Dementia In Observational Studies Research Articles

Genetic Evidence for Causal Association Between Atrial Fibrillation and Dementia: AMendelian Randomization Study.

Background The knowledge gap regarding whether the correlation between atrial fibrillation (AF) and dementia in observational studies is causation or driven by other shared risk factors remains substantially unfilled. Methods and Results We performed a comprehensive 2-sample Mendelian randomization study to evaluate the causal effect of AF on overall dementia and its subtypes, including vascular dementia, Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. The primary results in inverse variance-weighted analyses were further validated by various Mendelian randomization sensitivity analyses. Additionally, we conducted multivariable Mendelian randomization to examine 10 candidate mediators of the causal association of AF and dementia. Genetic predisposition to AF was modestly associated with an increased risk of overall dementia (odds ratio, 1.140 [95% CI, 1.023-1.271]; P=0.018) and strongly associated with vascular dementia (odds ratio, 1.350 [95% CI, 1.076-1.695]; P=0.010). Genetically predicted AF indicated neutral effects on Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. In multivariable Mendelian randomization analysis, the total effect of AF on overall dementia was remarkably attenuated by adjusting for genetic effect for ischemic stroke (odds ratio, 1.068 [95% CI, 0.953-1.197]; P=0.259) and low cardiac output (odds ratio, 1.046 [95% CI, 0.926-1.181]; P=0.475), indicating that the causal association of genetically predicted AF with dementia was potentially mediated by ischemic stroke and low cardiac output. The causal effect of genetically predicted AF on dementia was independent of cerebral small-vessel disease and brain volume phenotypes. Conclusions Our findings provided novel evidence supporting the causal effect of genetically predicted AF on dementia mediated by ischemic stroke and low cardiac output. Future clinical trials are warranted to evaluate the potential role of appropriate AF management in dementia prevention.

Abstract 54: Newly Initiation of Antihypertensive Medication on Reduction of Incident Dementia: Emulation of Target Trials Based on the Health and Retirement Study

Background: Although antihypertensive medication use is associated with a lower risk of dementia in observational studies, such an effect is rarely found in randomized controlled trials (RCTs). As midlife high blood pressure is more predictive of incident dementia than hypertension in late life, so midlife hypertension may be the target for intervention. However, no such an RCT has been conducted to prevent incident dementia through reducing high blood pressure from midlife. Therefore, we aimed to emulate a target trial with an observational study design to estimate the effect of initiating antihypertensive medication from midlife on reducing incident dementia. Hypothesis: We assessed the hypothesis that newly initiating antihypertensive medication among midlife adults with hypertension reduces incident dementia. Methods: New-user design was used to emulate a target trial using data from the Health and Retirement Study from 1996 to 2018 with non-institutional dementia-free participants aged 45 to 65 years without taking antihypertensive medication in past two years. Participants with information of self-reported hypertension diagnosis and new use of antihypertensive medication, as well as no dementia based on algorithm were included in the analysis and represented group with/without initiating antihypertensive medication. An intention-to-treat approach was applied for analysis, and sequential emulation was used to increase the efficiency of intention-to-treat analysis. Proportional hazards models were applied to estimate the effect of initiating antihypertensive medication on incident dementia. Inverse probability of treatment and censoring weights were created to adjust for confounding and selection bias due to loss to follow-up, and death was considered as a competing event. Another emulated target trial with the same specifications was conducted among late-life adults aged 66 years or older for comparison. Results: A total of 3,151 non-unique participants (baseline mean age: 59.0 ± 4.0 years, 54.6% (n=1,719) women, 78.3% (n=2468) Whites, 71.4% (n=2,249) initiating antihypertensive medication) were included in the analysis. Initiating antihypertensive medication showed benefit in reducing incident dementia over a total of 22-year follow-up, with a reduction of risk by 19% (hazards ratio=0.81, 95% confidence interval: 0.66, 0.99). No significant reduction was observed for initiators of antihypertensive medication from late life. Conclusions: Initiating antihypertensive medication from midlife, but not from late life may reduce incident dementia. Future studies are warranted to estimate the effect of blood pressure lowering in midlife through other means of intervention in reducing incident dementia.

