scholarly journals Mendelian Randomization of Dyslipidemia on Cognitive Impairment Among Older Americans

2021 ◽  
Vol 12 ◽  
Author(s):  
Mingzhou Fu ◽  
Kelly M. Bakulski ◽  
Cesar Higgins ◽  
Erin B. Ware
Keyword(s):  
Risk Factor ◽  
Cognitive Impairment ◽  
Total Cholesterol ◽  
Instrumental Variable ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Cognitive Status ◽  
European Ancestry ◽  
High Total Cholesterol ◽  
Low Hdl

Background: Altered lipid metabolism may be a risk factor for dementia, and blood cholesterol level has a strong genetic component. We tested the hypothesis that dyslipidemia (either low levels of high-density lipoprotein cholesterol (HDL-C) or high total cholesterol) is associated with cognitive status and domains, and assessed causality using genetic predisposition to dyslipidemia as an instrumental variable.Methods: Using data from European and African genetic ancestry participants in the Health and Retirement Study, we selected observations at the first non-missing biomarker assessment (waves 2006–2012). Cognition domains were assessed using episodic memory, mental status, and vocabulary tests. Overall cognitive status was categorized in three levels (normal, cognitive impairment non-dementia, dementia). Based on 2018 clinical guidelines, we compared low HDL-C or high total cholesterol to normal levels. Polygenic scores for dyslipidemia were used as instrumental variables in a Mendelian randomization framework. Multivariable logistic regressions and Wald-type ratio estimators were used to examine associations.Results: Among European ancestry participants (n = 8,781), at risk HDL-C levels were associated with higher odds of cognitive impairment (OR = 1.20, 95% CI: 1.03, 1.40) and worse episodic memory, specifically. Using cumulative genetic risk for HDL-C levels as a valid instrumental variable, a significant causal estimate was observed between at risk low HDL-C levels and higher odds of dementia (OR = 2.15, 95% CI: 1.16, 3.99). No significant associations were observed between total cholesterol levels and cognitive status. No significant associations were observed in the African ancestry sample (n = 2,101).Conclusion: Our study demonstrates low blood HDL-C is a potential causal risk factor for impaired cognition during aging in non-Hispanic whites of European ancestry. Dyslipidemia can be modified by changing diets, health behaviors, and therapeutic strategies, which can improve cognitive aging. Studies on low density lipoprotein cholesterol, the timing of cholesterol effects on cognition, and larger studies in non-European ancestries are needed.

scholarly journals Mendelian randomization of dyslipidemia on cognitive impairment among older Americans

2020 ◽  
Author(s):  
Mingzhou Fu ◽  
Kelly M. Bakulski ◽  
Cesar Higgins ◽  
Erin B. Ware
Keyword(s):  
Risk Factor ◽  
Cognitive Impairment ◽  
Total Cholesterol ◽  
Instrumental Variable ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Cognitive Status ◽  
European Ancestry ◽  
High Total Cholesterol ◽  
Low Hdl

AbstractBackgroundAltered lipid metabolism may be a risk factor for dementia, and blood cholesterol level has a strong genetic component. We tested the hypothesis that dyslipidemia (either low levels of high-density lipoprotein cholesterol (HDL-C) or high total cholesterol) is associated with cognitive status and domains, and assessed inferred causality using genetic predisposition to dyslipidemia as an instrumental variable.MethodsUsing data from European and African genetic ancestry participants in the Health and Retirement Study, we selected observations at the first non-missing biomarker assessment (waves 2006 to 2012). Cognition domains were assessed using episodic memory, mental status, and vocabulary tests. Overall cognitive status was categorized in three levels (normal, cognitive impairment non-dementia, dementia). Based on 2018 clinical guidelines, we compared low HDL-C or high total cholesterol to normal levels. Polygenic scores for dyslipidemia were used as instrumental variables in a Mendelian randomization framework. Multivariable logistic regressions and Wald-type ratio estimators were used to examine associations.ResultsAmong European ancestry participants (n = 8781), at risk HDL-C levels were associated with higher odds of cognitive impairment (OR = 1.20, 95%CI: 1.03, 1.40) and worse episodic memory, specifically. Using cumulative genetic risk for HDL-C levels as a valid instrumental variable, a significant causal estimate was observed between at risk low HDL-C levels and higher odds of dementia (OR = 2.15, 95%CI: 1.16, 3.99). No significant associations were observed between total cholesterol levels and cognitive status. No significant associations were observed in the African ancestry sample (n = 2101).ConclusionOur study demonstrates low blood HDL-C is a potential causal risk factor for impaired cognition during aging in non-Hispanic whites of European ancestry. Dyslipidemia can be modified by changing diets, health behaviors, and therapeutic strategies, which can improve cognitive aging. Studies on low density lipoprotein cholesterol, the timing of cholesterol effects on cognition, and larger studies in non-European ancestries are needed.

