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Abdul Aziz M, Md Ashraf G, Safiqul Islam M. Link of BIN1, CLU and IDE gene polymorphisms with the susceptibility of Alzheimer's disease: evidence from a meta-analysis. Curr Alzheimer Res 2022; 19:302-316. [PMID: 35546756 DOI: 10.2174/1567205019666220511140955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/15/2022] [Accepted: 03/06/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Alzheimer's disease (AD) is the most common form of neurodegenerative disorder. The association of BIN1, CLU and IDE genetic polymorphisms with AD risk have been evaluated overtimes that produced conflicting outcomes. OBJECTIVE We performed this meta-analysis to investigate the contribution of BIN1 (rs744373 and rs7561528), CLU (rs11136000 and rs9331888), and IDE (rs1887922) polymorphisms to AD risk. METHODS From a systemic literature search up to July 15, 2021, we included 25 studies with rs744373, 16 studies with rs7561528, 37 studies with rs11136000, 16 studies with rs9331888, and 4 studies with rs1887922. To analyze the correlation, we constructed seven genetic models that used odds ratio and 95% confidence intervals. We used RevMan 5.4 for meta-analysis. RESULTS Our study suggests that BIN1 rs744373 is associated with a significantly increased risk of AD in five genetic models (OR>1). Again, CLU rs11136000 showed reduced association in all genetic models (OR<1). CLU rs9331888 revealed an increased association in two models (OR>1). The IDE rs1887922 showed significantly increased risk in four models (OR>1). From subgroup analysis, a significantly increased risk of AD was observed in Caucasians and Asians for BIN1 rs744373. Again, BIN1 rs7561528 showed a significantly enhanced risk of AD only in Caucasians. CLU rs11136000 showed significantly reduced risk in Caucasians but rs9331888 showed increased risk in the same ethnicity. CONCLUSION Our meta-analysis confirms the association of BIN1 rs744373, CLU rs9331888 and IDE rs1887922 polymorphisms with an increased risk of AD, especially in Caucasians. Again, CLU rs11136000 is associated with reduced AD risk in the overall population and Caucasians.
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Affiliation(s)
- Md Abdul Aziz
- Department of Pharmacy, Faculty of Pharmacy and Health Sciences, State University of Bangladesh, Dhaka-1205, Bangladesh
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammad Safiqul Islam
- Laboratory of Pharmacogenomics and Molecular Biology, Department of Pharmacy, Faculty of Science, Noakhali Science and Technology University, Sonapur-3814, Noakhali, Bangladesh
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Caballero HS, McFall GP, Zheng Y, Dixon RA. Data-driven approaches to executive function performance and structure in aging: Integrating person-centered analyses and machine learning risk prediction. Neuropsychology 2021; 35:889-903. [PMID: 34570543 PMCID: PMC9907731 DOI: 10.1037/neu0000775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Objective: Executive function (EF) performance and structure in nondemented aging are frequently examined with variable-centered approaches. Person-centered analytics can contribute unique information about classes of persons by simultaneously considering EF performance and structure. The risk predictors of these classes can then be determined by machine learning technology. Using data from the Victoria Longitudinal Study we examined two goals: (a) detect different underlying subgroups (or classes) of EF performance and structure and (b) test multiple risk predictors for best discrimination of these detected subgroups. Method: We used a classification sample (n = 778; Mage = 71.42) for the first goal and a prediction subsample (n = 570; Mage = 70.10) for the second goal. Eight neuropsychological measures represented three EF dimensions (inhibition, updating, shifting). Fifteen predictors represented five domains (genetic, functional, lifestyle, mobility, demographic). Results: First, we observed two distinct classes: (a) lower EF performance and unidimensional structure (Class 1) and (b) higher EF performance and multidimensional structure (Class 2). Second, Class 2 was predicted by younger age, more novel cognitive activity, more education, lower body mass index, lower pulse pressure, female sex, faster balance, and more physical activity. Conclusions: Data-driven modeling approaches tested the possibility of an EF aging class that displayed both preserved EF performance levels and sustained multidimensional structure. The two observed classes differed in both performance level (lower, higher) and structure (unidimensional, multidimensional). Machine learning prediction analyses showed that the higher performing and multidimensional class was associated with multiple brain health-related protective factors. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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Affiliation(s)