The Effect of Multidomain Interventions on Global Cognition, Symptoms of Depression and Apathy \u2014 A Pooled Analysis of Two Randomized Controlled Trials

BackgroundCardiovascular risk factors and lifestyle factors are associated with an increased risk of cognitive decline and dementia in observational studies, and have been targeted by multidomain interventions.ObjectivesWe pooled individual participant data from two multi-domain intervention trials on cognitive function and symptoms of depression to increase power and facilitate subgroup analyses.DesignPooled analysis of individual participant data.SettingPrevention of Dementia by Intensive Vascular Care trial (preDIVA) and Multidomain Alzheimer Preventive Trial (MAPT).ParticipantsCommunity-dwelling individuals, free from dementia at baseline.InterventionMultidomain interventions focused on cardiovascular and lifestyle related risk factors.MeasurementsData on cognitive functioning, depressive symptoms and apathy were collected at baseline, 2 years and 3–4 years of follow-up as available per study. We analyzed crude scores with linear mixed models for overall cognitive function (Mini Mental State Examination [MMSE]), and symptoms of depression and apathy (15-item Geriatric Depression Scale). Prespecified subgroup analyses were performed for sex, educational level, baseline MMSE <26, history of hypertension, and history of stroke, myocardial infarction and/or diabetes mellitus.ResultsWe included 4162 individuals (median age 74 years, IQR 72, 76) with a median follow-up duration of 3.7 years (IQR 3.0 to 4.1 years). No differences between intervention and control groups were observed on change in cognitive functioning scores and symptoms of depression and apathy scores in the pooled study population. The MMSE declined less in the intervention groups in those with MMSE <26 at baseline (N=250; MD: 0.84; 95%CI: 0.15 to 1.54; p<0.001).ConclusionsWe found no conclusive evidence that multidomain interventions reduce the risk of global cognitive decline, symptoms of depression or apathy in a mixed older population. Our results suggest that these interventions may be more effective in those with lower baseline cognitive functioning. Extended follow-up for dementia occurrence is important to inform on the potential long-term effects of multidomain interventions.

Perspective: The Potential Role of Circulating Lysophosphatidylcholine in Neuroprotection against Alzheimer Disease

Alzheimer disease (AD), the most common cause of dementia, is a progressive disorder involving cognitive impairment, loss of learning and memory, and neurodegeneration affecting wide areas of the cerebral cortex and hippocampus. AD is characterized by altered lipid metabolism in the brain. Lower concentrations of long-chain PUFAs have been described in the frontal cortex, entorhinal cortex, and hippocampus in the brain in AD. The brain can synthesize only a few fatty acids; thus, most fatty acids must enter the brain from the blood. Recent studies show that PUFAs such as DHA (22:6) are transported across the blood-brain barrier (BBB) in the form of lysophosphatidylcholine (LPC) via a specific LPC receptor at the BBB known as the sodium-dependent LPC symporter 1 (MFSD2A). Higher dietary PUFA intake is associated with decreased risk of cognitive decline and dementia in observational studies; however, PUFA supplementation, with fatty acids esterified in triacylglycerols did not prevent cognitive decline in clinical trials. Recent studies show that LPC is the preferred carrier of PUFAs across the BBB into the brain. An insufficient pool of circulating LPC containing long-chain fatty acids could potentially limit the supply of long-chain fatty acids to the brain, including PUFAs such as DHA, and play a role in the pathobiology of AD. Whether adults with low serum LPC concentrations are at greater risk of developing cognitive decline and AD remains a major gap in knowledge. Preventing and treating cognitive decline and the development of AD remain a major challenge. The LPC pathway is a promising area for future investigators to identify modifiable risk factors for AD.

Menopause, cognition and dementia - A review.

