scholarly journals A non-APOE Polygenic score for Alzheimer’s disease and APOE-ε4 have independent associations with dementia in the Health and Retirement Study

2020 ◽  
Author(s):  
Kelly M. Bakulski ◽  
Harita S. Vadari ◽  
Jessica D. Faul ◽  
Steven G. Heeringa ◽  
Sharon LR Kardia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Cognitive Impairment ◽  
Genetic Risk ◽  
Population Based ◽  
Health And Retirement Study ◽  
Polygenic Score ◽  
Genetic Region ◽  
Apoe Ε4 ◽  
Normal Cognition ◽  
Retirement Study

AbstractINTRODUCTIONAlzheimer’s disease (AD) is a common and costly neurodegenerative disorder. A large proportion of risk is heritable and many genetic risk factors for AD have been identified. The cumulative genetic risk of known markers has not been benchmarked for dementia in a population-based sample.METHODSIn the United States population-based Health and Retirement Study (HRS) (waves 1995-2014), we evaluated the role of cumulative genetic risk for AD, with and without the APOE-ε4 alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry.RESULTSIn the European ancestry sample (n=8399), both AD polygenic score excluding the APOE genetic region (odds ratio (OR)=1.10; 95% confidence interval (CI): 1.00, 1.20) and the presence of any APOE-ε4 alleles (OR=2.42; 95% CI: 1.99, 2.95) were associated with the odds of dementia relative to normal cognition in a mutually-adjusted model. In the African ancestry sample (n=1605), the presence of any APOE-ε4 alleles was associated with 1.77 (95% CI: 1.20, 2.61) times higher odds of dementia, while the AD polygenic score excluding the APOE genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97, 1.30).DISCUSSIONCumulative genetic risk for AD and APOE-ε4 are both independent predictors of dementia. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.

scholarly journals Cumulative Genetic Risk and APOE ε4 Are Independently Associated With Dementia Status in a Multiethnic, Population-Based Cohort

2021 ◽  
Vol 7 (2) ◽  
pp. e576
Author(s):  
Kelly M. Bakulski ◽  
Harita S. Vadari ◽  
Jessica D. Faul ◽  
Steven G. Heeringa ◽  
Sharon L.R. Kardia ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Genetic Risk ◽  
Neurodegenerative Disorder ◽  
Population Based ◽  
European Ancestry ◽  
Polygenic Score ◽  
Genetic Region ◽  
Apoe Ε4 ◽  
Polygenic Scores ◽  
Normal Cognition

ObjectiveAlzheimer disease (AD) is a common and costly neurodegenerative disorder. A large proportion of AD risk is heritable, and many genetic risk factors have been identified. The objective of this study was to test the hypothesis that cumulative genetic risk of known AD markers contributed to odds of dementia in a population-based sample.MethodsIn the US population-based Health and Retirement Study (waves 1995–2014), we evaluated the role of cumulative genetic risk of AD, with and without the APOE ε4 alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, and cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry.ResultsIn the European ancestry sample (n = 8,399), both AD polygenic score excluding the APOE genetic region (odds ratio [OR] = 1.10; 95% confidence interval [CI]: 1.00–1.20) and the presence of any APOE ε4 alleles (OR = 2.42; 95% CI: 1.99–2.95) were associated with the odds of dementia relative to normal cognition in a mutually adjusted model. In the African ancestry sample (n = 1,605), the presence of any APOE ε4 alleles was associated with 1.77 (95% CI: 1.20–2.61) times higher odds of dementia, whereas the AD polygenic score excluding the APOE genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97–1.30).ConclusionsCumulative genetic risk of AD and APOE ε4 are both independent predictors of dementia in European ancestry. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.

scholarly journals Same-Sex Couples and Cognitive Impairment: Evidence From the Health and Retirement Study

2020 ◽  
Author(s):  
Hui Liu ◽  
Ning Hsieh ◽  
Zhenmei Zhang ◽  
Yan Zhang ◽  
Kenneth M Langa
Keyword(s):  
Cognitive Impairment ◽  
The United States ◽  
Population Based ◽  
Cognitive Status ◽  
Health And Retirement Study ◽  
Sex Partners ◽  
Physical And Mental Health ◽  
Same Sex ◽  
Same Sex Couples ◽  
Retirement Study

Abstract Objectives We provide the first nationally representative population-based study of cognitive disparities among same-sex and different-sex couples in the United States. Methods We analyzed data from the Health and Retirement Study (2000–2016). The sample included 23,669 respondents (196 same-sex partners and 23,473 different-sex partners) aged 50 and older who contributed to 85,117 person-period records (496 from same-sex partners and 84,621 from different-sex partners). Cognitive impairment was assessed using the modified version of the Telephone Interview for Cognitive Status. Mixed-effects discrete-time hazard regression models were estimated to predict the odds of cognitive impairment. Results The estimated odds of cognitive impairment were 78% (p < .01) higher for same-sex partners than for different-sex partners. This disparity was mainly explained by differences in marital status and, to a much lesser extent, by differences in physical and mental health. Specifically, a significantly higher proportion of same-sex partners than different-sex partners were cohabiting rather than legally married (72.98% vs. 5.42% in the study sample), and cohabitors had a significantly higher risk of cognitive impairment than their married counterparts (odds ratio = 1.53, p < .001). Discussion The findings indicate that designing and implementing public policies and programs that work to eliminate societal homophobia, especially among older adults, is a critical step in reducing the elevated risk of cognitive impairment among older same-sex couples.