scholarly journals Mendelian randomization of smoking behavior on cognitive status among older Americans

2019 ◽  
Author(s):  
Mingzhou Fu ◽  
Jessica D. Faul ◽  
Yuan Jin ◽  
Erin B. Ware ◽  
Kelly M. Bakulski
Keyword(s):  
Risk Factor ◽  
Cognitive Impairment ◽  
Mendelian Randomization ◽  
African Ancestry ◽  
Smoking Behavior ◽  
Cognitive Status ◽  
European Ancestry ◽  
Current Smoking ◽  
Polygenic Scores ◽  
Smoking Behaviors

AbstractBackgroundSmoking is a likely risk factor for dementia, and smoking behavior has a strong genetic component. In this study, we jointly test the associations between cumulative genetic risk for smoking, smoking behavior, and cognitive status using a Mendelian randomization framework.MethodsWe conducted a cross-sectional study using the 2010 wave of the Health and Retirement Study database. Individuals aged between 50 and 90 were included. Smoking status was self-reported. Polygenic scores (PGSs) were calculated by weighting participant genotype by published smoking genome-wide association estimates. Cognitive status (normal, impaired, dementia) was measured using multiple assessments. A Mendelian randomization framework was used to infer causal relationships between smoking behavior and cognitive status via genetic instruments.ResultsAmong European ancestry participants (N = 8,735), current smoking behavior was positively associated with cognitive impairment (OR = 1.62, 95% CI: 1.29, 2.01) relative to normal cognition. Using smoking PGS as an instrumental variable, a causal relationship was observed between current smoking and cognitive impairment (OR = 1.53, 95% CI: 1.07, 2.18). There were no associations between smoking PGS, smoking behaviors and cognitive status in the African ancestry study sample (N = 2,511).ConclusionsCurrent smoking is a modifiable risk factor which causes cognitive impairment. Promotion of smoking cessation is important for public health. Further studies on dose and duration of smoking behaviors on cognitive impairment are critically needed, as well as in research other ancestries.

scholarly journals Metabolic Traits and Stroke Risk in Individuals of African Ancestry: Mendelian Randomization Analysis

Stroke ◽  
2021 ◽  
Author(s):  
Segun Fatumo ◽  
Ville Karhunen ◽  
Tinashe Chikowore ◽  
Toure Sounkou ◽  
Brenda Udosen ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Genetic Association ◽  
Mendelian Randomization ◽  
African Ancestry ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
European Ancestry ◽  
Minority Population ◽  
Genome Wide Association Studies ◽  
Metabolic Traits

Background and Purpose: Metabolic traits affect ischemic stroke (IS) risk, but the degree to which this varies across different ethnic ancestries is not known. Our aim was to apply Mendelian randomization to investigate the causal effects of type 2 diabetes (T2D) liability and lipid traits on IS risk in African ancestry individuals, and to compare them to estimates obtained in European ancestry individuals. Methods: For African ancestry individuals, genetic proxies for T2D liability and circulating lipids were obtained from a meta-analysis of the African Partnership for Chronic Disease Research study, the UK Biobank, and the Million Veteran Program (total N=77 061). Genetic association estimates for IS risk were obtained from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (3734 cases and 18 317 controls). For European ancestry individuals, genetic proxies for the same metabolic traits were obtained from Million Veteran Program (lipids N=297 626, T2D N=148 726 cases, and 965 732 controls), and genetic association estimates for IS risk were obtained from the MEGASTROKE study (34 217 cases and 406 111 controls). Random-effects inverse-variance weighted Mendelian randomization was used as the main method, complemented with sensitivity analyses more robust to pleiotropy. Results: Higher genetically proxied T2D liability, LDL-C (low-density lipoprotein cholesterol), total cholesterol and lower genetically proxied HDL-C (high-density lipoprotein cholesterol) were associated with increased risk of IS in African ancestry individuals (odds ratio per doubling the odds of T2D liability [95% CI], 1.09 [1.07–1.11]; per standard-deviation increase in LDL-C, 1.12 [1.04–1.21]; total cholesterol: 1.23 [1.06–1.43]; HDL-C, 0.93 [0.89–0.99]). There was no evidence for differences in these estimates when performing analyses in European ancestry individuals. Conclusions: Our analyses support a causal effect of T2D liability and lipid traits on IS risk in African ancestry individuals, with Mendelian randomization estimates similar to those obtained in European ancestry individuals.