There is increasing evidence that menopausal changes can have an impact on women’s cognition and potentially, the future development of dementia. In particular, the role of reduced levels of estrogen in postmenopausal changes has been linked to an increased risk of developing dementia in observational studies. Not surprisingly, this has led to several clinical trials investigating whether postmenopausal hormone replacement therapy can potentially delay/avoid cognitive changes and subsequently, the onset of dementia. However, the evidence of these trials has been mixed, with some showing positive effects while others show no or even negative effects. In the current review, we investigate this controversy further by reviewing the existing studies and trials in cognition and dementia. Based on the current evidence, we conclude that previous approaches may have used a mixture of women with different genetic risk factors for dementia which might explain these contradicting findings. Therefore, it is recommended that future interventional studies take a more personalised approach towards hormone replacement therapy use in postmenopausal women, by taking into account the women’s genetic status for dementia risk.

Low-Dose Aspirin Use and Cognitive Function in Older Age: A Systematic Review and Meta-analysis.

To investigate whether low-dose aspirin (<300 mg/d) can influence the onset of cognitive impairment or dementia in observational studies and improve cognitive test scores in randomized controlled trials (RCTs) in participants without dementia. Systematic review and meta-analysis. Observational and interventional studies. Individuals with no dementia or cognitive impairment initially. Odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for the maximum number of covariates from each study, were used to summarize data on the incidence of dementia and cognitive impairment in observational studies. Standardized mean differences (SMDs) were used for cognitive test scores in RCTs. Of 2,341 potentially eligible articles, eight studies were included and provided data for 36,196 participants without dementia or cognitive impairment at baseline (mean age 66, 63% female). After adjusting for a median of three potential confounders over a median follow-up period of 6 years, chronic use of low-dose aspirin was not associated with onset of dementia or cognitive impairment (5 studies, N = 26,159; OR = 0.82, 95% CI = 0.55-1.22, P = .33, I2 = 67%). In three RCTs (N = 10,037; median follow-up 5 years), the use of low-dose aspirin was not associated with significantly better global cognition (SMD=0.005, 95% CI=-0.04-0.05, P = .84, I2 = 0%) in individuals without dementia. Adherence was lower in participants taking aspirin than in controls, and the incidence of adverse events was higher. This review found no evidence that low-dose aspirin buffers against cognitive decline or dementia or improves cognitive test scores in RCTs.

Targets for the Prevention of Dementia

The prevalence of dementia is expected to increase dramatically over the upcoming decades due to the aging population. Since treatment is still short of a cure, preventative strategies are of the utmost importance. Stimulating activity (cognitive, physical, and social), vascular risk factors, and diet may be important in preventative strategies. Dementia risk may be modified by participation in stimulating activities. One study suggested that the cognitive, physical, and social components of activity were of equal importance to cognitive outcomes. However, while exercise interventions appear to benefit global cognition, the benefits from cognitive training appear to be domain specific. People with vascular risk factors (hypertension, diabetes, dyslipidemia, and obesity) appear to be at higher risk for dementia than those without in observational and clinical trials. Controlled trials suggest that vascular risk management via some pharmaceutical interventions may benefit cognition, though results are inconsistent. Finally, people who adhere to a Mediterranean diet or who have high intake of antioxidants and omega-3 fatty acids have reduced likelihood of dementia in observational studies. However, supplementation in controlled trials has not generally proved successful at improving cognitive outcomes. A single supplement may be insufficient to prevent dementia; it may be that the overall diet is more important. Future large randomized controlled studies should examine whether interventions can reduce the risk of dementia and whether combining cognitive, physical, and social activity, vascular risk reduction, and dietary interventions might have additive or multiplicative effects.

