Systemic inflammatory markers in relation to cognitive function and measures of brain atrophy: a Mendelian randomization study
GeroScience, vol. 44, pp. 2259–2270
Abstract
Abstract Observational studies have implied associations between multiple cytokines and cognitive decline, anti-inflammatory drugs however did not yield any protective effects on cognitive decline. We aimed to assess the associations of systemic inflammation, as measured by multiple cytokine and growth factor, with cognitive performance and brain atrophy using two-sample Mendelian randomization (MR). Independent genetic instruments (p < 5e − 8 andp < 5e − 6) for 41 systemic inflammatory markers were retrieved from a genome-wide association study conducted in 8293 Finnish participants. Summary statistics for gene-outcome associations were obtained for cognitive performance (N = 257,841) and for brain atrophy measures of cerebral cortical surface area and thickness (N = 51,665) and hippocampal volume (N = 33,536). To rule out the heterogeneity in the cognitive performance, we additionally included three domains: the fluid intelligence score (N = 108,818), prospective memory result (N = 111,099), and reaction time (N = 330,069). Main results were computed by inverse-variance weighting; sensitivity analyses taking pleiotropy and invalid instruments into account were performed by using weighted-median estimator, MR-Egger, and MR PRESSO. After correcting for multiple testing using false discovery rate, only genetically predicted (withp < 5e − 6 threshold) per-SD (standard deviation) higher IL-8 was associated with − 0.103 (− 0.155, − 0.051,padjusted = 0.004) mm3smaller hippocampal volume and higher intelligence fluid score [β: 0.103 SD (95% CI: 0.042, 0.165),padjusted = 0.041]. Sensitivity analyses generally showed similar results, and no pleiotropic effect, heterogeneity, or possible reverse causation was detected. Our results suggested a possible causal association of high IL-8 levels with better cognitive performance but smaller hippocampal volume among the general healthy population, highlighting the complex role of inflammation in dementia-related phenotypes. Further research is needed to elucidate mechanisms underlying these associations.
Authors 6
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Jiao Min Luo corresponding Aachen Department of Clinical Epidemiology Department of Internal Medicine Section of Gerontology and Geriatrics
Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. j.luo@lumc.nl
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300RC, Leiden, The Netherlands. j.luo@lumc.nl
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300RC, Leiden, The Netherlands
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Affiliation as printed
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
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Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300RC, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300RC, Leiden, The Netherlands
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