scholarly journals Type 2 Diabetes and Cognitive Status in the Health and Retirement Study: A Mendelian Randomization Approach

2021 ◽  
Vol 12 ◽  
Author(s):  
Erin B. Ware ◽  
Cristina Morataya ◽  
Mingzhou Fu ◽  
Kelly M. Bakulski
Keyword(s):  
Type 2 Diabetes ◽  
Cognitive Impairment ◽  
Confidence Interval ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Cognitive Status ◽  
European Ancestry ◽  
Normal Cognition ◽  
Retirement Study

BackgroundType 2 diabetes mellitus (T2DM) and dementia are leading causes of mortality and disability in the US. T2DM has been associated with dementia; however, causality has not been clearly established. This study tested inferred causality between T2DM and dementia status using a Mendelian randomization approach.MethodsParticipants (50+ years) from the 2010 wave of the Health and Retirement Study of European or African genetic ancestry were included (n = 10,322). History of T2DM was self-reported. Cognitive status (dementia, cognitive impairment non-dementia, or normal cognition) was defined from clinically validated cognitive assessments. Cumulative genetic risk for T2DM was determined using a polygenic score calculated from a European ancestry T2DM genome-wide association study by Xue et al. (2018). All models were adjusted for age, sex, education, APOE-ε4 carrier status, and genetic principal components. Multivariable logistic regression was used to test the association between cumulative genetic risk for T2DM and cognitive status. To test inferred causality using Mendelian randomization, we used the inverse variance method.ResultsAmong included participants, 20.9% had T2DM and 20.7% had dementia or cognitive impairment. Among European ancestry participants, T2DM was associated with 1.66 times odds of cognitive impairment non-dementia (95% confidence interval: 1.55–1.77) relative to normal cognition. A one standard deviation increase in cumulative genetic risk for T2DM was associated with 1.30 times higher odds of T2DM (95% confidence interval: 1.10–1.52). Cumulative genetic risk for T2DM was not associated with dementia status or cognitive-impaired non-dementia in either ancestry (P > 0.05); lack of association here is an important assumption of Mendelian randomization. Using Mendelian randomization, we did not observe evidence for an inferred causal association between T2DM and cognitive impairment (odds ratio: 1.04; 95% confidence interval: 0.90–1.21).DiscussionConsistent with prior research, T2DM was associated with cognitive status. Prevention of T2DM and cognitive decline are both critical for public health, however, this study does not provide evidence that T2DM is causally related to impaired cognition. Additional studies in other ancestries, larger sample sizes, and longitudinal studies are needed to confirm these results.

scholarly journals Aerobic fitness modulates the association between APOE genotypes and serum lipemia in adolescents

2014 ◽  
Vol 20 (3) ◽  
pp. 332-338
Author(s):  
Maria Fátima Glaner ◽  
Thales Boaventura Rachid Nascimento ◽  
Otávio de Tôledo Nóbrega
Keyword(s):  
High Density Lipoprotein ◽  
Total Cholesterol ◽  
Aerobic Fitness ◽  
Low Density Lipoprotein ◽  
Apoe Genotype ◽  
Density Lipoprotein ◽  
European Ancestry ◽  
Low Density ◽  
Genotype Group ◽  
Apoe Genotypes

The purpose of this study was to analyze the association between APOE alleles and serum lipemia in adolescents with low and adequate aerobic fitness. The sample was comprised of 105 boys and 151 girls (49% and 46% from rural area) of European ancestry, aged 11 to 17 years, and classified according to: 1) APOE genotype: group ε2 (ε2/3+ε2/2), ε3 (ε3/3), and ε4 (ε3/4+ε4/4); 2) aerobic fitness: adequate or low; 3) serum lipemia: elevated total cholesterol (TC), low-density lipoprotein (LDL) and triglycerides, and low high-density lipoprotein (HDL). The results showed that aerobic fitness modulates the association between APOE alleles and serum lipemia in adolescents, suggesting that adequate aerobic fitness levels exert a greater effect of reducing TC and LDL in ε2 carriers, as well as of increasing HDL and reducing triglycerides in ε3 and ε4 carriers.

scholarly journals Causal Associations Between Blood Lipids and COVID-19 Risk: A Two-Sample Mendelian Randomization Study

