, highlighting subtype-specific associations.
Observational studies suggest a link between sleep apnea and dementia, but causality and directionality are unclear. This study investigated bidirectional causal relationships between sleep apnea and various dementia types using two-sample Mendelian randomization (MR).
Material and methods:
This study utilized summary-level data from genome-wide association studies (GWAS). Sleep apnea (including obstructive sleep apnea (OSA) and generalized sleep apnea) exposure data were from a European ancestry study. Dementia (general, Alzheimer's, vascular, etc.) outcome/exposure data were from the Finnish FinnGen consortium. The inverse variance weighted (IVW) method was used as the primary analysis, supplemented by multiple analyses (MR-Egger, weighted median, weighted mode). Robustness was assessed using several sensitivity analyses, including MR-PRESSO, Cochran's Q test, and leave-one-out analysis.
Results:
Forward analysis, after MR-PRESSO outlier correction, showed OSA associated with reduced unspecified dementia risk (IVW, OR=0.830, 95%CI=0.700-0.970). Reverse analysis, post-outlier removal, linked general dementia with reduced OSA risk (IVW, OR=0.9399, 95%CI=0.9187-0.9615) and generalized sleep apnea risk (IVW, OR=0.9141, 95%CI=0.8863-0.9427). Alzheimer's dementia was also associated with reduced OSA and generalized sleep apnea risk. Sensitivity analyses did not reveal significant horizontal pleiotropy for the main findings, and heterogeneity was generally within acceptable limits.
Conclusions:
This MR study reveals complex, bidirectional genetic associations between sleep apnea and dementia subtypes. These findings offer new genetic insights into the complex sleep apnea-dementia interplay, highlighting subtype-specific associations.
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