Hemostasis and Vascular Dementia

Vascular dementia (VaD) comprises a group of syndromes caused by vascular lesions in the brain. Cognitive impairment may follow a single cortical or lacunar infarct in a strategic area of the brain, multiple infarcts, small-vessel disease (leukoaraiosis), intracerebral hemorrhage, or any of these conditions coexisting with Alzheimer dementia (so-called mixed dementia). Depending on case mix and the type of observational study, 10% of patients already have dementia before their first stroke, 10% develop it soon after their first stroke, and more than 33% have dementia after a recurrent stroke.1 Typically, dementia develops at a rate of 3% per year after stroke, and it is the stroke, rather than its underlying risk factors, that appears to be the dominant cause of subsequent dementia.1 See accompanying articles on pages 599 and 605 Although VaD, including poststroke dementia, is associated with conventional risk factors, such as hypertension and hypercholesterolemia,2,3 their relationship with hemostatic factors is less clear. This contrasts with the relationship between hemostatic factors and stroke, which is well established and involves both soluble (eg, fibrinogen4) and cellular (eg, mean platelet volume5) biomarkers. Several hemostatic factors, including fibrinogen and fibrin d-dimer levels, are associated with subsequent cognitive impairment and dementia in observational studies (Table).6–10 This issue of Arteriosclerosis, Thrombosis, and Vascular Biology expands on this relationship between “sticky blood” and cognition.11 Two new studies are described. View this table: Table. Selected Hemostatic Factors With …

Use of lipid lowering agents and the risk of cognitive impairment not meeting dementia criteria in relation to apolipoprotein E status

Background: The use of lipid lowering agents (LLAs) has been associated with a lower odds of dementia in observational studies, but the impact on earlier presentation of dementia in the forms of cognitive impairment in older adults, who do not meet the accepted criteria for dementia, is not clear. Objective(s): To examine the association between the use of LLAs and cognitive impairment that does not meet criteria for dementia (Cognitive Impairment, No Dementia CIND); and to assess whether the effect is modified by apolipoprotein E4 status. Methods: In a case-control study, as a secondary analysis from the Canadian Study of Health and Aging (CSHA), we examined cases (n 347, aged 65 years) with incident CIND between the first (CSHA-1) and second (CSHA-2) waves, i.e. those who had either a clinical diagnosis of No Cognitive Impairment (NCI) at baseline, or a screening Modified Mini-Mental State Examination Score of 81, and who had a clinical diagnosis of CIND at CSHA-2. Controls (n 693) consisted of older adults diagnosed with NCI during CSHA-2. Results: Use of LLAs was associated with a lower odds of new-onset CIND in those less than 80 years of age (OR 0.37; 95%CI 0.15-0.93) but not for those aged 80 years (OR 0.56; 95% CI 0.15-2.10). There was no difference in the odds ratios by apolipoprotein E4 status. The protective effect of LLA’s for CIND was chiefly seen for people with the CIND subtype Circumscribed Memory Impairment (CMI), and was restricted to those using statins. Conclusions: Lipid-lowering agent use, statins in particular, was associated with a lower odds of new onset CIND, particularly amongst those with CMI. This additional report on LLA use from the CSHA study supports earlier observations of a protective effect of LLAs, statins in particular, on dementia.

Rapid ELISA for detecting Epstein-Barr virus infection.

<h3>Abstract</h3> <h3>Importance</h3> 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. <h3>Objective</h3> 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. <h3>Data sources</h3> MR studies identified by systematic search of Web of Science, OVID and Scopus. <h3>Study selection</h3> 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. <h3>Data extraction and synthesis</h3> 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. <h3>Main outcomes and measures</h3> Odds ratio (OR) of developing dementia per standardized unit increase in the risk factor of interest. <h3>Results</h3> 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. <h3>Conclusion and relevance</h3> Genetically predicted body mass index was associated with an increase in risk of dementia. <h3>Key points</h3> <h3>Question</h3> Are genetically predicted modifiable risk factors associated with dementia? <h3>Findings</h3> Genetically predicted higher body mass index was associated with a higher odds of dementia. No evidence was found to support an association between genetically predicted type 2 diabetes mellitus, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, plasma glucose and dementia risk. <h3>Meaning</h3> Many modifiable risk factors associated with dementia in observational studies may not play a causative role.