C‐reactive protein levels and risk of dementia—Observational and genetic studies of 111,242 individuals from the general population

Hegazy, Sharif H.; Thomassen, Jesper Qvist; Rasmussen, Ida Juul; Nordestgaard, Børge G.; Tybjærg‐Hansen, Anne; Frikke‐Schmidt, Ruth

doi:10.1002/alz.12568

Cited by 35 publications

(39 citation statements)

References 48 publications

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“…We also did not consider potential adverse effects of perturbing IL-6 signaling, including implications for allergic, autoimmune and infectious disease [10]. Of note, observational and genetic evidence has supported an association of low CRP levels with increased risk of Alzheimer's disease [29], and further work is required to delineate the dose-response relationship between IL-6 signaling mediated changes in CRP levels and potential adverse outcomes. Finally, these genetic analyses explore small lifelong effects, and may not be directly extrapolated to short-term clinical interventions [6].…”

Section: Discussionmentioning

confidence: 99%

Associations of genetically predicted IL-6 signaling with cardiovascular disease risk across population subgroups

Georgakis

Malik

Richardson

et al. 2022

BMC Med

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Background Interleukin 6 (IL-6) signaling is being investigated as a therapeutic target for atherosclerotic cardiovascular disease (CVD). While changes in circulating high-sensitivity C-reactive protein (hsCRP) are used as a marker of IL-6 signaling, it is not known whether there is effect heterogeneity in relation to baseline hsCRP levels or other cardiovascular risk factors. The aim of this study was to explore the association of genetically predicted IL-6 signaling with CVD risk across populations stratified by baseline hsCRP levels and cardiovascular risk factors. Methods Among 397,060 White British UK Biobank participants without known CVD at baseline, we calculated a genetic risk score for IL-6 receptor (IL-6R)-mediated signaling, composed of 26 variants at the IL6R gene locus. We then applied linear and non-linear Mendelian randomization analyses exploring associations with a combined endpoint of incident coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, and cardiovascular death stratifying by baseline hsCRP levels and cardiovascular risk factors. Results The study participants (median age 59 years, 53.9% females) were followed-up for a median of 8.8 years, over which time a total of 46,033 incident cardiovascular events occurred. Genetically predicted IL-6R-mediated signaling activity was associated with higher CVD risk (hazard ratio per 1-mg/dL increment in absolute hsCRP levels: 1.11, 95% CI: 1.06–1.17). The increase in CVD risk was linearly related to baseline absolute hsCRP levels. There was no evidence of heterogeneity in the association of genetically predicted IL-6R-mediated signaling with CVD risk when stratifying the population by sex, age, body mass index, estimated glomerular filtration rate, or systolic blood pressure, but there was evidence of greater associations in individuals with low-density lipoprotein cholesterol ≥ 160 mg/dL. Conclusions Any benefit of inhibiting IL-6 signaling for CVD risk reduction is likely to be proportional to absolute reductions in hsCRP levels. Therapeutic inhibition of IL-6 signaling for CVD risk reduction should therefore prioritize those individuals with the highest baseline levels of hsCRP.

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Section: Discussionmentioning

confidence: 99%

Associations of genetically predicted IL-6 signaling with cardiovascular disease risk across population subgroups

Georgakis

Malik

Richardson

et al. 2022

BMC Med

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“…Briefly, in the healthy state or preclinical stage of neurological diseases, a modest inflammatory response would be beneficial for the clearance of waste products, whereas in advanced stages, overreacted excessive inflammatory response that exceeds the capacity of self-repair would exacerbate the (neuro)inflammation. A fine example is that lower levels of both C-reactive protein and complement C3, representing a low inflammation profile, are causally associated with higher risk of AD in the general Danish population [45,46]. However, the dynamics of IL-8 in the pathogenesis of neurological diseases needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Systemic inflammatory markers in relation to cognitive function and measures of brain atrophy: a Mendelian randomization study

et al. 2022

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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 and p < 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 (with p < 5e − 6 threshold) per-SD (standard deviation) higher IL-8 was associated with − 0.103 (− 0.155, − 0.051, padjusted = 0.004) mm3 smaller 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.

