High Blood Pressure and Risk of Dementia: A Two-Sample Mendelian Randomization Study in the UK Biobank

Sproviero, William; Winchester, Laura; Newby, Danielle; Fernandes, Marco; Shi, Liu; Goodday, Sarah M.; Prats‐Uribe, Albert; Alhambra, D Prieto; Buckley, Noel J.; Nevado‐Holgado, Alejo J.

doi:10.1016/j.biopsych.2020.12.015

Cited by 44 publications

(34 citation statements)

References 39 publications

(58 reference statements)

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“…First, although the study design was prospective and longitudinal, there were no interventions, so it is difficult to completely exclude reverse causations. As described in the Introduction, some studies suggest that low BP is a symptom (not a cause) of pre-clinical dementia [4], while a Mendelian randomization study suggested a causal effect of lower BP on dementia risk [5]. The neurological processes of Alzheimer's disease start 20 years before onset [49], and disentangling causes from outcomes over this period is difficult.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Diastolic Blood Pressure on Brain Structures and Cognitive Functions in Middle and Old Ages: Longitudinal Analyses

Takeuchi

Kawashima

2022

Nutrients

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Hypertension is a pervasive public health concern due to strong associations with cardiovascular diseases and stroke. Alternatively, the associations between hypertension and the risk of Alzheimer’s disease are complex and recent large sample studies reported positive associations. In this paper, we examine the associations between diastolic blood pressure (BP) and subsequent changes in brain structure and cognitive function over several years by multiple regression analyses (with adjustment for a wide range of potential confounding variables) among a large cohort from the UK Biobank. Higher baseline diastolic BP was associated with a slightly smaller relative increase (relative improvements) in reaction time and a slightly greater reduction in depression scores. Higher baseline diastolic BP was also associated with a greater total gray matter volume (GMV) retention, while aging alone was associated with GMV reduction. White matter microstructural analyses revealed that a greater diastolic BP was associated with reduced longitudinal mean and regional fractional anisotropy, greater increases in mean and regional mean diffusivity, radial diffusivity, and axial diffusivity, a greater decline in mean intracellular volume fraction, and greater increases in mean and regional isotropic volume fraction. These white matter microstructural changes were consistent with those seen in the aging process. Additional analyses revealed a greater cheese intake level at baseline, which is associated with a subsequent decline in diastolic BP and a relative subsequent increase in depressive tendency together with a relative increase in fluid intelligence and visuospatial memory performance. These results are congruent with the view that a higher BP in the aging brain has a complex role.

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Section: Discussionmentioning

confidence: 99%

“…It has also been suggested that low BP is a pre-clinical symptom rather than a cause of dementia [4]. However, a recent Mendelian randomization study reported that high blood pressure is causally linked to a lower risk of dementia [5].…”

Section: Introductionmentioning

confidence: 99%

Effects of Diastolic Blood Pressure on Brain Structures and Cognitive Functions in Middle and Old Ages: Longitudinal Analyses

Takeuchi

Kawashima

2022

Nutrients

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“…Hence, we used the GWAS datasets from the exposure (serum calcium) and the outcome (AD) to estimate the effect of exposure on outcome ( He et al, 2020 ). MR analysis has three assumptions, which have been widely described ( Liu et al, 2018 ; Anderson et al, 2020 ; He et al, 2020 ; Wang L. et al, 2020 ; Zhang et al, 2020 ; Ou et al, 2021 ; Sproviero et al, 2021 ). Ethical approvals were provided in the original articles ( Lambert et al, 2013 ; Young et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…AD cases were autopsy-confirmed or clinically confirmed using the NINCDS-ADRDA criteria or DSM-IV guidelines ( Kunkle et al, 2019 ). The IGAP AD GWAS summary statistics have been widely used in recent MR analysis ( Liu et al, 2018 ; Anderson et al, 2020 ; He et al, 2020 ; Wang L. et al, 2020 ; Zhang et al, 2020 ; Ou et al, 2021 ; Sproviero et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