| | - G. Peggy McFall
- Neurosicence and Mental Health Institute, University of Alberta, Edmonton, Canada,Department of Psychology, University of Alberta, Edmonton, Canada
| | - Yao Zheng
- Department of Psychology, University of Alberta, Edmonton, Canada
| | - Roger A. Dixon
- Neurosicence and Mental Health Institute, University of Alberta, Edmonton, Canada,Department of Psychology, University of Alberta, Edmonton, Canada
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3
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Leissring MA, González-Casimiro CM, Merino B, Suire CN, Perdomo G. Targeting Insulin-Degrading Enzyme in Insulin Clearance. Int J Mol Sci 2021; 22:ijms22052235. [PMID: 33668109 PMCID: PMC7956289 DOI: 10.3390/ijms22052235] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/20/2021] [Accepted: 02/21/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50–80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn2+-metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven. Because historically IDE has been proposed as the main enzyme involved in insulin degradation, efforts in the development of IDE inhibitors as therapeutics in diabetic patients has attracted attention during the last decades. In this review, we retrace the path from Mirsky’s seminal discovery of IDE to the present, highlighting the pros and cons of the development of IDE inhibitors as a pharmacological approach to treating diabetic patients.
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Affiliation(s)
- Malcolm A. Leissring
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI MIND), Irvine, CA 92697-4545, USA
- Correspondence: (M.A.L.); (G.P.); Tel.: +1-904-254-3050 (M.A.L.); +34-983-184-805 (G.P.)
| | - Carlos M. González-Casimiro
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), 47003 Valladolid, Spain; (C.M.G.-C.); (B.M.)
| | - Beatriz Merino
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), 47003 Valladolid, Spain; (C.M.G.-C.); (B.M.)
| | - Caitlin N. Suire
- Department of Biomedical Sciences, Florida State University, Tallahassee, FL 32306-4300, USA;
| | - Germán Perdomo
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), 47003 Valladolid, Spain; (C.M.G.-C.); (B.M.)
- Correspondence: (M.A.L.); (G.P.); Tel.: +1-904-254-3050 (M.A.L.); +34-983-184-805 (G.P.)
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4
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Integrating Three Characteristics of Executive Function in Non-Demented Aging: Trajectories, Classification, and Biomarker Predictors. J Int Neuropsychol Soc 2021; 27:158-171. [PMID: 32772936 PMCID: PMC7873176 DOI: 10.1017/s1355617720000703] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE With longitudinal executive function (EF) data from the Victoria Longitudinal Study, we investigated three research goals pertaining to key characteristics of EF in non-demented aging: (a) examining variability in EF longitudinal trajectories, (b) establishing trajectory classes, and (c) identifying biomarker predictors discriminating these classes. METHOD We used a trajectory analyses sample (n = 781; M age = 71.42) for the first and second goals and a prediction analyses sample (n = 570; M age = 70.10) for the third goal. Eight neuropsychological EF measures were used as indicators of three EF dimensions: inhibition, updating, and shifting. Data-driven classification analyses were applied to the full trajectory distribution. Machine learning prediction analyses tested 15 predictors from genetic, functional, lifestyle, mobility, and demographic risk domains. RESULTS First, we observed: (a) significant variability in EF trajectories over a 40-year band of aging and (b) significantly variable patterns of EF decline. Second, a four-class EF trajectory model was observed, characterized with classes differentiated by an algorithm of level and slope information. Third, the highest group class was discriminated from lowest by several prediction factors: more education, more novel cognitive activity, lower pulse pressure, younger age, faster gait, lower body mass index, and better balance. CONCLUSION First, with longitudinal variability in EF aging, the data-driven approach showed that long-term trajectories can be differentiated into separable classes. Second, prediction analyses discriminated class membership by a combination of multiple biomarkers from demographic, lifestyle, functional, and mobility domains of risk for brain and cognitive aging decline.
