Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank

Malik, Rainer; Georgakis, Marios K.; Neitzel, Julia; Rannikmäe, Kristiina; Ewers, Michael; Seshadri, Sudha; Sudlow, Cathie; Dichgans, Martin

doi:10.1002/alz.12320

Cited by 88 publications

(95 citation statements)

References 47 publications

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“…Another interesting but yet to be tested hypothesis emerging from the current data implicates that changes in system segregation due to high blood pressure may be a pathway by which poor cardiovascular health is linked to cognitive impairment and dementia 54 . In agreement with this notion are the results from a recent study in the UK Biobank which show that a history of hypertension was related to reduced hippocampus connectivity which in turn was associated with poorer memory performance 55 .…”

Section: Discussionmentioning

confidence: 98%

Genetic variants link lower segregation of brain networks to higher blood pressure and worse cognition within the general aging population

Neitzel

Malik

Muetzel

et al. 2021

Preprint

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The functional architecture of the brain is composed of distinct networks, where higher system segregation, i.e. greater differentiation of such functional networks, is associated with better cognitive performance. Aging and many neurological diseases have been associated with reduced system segregation and thus cognitive impairment. The genetic basis and risk factors of system segregation are largely unknown. Here, we present the first genome-wide association study of fMRI-assessed system segregation in 16,635 UK Biobank participants, identifying nine independent genomic loci. The 66 implicated genes were significantly downregulated in brain tissue and upregulated in vascular tissue. Of major vascular risk factors (Life's Simple 7), blood pressure showed a robust genetic correlation with system segregation. Observational and Mendelian randomization analyses confirmed a unfavourable effect of higher blood pressure on system segregation and of lower system segregation on cognition. Replication analyses in 2,414 Rotterdam Study participants supported these conclusions.

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Section: Discussionmentioning

confidence: 98%

Genetic variants link lower segregation of brain networks to higher blood pressure and worse cognition within the general aging population

Neitzel

Malik

Muetzel

et al. 2021

Preprint

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“…Despite strong epidemiological foundation for a role of vascular risk factors in cognitive decline and dementia, 132,189–191 there is limited evidence from RCTs that controlling vascular risk factors through interventions would lower the risk of incident PSCID. 28,189…”

Section: Managementmentioning

confidence: 99%

“…Despite strong epidemiological foundation for a role of vascular risk factors in cognitive decline and dementia, 132,[189][190][191] there is limited evidence from RCTs that controlling vascular risk factors through interventions would lower the risk of incident PSCID. 28,189 Few RCTs have examined the effects of intensive BP management on cognitive decline and incident dementia in patients with a antecedent stroke: the NICE (Nimodipine in Preventing Cognitive Impairment in Ischemic Cerebrovascular Events), 192 PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes), 193 and SPS3 (Secondary Prevention of SubCortical Stroke Study) 194 trials included patients with a recent IS (maximum interval from stroke onset: 90 days), whereas the PROGRESS trial 195 included patients with either IS or hemorrhagic stroke within an interval up to 5 years from stroke onset.…”

Section: Management Preventionmentioning

confidence: 99%

Post-Stroke Cognitive Impairment and Dementia

Rost

Brodtmann

Pase

et al. 2022

Circulation Research

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194

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Poststroke cognitive impairment and dementia (PSCID) is a major source of morbidity and mortality after stroke worldwide. PSCID occurs as a consequence of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Cognitive impairment and dementia manifesting after a clinical stroke is categorized as vascular even in people with comorbid neurodegenerative pathology, which is common in elderly individuals and can contribute to the clinical expression of PSCID. Manifestations of cerebral small vessel disease, such as covert brain infarcts, white matter lesions, microbleeds, and cortical microinfarcts, are also common in patients with stroke and likewise contribute to cognitive outcomes. Although studies of PSCID historically varied in the approach to timing and methods of diagnosis, most of them demonstrate that older age, lower educational status, socioeconomic disparities, premorbid cognitive or functional decline, life-course exposure to vascular risk factors, and a history of prior stroke increase risk of PSCID. Stroke characteristics, in particular stroke severity, lesion volume, lesion location, multiplicity and recurrence, also influence PSCID risk. Understanding the complex interaction between an acute stroke event and preexisting brain pathology remains a priority and will be critical for developing strategies for personalized prediction, prevention, targeted interventions, and rehabilitation. Current challenges in the field relate to a lack of harmonization of definition and classification of PSCID, timing of diagnosis, approaches to neurocognitive assessment, and duration of follow-up after stroke. However, evolving knowledge on pathophysiology, neuroimaging, and biomarkers offers potential for clinical applications and may inform clinical trials. Preventing stroke and PSCID remains a cornerstone of any strategy to achieve optimal brain health. We summarize recent developments in the field and discuss future directions closing with a call for action to systematically include cognitive outcome assessment into any clinical studies of poststroke outcome.

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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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Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank

Cited by 88 publications

References 47 publications

Genetic variants link lower segregation of brain networks to higher blood pressure and worse cognition within the general aging population

Genetic variants link lower segregation of brain networks to higher blood pressure and worse cognition within the general aging population

Post-Stroke Cognitive Impairment and Dementia

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

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