2021 ◽  
Author(s):  
Kun Zhang ◽  
Shan-Shan Dong ◽  
Yan Guo ◽  
Shi-Hao Tang ◽  
Hao Wu ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Blood Lipids ◽  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Outcome Data ◽  
Causal Effects ◽  
Lipoprotein Cholesterol ◽  
Global Pandemic ◽  
The Uk

Objective: Coronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus 2. It has been reported that dyslipidemia is correlated with COVID-19, and blood lipids levels, including total cholesterol, HDL-C (high-density lipoprotein cholesterol), and LDL-C (low-density lipoprotein cholesterol) levels, were significantly associated with disease severity. However, the causalities of blood lipids on COVID-19 are not clear. Approach and Results: We performed 2-sample Mendelian randomization (MR) analyses to explore the causal effects of blood lipids on COVID-19 susceptibility and severity. Using the outcome data from the UK Biobank (1221 cases and 4117 controls), we observed potential positive causal effects of dyslipidemia (odds ratio [OR], 1.27 [95% CI, 1.08–1.49], P =3.18×10 −3 ), total cholesterol (OR, 1.19 [95% CI, 1.07–1.32], P =8.54×10 −4 ), and ApoB (apolipoprotein B; OR, 1.18 [95% CI, 1.07–1.29], P =1.01×10 −3 ) on COVID-19 susceptibility after Bonferroni correction. In addition, the effects of total cholesterol (OR, 1.01 [95% CI, 1.00–1.02], P =2.29×10 −2 ) and ApoB (OR, 1.01 [95% CI, 1.00–1.02], P =2.22×10 −2 ) on COVID-19 susceptibility were also identified using outcome data from the host genetics initiative (14 134 cases and 1 284 876 controls). Conclusions: In conclusion, we found that higher total cholesterol and ApoB levels might increase the risk of COVID-19 infection.

Lipids, lipoproteins, and atherogenesis

2011 ◽  
pp. 11-24
Author(s):  
Joanna Gouni-Berthold ◽  
Wilhelm Krone
Keyword(s):  
Risk Factor ◽  
High Density Lipoprotein ◽  
Independent Risk Factor ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Apolipoprotein A ◽  
Low Hdl ◽  
Lipids And Lipoproteins

• Lipids and lipoproteins have a central role in the pathogenesis of atherosclerosis. • The concentration of low-density lipoprotein (LDL) is strongly and directly related to risk of atherosclerosis whereas high-density lipoprotein (HDL) is inversly related, low HDL being an independent risk factor. • The role of plasma triglycerides is less well defined. • The ratio of apolipoprotein B (the major apolipoprotein of LDL) to apolipoprotein A-1 (the major apolipoprotein of HDL) is emerging as the best predictor of atherosclerotic risk.

scholarly journals Using a two-sample Mendelian randomization design to investigate a possible causal effect of maternal lipid concentrations on offspring birth weight

2019 ◽  
Vol 48 (5) ◽  
pp. 1457-1467 ◽  
Author(s):  
Liang-Dar Hwang ◽  
Deborah A Lawlor ◽  
Rachel M Freathy ◽  
David M Evans ◽  
Nicole M Warrington
Keyword(s):  
Birth Weight ◽  
Standard Deviation ◽  
Structural Equation ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
European Ancestry ◽  
The Impact

Abstract Background The intrauterine environment is critical for fetal growth and development. However, observational associations between maternal gestational lipid concentrations and offspring birth weight (BW) have been inconsistent and ascertaining causality is challenging. Methods We used a novel two-sample Mendelian randomization (MR) approach to estimate the causal effect of maternal gestational high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride concentrations on offspring BW. Single nucleotide polymorphisms (SNPs) associated with serum HDL-C, LDL-C and triglyceride concentrations identified in the Global Lipids Genetics Consortium genome-wide association study meta-analysis (n = 188 577 European-ancestry individuals; sample 1) were selected as instrumental variables. The effects of these SNPs on offspring BW were estimated using a structural equation model in the UK Biobank and Early Growth Genetics consortium (n = 230 069 European-ancestry individuals; sample 2) that enabled partitioning of the genetic associations into maternal- (intrauterine) and fetal-specific effects. Results We found no evidence for a causal effect of maternal gestational HDL-C, LDL-C or triglyceride concentrations on offspring BW [standard deviation change in BW per standard deviation higher in HDL-C = −0.005 (95% confidence interval: −0.039, 0.029), LDL-C = 0.014 (−0.017, 0.045), and triglycerides = 0.014 (−0.025, 0.052)]. Conclusions Our findings suggest that maternal gestational HDL-C, LDL-C and triglyceride concentrations play a limited role in determining offspring BW. However, we cannot comment on the impact of these and other lipid fractions on fetal development more generally. Our study illustrates the power and flexibility of two-sample MR in assessing the causal effect of maternal environmental exposures on offspring outcomes.