Apolipoprotein E allele 4 is not a sufficient or a necessary predictor of the development of Mild Cognitive Impairment

2010 ◽  
Vol 25 (1) ◽  
pp. 15-18 ◽  
Author(s):  
R. Heun ◽  
U. Gühne ◽  
T. Luck ◽  
M.C. Angermeyer ◽  
U. Ueberham ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Apolipoprotein E ◽  
Target Population ◽  
Population Based ◽  
Initial Development ◽  
Apoe Ε4 ◽  
Ε4 Allele

AbstractThe presence of Mild Cognitive Impairment (MCI) and of an apolipoprotein E (apoE) ε4 allele both predict the development of Alzheimer's disease. However, the extent to which this allele also predicts the development of MCI is unclear even though MCI is an early transitional stage in the development of Alzheimer's disease. The present study investigates the prevalence of the apoE ε4 allele in incipient MCI. Participants were recruited from the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). All subjects who were initially cognitively healthy, i.e. did not meet MCI criteria described by Petersen [Petersen RC. Mild cognitive impairment. J Intern Med 2004; 256(3): 183–94], and whose apoE status could be determined were followed-up. After 4.5 years, 15.5% of the cognitively healthy target population had developed MCI. The frequencies of the apoE ε4 genotype did not differ between individuals with incipient MCI (12.9%) and individuals who remained cognitively healthy during the study (18.4%, p > 0.5). Consequently, the apoE ε4 genotype is not a necessary or sufficient risk factor for MCI. Further studies need to investigate the influence of the whole range of genetic and environmental risk factors on the course of Alzheimer's disease including the initial development of MCI and the later conversion to Alzheimer's disease.

scholarly journals Considering the APOE locus in Alzheimer’s disease polygenic scores in the Health and Retirement Study: a longitudinal panel study

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Erin B. Ware ◽  
Jessica D. Faul ◽  
Colter M. Mitchell ◽  
Kelly M. Bakulski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Repeated Measures ◽  
Panel Study ◽  
European Ancestry ◽  
Health And Retirement Study ◽  
Carrier Status ◽  
Polygenic Score ◽  
Polygenic Scores ◽  
Retirement Study

Abstract Background Polygenic scores are a strategy to aggregate the small, additive effects of single nucleotide polymorphisms across the genome. With phenotypes like Alzheimer’s disease, which have a strong and well-established genomic locus (APOE), the cumulative effect of genetic variants outside of this area has not been well established in a population-representative sample. Methods Here we examine the association between polygenic scores for Alzheimer’s disease both with and without the APOE region (chr19: 45,384,477 to 45,432,606, build 37/hg 19) at different P value thresholds and dementia. We also investigate the addition of APOE-ε4 carrier status and its effect on the polygenic score—dementia association in the Health and Retirement Study using generalized linear models accounting for repeated measures by individual and use a binomial distribution, logit link, and unstructured correlation structure. Results In a large sample of European ancestry participants of the Health and Retirement Study (n = 9872) with an average of 5.2 (standard deviation 1.8) visit spaced two years apart, we found that including the APOE region through weighted variants in a polygenic score was insufficient to capture the large amount of risk attributed to this region. We also found that a polygenic score with a P value threshold of 0.01 had the strongest association with the odds of dementia in this sample (odds ratio = 1.10 95%CI 1.0 to 1.2). Conclusion We recommend removing the APOE region from polygenic score calculation and treating the APOE locus as an independent covariate when modeling dementia. We also recommend using a moderately conservative P value threshold (e.g. 0.01) when creating polygenic scores for Alzheimer’s disease on dementia. These recommendations may help elucidate relationships between polygenic scores and regions of strong significance for phenotypes similar to Alzheimer’s disease.

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 Interaction of Alzheimer’s Disease-Associated Genetic Risk with Indicators of Socioeconomic Position on Mild Cognitive Impairment in the Heinz Nixdorf Recall Study

2021 ◽  
pp. 1-11
Author(s):  
Mirjam Frank ◽  
Jonas Hensel ◽  
Lisa Baak ◽  
Sara Schramm ◽  
Nico Dragano ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Socioeconomic Position ◽  
Genetic Risk ◽  
Late Onset ◽  
Heinz Nixdorf Recall Study ◽  
Low Education ◽  
Additive Scale