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“…As for inflammatory markers such as CRP, an important signaling molecule in inflammation that has effects on the brains or the periphery of people with dementia [40], which can explain why high CRP levels may be harmful. In addition, two prospective cohort studies previously examined change in CRP level with dementia and cognition [41,42], which suggesting low plasma CRP level were also associated with high risk of dementia and cognitive impairment. Mechanistically, it possibly because low CRP levels is a marker of poor immune function, which can lead to decreased phagocytosis of Aβ by microglia, decreased opsonization, and decreased activation of the complement system, thus resulting in a less efficient clearance of Aβ [41,42].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, two prospective cohort studies previously examined change in CRP level with dementia and cognition [41,42], which suggesting low plasma CRP level were also associated with high risk of dementia and cognitive impairment. Mechanistically, it possibly because low CRP levels is a marker of poor immune function, which can lead to decreased phagocytosis of Aβ by microglia, decreased opsonization, and decreased activation of the complement system, thus resulting in a less efficient clearance of Aβ [41,42]. Moreover, we find a significant association between dementia incidence and lower lipid fractions (triglycerides and LDL) levels, in contrast to some prior studies [7].…”

Section: Discussionmentioning

confidence: 99%

Serum clinical laboratory tests and risk of incident dementia: a prospective cohort study of 407,190 individuals

Kuo

Liu

et al. 2022

Transl Psychiatry

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Prevention of dementia is a public health priority, and the identification of potential biomarkers may provide benefits for early detection and prevention. This study investigates the association of common serum laboratory tests with the risk of incident dementia. Among 407,190 participants from the UK Biobank (median follow-up of 9.19 years), we investigated the linear and nonlinear effects of 30 laboratory measures on the risk of all-cause dementia using Cox models and restricted cubic spline models. We found that dementia incidence was associated with low vitamin D concentration (hazard ratio 0.994, 95% confidence interval 0.993–0.996), indicators of endocrine disorders: IGF-1 level (P for non-linearity = 1.1E-05), testosterone level (P for non-linearity = 0.006); high sex-hormone-binding globulin level (HR 1.004, 95% CI: 1.003–1.006); reduced liver function: lower alanine aminotransferase (HR 0.990, 95% CI: 0.986–0.995); renal dysfunction: cystatin C level (P for non-linearity = 0.028); oxidative stress: lower urate level (HR 0.998, 95% CI: 0.998–0.999); lipids dysregulation: lower LDL (HR 0.918, 95% CI: 0.872–0.965) and triglycerides (HR 0.924, 95% CI: 0.882–0.967) concentrations; insulin resistance: high glucose (HR 1.093, 95% CI: 1.045–1.143) and HbA1c (HR 1.017, 95% CI: 1.009–1.025) levels; immune dysbiosis: C−reactive protein (P for non-linearity = 5.5E-09). In conclusion, markers of vitamin D deficiency, GH-IGF-1 axis disorders, bioactive sex hormone deficiency, reduced liver function, renal abnormalities, oxidation, insulin resistance, immune dysbiosis, and lipids dysregulation were associated with incident dementia. Our results support a contributory role of systemic disorders and diverse biological processes to onset of dementia.

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C‐reactive protein levels and risk of dementia—Observational and genetic studies of 111,242 individuals from the general population

Cited by 35 publications

References 48 publications

Associations of genetically predicted IL-6 signaling with cardiovascular disease risk across population subgroups

Associations of genetically predicted IL-6 signaling with cardiovascular disease risk across population subgroups

Systemic inflammatory markers in relation to cognitive function and measures of brain atrophy: a Mendelian randomization study

Serum clinical laboratory tests and risk of incident dementia: a prospective cohort study of 407,190 individuals

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