An Updated Mendelian Randomization Analysis of the Association Between Serum Calcium Levels and the Risk of Alzheimer’s Disease

et al. 2021

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It has been a long time that the relationship between serum calcium levels and Alzheimer’s disease (AD) remains unclear. Until recently, observational studies have evaluated the association between serum calcium levels and the risk of AD, however, reported inconsistent findings. Meanwhile, a Mendelian randomization (MR) study had been conducted to test the causal association between serum calcium levels and AD risk, however, only selected 6 serum calcium SNPs as the instrumental variables. Hence, these findings should be further verified using additional more genetic variants and large-scale genome-wide association study (GWAS) dataset to increase the statistical power. Here, we conduct an updated MR analysis of the causal association between serum calcium levels and the risk of AD using a two-stage design. In discovery stage, we conducted a MR analysis using 14 SNPs from serum calcium GWAS dataset (N = 61,079), and AD GWAS dataset (N = 63,926, 21,982 cases, 41,944 cognitively normal controls). All four MR methods including IVW, weighted median, MR-Egger, and MR-PRESSO showed a reduced trend of AD risk with the increased serum calcium levels. In the replication stage, we performed a MR analysis using 166 SNPs from serum calcium GWAS dataset (N = 305,349), and AD GWAS dataset (N = 63,926, 21,982 cases, 41,944 cognitively normal controls). Only the weighted median indicated that genetically increased serum calcium level was associated with the reduced risk of AD. Hence, additional studies are required to investigate these findings.

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“…There were three primary MR studies each for type 2 diabetes [16][17][18] and LDL cholesterol [19][20][21] ; two studies each for HDL cholesterol 19,22 , total cholesterol 19,23 , triglycerides 19,21 , and systolic blood pressure 20,24 ; and one study each for diastolic blood pressure 25 , BMI 26 and circulating glucose 27 (Figure 1). The MR studies for diastolic blood pressure, BMI, and circulating glucose reported an overall estimate produced through the meta-analysis of two or more outcome cohorts.…”

Section: Identification Of Primary Mr Studiesmentioning

confidence: 99%

Assessing the role of vascular risk factors in dementia: Mendelian randomization meta-analysis and comparison with observational estimates

Lee

Martin

Whiteley

2022

Preprint

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Importance: Although observational studies demonstrate that higher levels of vascular risk factors are associated with an increased risk of dementia, these associations might be explained by confounding or other biases. Mendelian randomization (MR) uses genetic instruments to test causal relationships in observational data. Objective: To determine if genetically predicted modifiable risk factors (type 2 diabetes mellitus, low density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, body mass index, and circulating glucose) are associated with dementia by meta-analysing published MR studies. Secondary objectives were to identify heterogeneity in effect estimates across primary MR studies and to compare meta-analysis results with observational studies. Data sources: MR studies identified by systematic search of Web of Science, OVID and Scopus. Study selection: Primary MR studies investigating the modifiable risk factors of interest. Only one study from each cohort per risk factor was included. A quality assessment tool was developed to primarily assess the three assumptions of MR for each MR study. Data extraction and synthesis: Data were extracted on study characteristics, exposure and outcome, effect estimates per unit increase, and measures of variation. Effect estimates were pooled to generate an overall estimate, I2 and Cochrane Q values using fixed-effect model. Main outcomes and measures: Odds ratio (OR) of developing dementia per standardized unit increase in the risk factor of interest. Results: We screened 5211 studies and included 12 primary MR studies after applying inclusion and exclusion criteria. Higher genetically predicted body mass index was associated with a higher odds of dementia (OR 1.03 [1.01, 1.05] per 5 kg/m2 increase, one study, p = 0.00285). Overall estimates from MR studies showed a smaller number of associations than those from meta-analyses of observational studies. Conclusion and relevance: Genetically predicted body mass index was associated with an increase in risk of dementia.

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High Blood Pressure and Risk of Dementia: A Two-Sample Mendelian Randomization Study in the UK Biobank

Cited by 44 publications

References 39 publications

Effects of Diastolic Blood Pressure on Brain Structures and Cognitive Functions in Middle and Old Ages: Longitudinal Analyses

Effects of Diastolic Blood Pressure on Brain Structures and Cognitive Functions in Middle and Old Ages: Longitudinal Analyses

An Updated Mendelian Randomization Analysis of the Association Between Serum Calcium Levels and the Risk of Alzheimer’s Disease

Assessing the role of vascular risk factors in dementia: Mendelian randomization meta-analysis and comparison with observational estimates

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