Background: The apolipoprotein E (APOE) ɛ4 allele is reported to be a strong genetic risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Additional genetic loci have been detected that influence the risk for late-onset AD. As socioeconomic position (SEP) is also strongly related to cognitive decline, SEP has been suggested to be a possible modifier of the genetic effect on MCI. Objective: To investigate whether APOE ɛ4 and a genetic sum score of AD-associated risk alleles (GRSAD) interact with SEP indicators to affect MCI in a population-based cohort. Methods: Using data of 3,834 participants of the Heinz Nixdorf Recall Study, APOE ɛ4 and GRSAD by SEP interactions were assessed using logistic regression models, as well as SEP-stratified genetic association analysis. Interaction on additive scale was calculated using the relative excess risk due to interaction (RERI). All analysis were additionally stratified by sex. Results: Indication for interaction on the additive scale was found between APOE ɛ4 and low education on MCI (RERI: 0.52 [95% -confidence interval (CI): 0.01; 1.03]). The strongest genetic effects of the APOE ɛ4 genotype on MCI were observed in groups of low education (Odds ratio (OR): 1.46 [95% -CI: 0.79; 2.63] for≤10 years of education versus OR: 1.00 [95% -CI: 0.43; 2.14] for≥18 years of education). Sex stratified results showed stronger effects in women. No indication for interaction between the GRSAD and SEP indicators on MCI was observed. Conclusion: Results indicate that low education may have an impact on APOE ɛ4 expression on MCI, especially among women.

scholarly journals Analysis of EEG networks and their correlation with cognitive impairment in preschool children with epilepsy

2017 ◽  
Author(s):  
Eli Kinney-Lang ◽  
Michael Yoong ◽  
Matthew Hunter ◽  
Krishnaraya Kamath Tallur ◽  
Jay Shetty ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Network Analysis ◽  
Nearest Neighbor ◽  
Rank Correlation ◽  
Population Based ◽  
Classification Model ◽  
Phase Slope ◽  
Network Properties ◽  
Normal Cognition

AbstractObjective: Cognitive impairment (CI) is common in children with epilepsy and can have devastating effects on their quality of life and that of their family. Early identification of CI is a priority to improve outcomes, but the current gold standard of detection with psychometric assessment is resource intensive and not always available. This paper proposes a novel technique of network analysis using routine clinical electroencephalography (EEG) to help identify CI in children with early-onset epilepsy (CWEOE) (0-5 y.o.).Methods: We analyzed functional networks from routinely acquired EEGs of 51 newly diagnosed CWEOE from a prospective population-based study. Combinations of connectivity metrics (e.g. phase-slope index (PSI)) with sub-network analysis (e.g. cluster-span threshold (CST)) identified significant correlations between network properties and cognition scores via rank correlation analysis with Kendall’s τ. Predictive properties were investigated using a 5-fold cross-validated K-Nearest Neighbor classification model with normal cognition, mild/moderate CI and severe CI classes.Results: Phase-dependent connectivity metrics had higher sensitivity to cognition scores, with sub-networks identifying significant functional network changes over a broad range of spectral frequencies. Approximately 70.5% of all children were appropriately classified as normal cognition, mild/moderate CI or severe CI using CST network features. CST classification predicted CI classes 55% better than chance, and reduced misclassification penalties by half.Conclusions: CI in CWEOE can be detected with sensitivity at 85% (with respect to identifying either mild/moderate or severe CI) and specificity of 84%, by EEG network analysis.Significance: This study outlines a data-driven methodology for identifying candidate biomarkers of CI in CWEOE from network features. Following additional replication, the proposed method and its use of routinely acquired EEG forms an attractive proposition for supporting clinical assessment of CI.

Ozone and Particulate Matter Exposure and Alzheimer’s Disease: A Review of Human and Animal Studies

2021 ◽  
Author(s):  
Rui-Ming Liu ◽  
Zechen Chong ◽  
Jiu-Chiuan Chen
Keyword(s):  
Alzheimer’S Disease ◽  
Risk Factor ◽  
Particulate Matter ◽  
Environmental Exposure ◽  
Environmental Risk ◽  
Genetic Risk ◽  
The Elderly ◽  
Genetic Risk Factor ◽  
Apoe Ε4 ◽  
Particulate Matter Exposure

Alzheimer’s disease (AD), an aging-related neurodegenerative disease, is a major cause of dementia in the elderly. Although the early-onset (familial) AD is attributed to mutations in the genes coding for amyloid-β protein precursor (AβPP) and presenilin 1/presenilin 2 (PS1/PS2), the cause for the late-onset AD (LOAD), which accounts for more than 95% of AD cases, remains unclear. Aging is the greatest risk factor for LOAD, whereas the apolipo protein E4 allele (APOEε4) is believed to be a major genetic risk factor in acquiring LOAD, with female APOE ε4 carriers at highest risk. Nonetheless, not all the elderly, even older female APOE ε4 carriers, develop LOAD, suggesting that other factors, including environmental exposure, must play a role. This review summarizes recent studies that show a potential role of environmental exposure, especially ozone and particulate matter exposure, in the development of AD. Interactions between environmental exposure, genetic risk factor (APOE ε4), and sex in AD pathophysiology are also discussed briefly. Identification of environmental risk factor(s) and elucidation of the complex interactions between genetic and environmental risk factors plus aging and female sex in the onset of AD will be a key to our understanding of the etiology and pathogenesis of AD and the development of the strategies for its prevention and treatment.

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