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Zhao Q, Zhang Y, Liao X, Wang W. Executive Function and Diabetes: A Clinical Neuropsychology Perspective. Front Psychol 2020; 11:2112. [PMID: 32973635 PMCID: PMC7468478 DOI: 10.3389/fpsyg.2020.02112] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/29/2020] [Indexed: 02/05/2023] Open
Abstract
Objective Diabetes is a global public health concern. Management of diabetes depends on successful implementation of strategies to alleviate decline in executive functions (EFs), a characteristic of diabetes progression. In this review, we describe recent research on the relationship between diabetes and EF, summarize the existing evidence, and put forward future research directions and applications. Methods Herein, we provide an overview of recent studies, to elucidate the relationship between DM and EF. We identified new screening objectives, management tools, and intervention targets for diabetes management. We also discuss the implications for clinical practice. Results In both types 1 and 2 diabetes mellitus (DM), hyperglycemia substantially impairs EF in people of all age groups and ethnicities. Hypoglycemia can similarly impair EF. Interestingly, a decline in EF contributes to DM progression. Glucose dysregulation and EF decline exacerbate each other in a vicious cycle: poor blood glucose control, impaired EF, diabetes management task failure, then back to poor blood glucose control. Many pathophysiological indexes (e.g., obesity, metabolic index, inflammatory and immune factors), neuropsychological indexes (e.g., compliance, eating habits, physical exercise, sleep, and depression), and genetic factors are changed by this pathological interaction between DM and EF. These changes can provide insight into the pathophysiological mechanisms of diabetes-related EF decline. Conclusion Further studies, including large-scale prospective and randomized controlled trials, are needed to elucidate the mechanism of the interaction between diabetes and EF and to develop novel strategies for breaking this cycle.
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Affiliation(s)
- Qian Zhao
- International Medical Center/Ward of General Practice and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yonggang Zhang
- Department of Periodical Press and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoyang Liao
- International Medical Center/Ward of General Practice and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Weiwen Wang
- Department of Neurology, General Hospital of Western Theater Command, Chengdu, China
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6
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Caputo V, Termine A, Strafella C, Giardina E, Cascella R. Shared (epi)genomic background connecting neurodegenerative diseases and type 2 diabetes. World J Diabetes 2020; 11:155-164. [PMID: 32477452 PMCID: PMC7243483 DOI: 10.4239/wjd.v11.i5.155] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 02/10/2020] [Accepted: 03/22/2020] [Indexed: 02/05/2023] Open
Abstract
The progressive aging of populations has resulted in an increased prevalence of chronic pathologies, especially of metabolic, neurodegenerative and movement disorders. In particular, type 2 diabetes (T2D), Alzheimer’s disease (AD) and Parkinson’s disease (PD) are among the most prevalent age-related, multifactorial pathologies that deserve particular attention, given their dramatic impact on patient quality of life, their economic and social burden as well the etiopathogenetic mechanisms, which may overlap in some cases. Indeed, the existence of common triggering factors reflects the contribution of mutual genetic, epigenetic and environmental features in the etiopathogenetic mechanisms underlying T2D and AD/PD. On this subject, this review will summarize the shared (epi)genomic features that characterize these complex pathologies. In particular, genetic variants and gene expression profiles associated with T2D and AD/PD will be discussed as possible contributors to determine the susceptibility and progression to these disorders. Moreover, potential shared epigenetic modifications and factors among T2D, AD and PD will also be illustrated. Overall, this review shows that findings from genomic studies still deserves further research to evaluate and identify genetic factors that directly contribute to the shared etiopathogenesis. Moreover, a common epigenetic background still needs to be investigated and characterized. The evidences discussed in this review underline the importance of integrating large-scale (epi)genomic data with additional molecular information and clinical and social background in order to finely dissect the complex etiopathogenic networks that build up the “disease interactome” characterizing T2D, AD and PD.
