A genome‐wide association meta‐analysis of all‐cause and vascular dementia

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doi:10.1002/alz.14115

Cited by 6 publications

References 74 publications

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Causal cardiovascular risk factors for dementia: insights from observational and genetic studies

Kjeldsen,

Frikke-Schmidt

2024

Cardiovascular Research

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The escalating prevalence of dementia worldwide necessitates preventive strategies to mitigate its extensive health, psychological, and social impacts. As the prevalence of dementia continues to rise, gaining insights into its risk factors and causes become paramount, given the absence of a definitive cure. Cardiovascular disease has emerged as a prominent player in the complex landscape of dementia. Preventing, dyslipidaemia, unhealthy Western type diets, hypertension, diabetes, being overweight, physical inactivity, smoking, and high alcohol intake have the potential to diminish not only cardiovascular disease but also dementia. The purpose of this review is to present our current understanding of cardiovascular risk factors for Alzheimer's disease (AD) and vascular dementia (VaD) by using clinical human data from observational, genetic studies and clinical trials, while elaborating on potential mechanisms. Hypertension and type 2 diabetes surface as significant causal risk factors for both AD and VaD, as consistently illustrated in observational and Mendelian randomization studies. Antihypertensive drugs and physical activity have been shown to improve cognitive function in clinical trials. Important to note is, that robust genome wide associations studies are lacking for VaD, and indeed more and prolonged clinical trials are needed to establish these findings and investigate other risk factors. Trials should strategically target individuals at the highest dementia risk, identified using risk charts incorporating genetic markers, biomarkers, and cardiovascular risk factors. Understanding causal risk factors for dementia will optimise preventive measures, and implementation of well-known therapeutics can halt or alleviate dementia symptoms if started early. Needless to mention is that future health policies should prioritise primordial prevention from early childhood to prevent risk factors from even occurring in the first place. Together, understanding the role of cardiovascular risk factors in dementia, improving GWASs for VaD, and advancing clinical trials are crucial steps in addressing this significant public health challenge.

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Causal cardiovascular risk factors for dementia: insights from observational and genetic studies

Kjeldsen,

Frikke-Schmidt

2024

Cardiovascular Research

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Gene-diet interaction analysis in UK Biobank identified genetic loci that modify the association between fish oil supplementation and the incidence of dementia

Lu,

Xu,

Sun

et al. 2024

Preprint

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Background: Dementia is a common disease influenced by both genetic and environmental factors. APOE4 is well-known to increase the risk of dementia, and it has been shown to attenuate the protective association of fish oil supplementation and the incidence of dementia. To identify more genetic factors with similar modifying effects, we performed a genome-wide scan. Methods: We first performed time-to-event genome-wide association study (GWAS) of all-cause dementia and two of its subtypes, Alzheimer's disease (AD) and vascular dementia, in the UK Biobank. GWAS were performed in all participants (N = 357,631) and in two subgroups with or without fish oil supplementation (N = 113,267 and 244,364, respectively). Single nucleotide polymorphisms (SNPs) suggestively associated with dementia were then evaluated for their interactions with fish oil status in Cox-regression models. Furthermore, we conducted gene set enrichment analysis to identify the relevant cell types for these interaction signals. Results: Time-to-event GWAS identified 6, 5, and 2 genome-wide significant loci (p < 5e-8) for the incidence of all-cause dementia, AD, and vascular dementia, respectively. Most of them overlapped with previously known GWAS loci for AD and related dementia. A total of 178 suggestive GWAS loci (p < 1e-5) were passed onto interaction analysis, and 43 of them were found to significantly modify the association between fish oil supplementation and dementia incidence (p < 2.8e-4 with Bonferroni correction). One locus overlapped with a known AD GWAS locus (EED/PICALM) and two overlapped with GWAS loci for circulating omega-3 fatty acids (SRSF4, PSMG1). Gene set enrichment analysis found that candidate genes of interaction signals demonstrated tissue or cell-type specificity in the brain. Conclusion: We identified 43 genetic loci that modify the association between fish oil supplementation and dementia. These findings indicate a need for genome-informed personalized nutrition of fish oil supplementation for the purpose of dementia prevention.

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Genetic downregulation of interleukin-6 signaling and arteriolosclerotic cerebral small vessel disease: a drug target Mendelian randomization analysis

Tchuisseu-Kwangoua,

Omarov,

Shatunov

et al. 2024

Preprint

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Background: Arteriolosclerotic cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia, yet no disease-modifying therapies exist. Anti-inflammatory strategies targeting IL-6 signaling have shown efficacy in preventing atherosclerotic cardiovascular disease, but their potential in arteriolosclerotic cSVD remains unexplored. We investigated whether genetically downregulated IL-6 signaling is associated with clinical, imaging, and pathological manifestations of arteriolosclerotic cSVD. Methods: We applied two-sample Mendelian randomization (MR) using (i) 26 genetic variants near IL6R associated with circulating C-reactive protein (CRP) levels and (ii) rs2228145, a well-characterized IL6R missense variant, as proxies of IL-6 signaling downregulation. Outcomes included clinical (small-vessel stroke, MRI-defined lacunar stroke, non-lobar intracerebral hemorrhage [ICH], vascular dementia), imaging (white matter hyperintensity volume, extensive basal ganglia perivascular space, non-lobar/mixed cerebral microbleeds), and pathological (arteriolosclerosis burden in autopsy) traits of cSVD, as well as atherosclerosis traits (ultrasound-defined carotid plaque, large artery stroke) as positive controls. We used inverse-variance weighting and the Wald ratio estimator for primary analyses. MR-Egger regression, weighted median, and weighted mode estimators were used as sensitivity analyses. Results: Genetically downregulated IL-6 signaling (30%-decrement in CRP via 26 IL6R variants) was not associated with small-vessel stroke (OR: 1.02, 95%CI: 0.95-1.10), MRI-confirmed lacunar stroke (OR: 0.95, [0.81-1.11]), non-lobar ICH (OR: 1.04, [0.72-1.50]), or vascular dementia (OR: 1.09, [0.95-1.25]). Similarly, we found no significant association with cSVD imaging biomarkers or pathology-defined arteriolosclerosis. As expected, genetically downregulated IL-6 signaling was associated with lower odds of large artery stroke (OR: 0.79, [0.74-0.84]) and carotid plaque (OR: 0.88, [0.83-0.94]). Results were consistent across sensitivity analyses and when using the rs2228145 missense variant to proxy IL-6 signaling downregulation. Conclusion: Genetically proxied IL-6 signaling downregulation is not associated with clinical, imaging or pathological manifestations of arteriolosclerotic cSVD. Therefore, genetic data suggest that targeting IL-6 signaling is unlikely to prevent cSVD manifestations.

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A genome‐wide association meta‐analysis of all‐cause and vascular dementia

Cited by 6 publications

References 74 publications

Causal cardiovascular risk factors for dementia: insights from observational and genetic studies

Causal cardiovascular risk factors for dementia: insights from observational and genetic studies

Gene-diet interaction analysis in UK Biobank identified genetic loci that modify the association between fish oil supplementation and the incidence of dementia

Genetic downregulation of interleukin-6 signaling and arteriolosclerotic cerebral small vessel disease: a drug target Mendelian randomization analysis

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