scholarly journals GAIT UNSTEADINESS AS AN INDICATOR OF COGNITIVE STATUS IN INDIVIDUALS WITH PERIPHERAL NEUROPATHY

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S845-S845
Author(s):  
Gu Eon Kang ◽  
Jacqueline Yang ◽  
He Zhou ◽  
Changhong Wang ◽  
Bareera Akhtar ◽  
...  
Keyword(s):  
Risk Factor ◽  
Cognitive Impairment ◽  
Dual Task ◽  
Stride Length ◽  
Cognitive Status ◽  
Additional Risk Factor ◽  
Normal Walking ◽  
Intact Group ◽  
Impaired Group ◽  
Risk Of Falls

Abstract Neuropathic individuals are at risk of falls, however potential impact of cognitive impairment in neuropathic individuals is not well-understood. Since cognitive impairment is considered an independent risk factor for falls, knowing its potential, additional impact may help better understand underlying mechanism of risk of falls in neuropathic individuals. We aimed to investigate stride-to-stride variability in neuropathic individuals with cognitive impairment (NP-Cog-Impaired) and without cognitive impairment (NP-Cog-Intact) during normal and dual-task walking. Neuropathic symptoms and cognitive status was measured using maximum vibration perception threshold (VPTmax) in the feet and the Montreal Cognitive Assessment (MoCA), respectively. We analyzed data from 19 NP-Cog-Impaired (8 men; 68.5±9.1 years; 29.0±6.2 kg/m2; VPTmax=27.2±12.1 volts; MoCA=19.6±2.4) and 25 NP-Cog-Intact (15 men; 66.5±9.1 years; 31.3±5.9 kg/m2; VPTmax=26.3±12.7 volts; MoCA=25.6±1.6). We collected movement data using five inertial sensors (LEGSysTM, BioSensics LLC, Watertown, MA) attached on the shanks, thighs and lower back. We used previously validated algorithm to calculate coefficient of variations (CV) of stride velocity and stride length. CV of stride velocity and stride length were significantly greater for the NP-Cog-Impaired group (11.07±5.22% and 7.31±3.20%, respectively) than for the NP-Cog-Intact group (7.31±3.20% and 4.81±2.80%, respectively) for dual-task walking but not for normal walking. Between normal and dual-task walking, CV of stride velocity and stride length increased 43.2% (significantly) and 46.4% (marginally), respectively, from normal walking to dual-task walking for the NP-Cog-Impaired group but not for the NP-Cog-Intact group. Results suggest that cognitive impairment may be an additional risk factor of falls in neuropathic individuals.

scholarly journals Cumulative health deficits, APOE genotype, and risk for later-life mild cognitive impairment and dementia

2020 ◽  
pp. jnnp-2020-324081
Author(s):  
David D Ward ◽  
Lindsay M K Wallace ◽  
Kenneth Rockwood
Keyword(s):  
Risk Factor ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Frailty Index ◽  
Apoe Genotype ◽  
Cognitive Status ◽  
Lower Probability ◽  
Deficit Accumulation ◽  
Cognitive Improvement ◽  
Health Deficit

ObjectiveTo determine whether health-deficit accumulation is associated with the risks of mild cognitive impairment (MCI) and dementia independently of APOE genotype.MethodsA frailty index was calculated using the deficit-accumulation approach in participants aged 50 years and older from the National Alzheimer’s Coordinating Center. Cognitive status was determined by clinical evaluation. Using multistate transition models, we assessed the extent to which an increasing degree of frailty affected the probabilities of transitioning between not cognitively impaired (NCI), MCI, and dementia.ResultsParticipants (n=14 490) had a mean age of 72.2 years (SD=8.9 years; range=50–103 years). Among those NCI at baseline (n=9773), each 0.1 increment increase in the frailty index was associated with a higher risk of developing MCI and a higher risk of progressing to dementia. Among those with MCI at baseline (n=4717), higher frailty was associated with a higher risk of progressing to dementia, a lower probability of being reclassified as NCI, and a higher likelihood of returning to MCI in those that were reclassified as NCI. These risk effects were present and similar in both carriers and non-carriers of the APOE ε4 allele.ConclusionAmong older Americans, health-deficit accumulation affects the likelihood of progressive cognitive impairment and the likelihood of cognitive improvement independently of a strong genetic risk factor for dementia. Frailty represents an important risk factor for cognitive dysfunction and a marker of potential prognostic value.

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