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Affiliation(s)
- Valerio Caputo
- Department of Biomedicine and Prevention, Tor Vergata University, Rome 00133, Italy
- Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, Rome 00142, Italy
| | - Andrea Termine
- Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, Rome 00142, Italy
- Experimental and Behavioral Neurophysiology Laboratory, Santa Lucia Foundation, Rome 00142, Italy
| | - Claudia Strafella
- Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, Rome 00142, Italy
- Department of Biomedicine and Prevention, Tor Vergata University, Rome 00133, Italy
| | - Emiliano Giardina
- Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, Rome 00142, Italy
- Department of Biomedicine and Prevention, Tor Vergata University, Rome 00133, Italy
| | - Raffaella Cascella
- Department of Biomedicine and Prevention, Tor Vergata University, Rome 00133, Italy
- Department of Biomedical Sciences, Catholic University Our Lady of Good Counsel, Tirana 1000, Albania
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Karr JE, Areshenkoff CN, Rast P, Hofer SM, Iverson GL, Garcia-Barrera MA. The unity and diversity of executive functions: A systematic review and re-analysis of latent variable studies. Psychol Bull 2018; 144:1147-1185. [PMID: 30080055 DOI: 10.1037/bul0000160] [Citation(s) in RCA: 299] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Confirmatory factor analysis (CFA) has been frequently applied to executive function measurement since first used to identify a three-factor model of inhibition, updating, and shifting; however, subsequent CFAs have supported inconsistent models across the life span, ranging from unidimensional to nested-factor models (i.e., bifactor without inhibition). This systematic review summarized CFAs on performance-based tests of executive functions and reanalyzed summary data to identify best-fitting models. Eligible CFAs involved 46 samples (N = 9,756). The most frequently accepted models varied by age (i.e., preschool = one/two-factor; school-age = three-factor; adolescent/adult = three/nested-factor; older adult = two/three-factor), and most often included updating/working memory, inhibition, and shifting factors. A bootstrap reanalysis simulated 5,000 samples from 21 correlation matrices (11 child/adolescent; 10 adult) from studies including the three most common factors, fitting seven competing models. Model results were summarized as the mean percent accepted (i.e., average rate at which models converged and met fit thresholds: CFI ≥ .90/RMSEA ≤ .08) and mean percent selected (i.e., average rate at which a model showed superior fit to other models: ΔCFI ≥ .005/.010/ΔRMSEA ≤ -.010/-.015). No model consistently converged and met fit criteria in all samples. Among adult samples, the nested-factor was accepted (41-42%) and selected (8-30%) most often. Among child/adolescent samples, the unidimensional model was accepted (32-36%) and selected (21-53%) most often, with some support for two-factor models without a differentiated shifting factor. Results show some evidence for greater unidimensionality of executive function among child/adolescent samples and both unity and diversity among adult samples. However, low rates of model acceptance/selection suggest possible bias toward the publication of well-fitting but potentially nonreplicable models with underpowered samples. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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8
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McDermott KL, McFall GP, Andrews SJ, Anstey KJ, Dixon RA. Memory Resilience to Alzheimer's Genetic Risk: Sex Effects in Predictor Profiles. J Gerontol B Psychol Sci Soc Sci 2017; 72:937-946. [PMID: 28025282 DOI: 10.1093/geronb/gbw161] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 11/12/2016] [Indexed: 02/05/2023] Open
Abstract
Objectives Apolipoprotein E (APOE) ɛ4 and Clusterin (CLU) C alleles are risk factors for Alzheimer's disease (AD) and episodic memory (EM) decline. Memory resilience occurs when genetically at-risk adults perform at high and sustained levels. We investigated whether (a) memory resilience to AD genetic risk is predicted by biological and other risk markers and (b) the prediction profiles vary by sex and AD risk variant. Method Using a longitudinal sample of nondemented adults (n = 642, aged 53-95) we focused on memory resilience (over 9 years) to 2 AD risk variants (APOE, CLU). Growth mixture models classified resilience. Random forest analysis, stratified by sex, tested the predictive importance of 22 nongenetic risk factors from 5 domains (n = 24-112). Results For both sexes, younger age, higher education, stronger grip, and everyday novel cognitive activity predicted memory resilience. For women, 9 factors from functional, health, mobility, and lifestyle domains were also predictive. For men, only fewer depressive symptoms was an additional important predictor. The prediction profiles were similar for APOE and CLU. Discussion Although several factors predicted resilience in both sexes, a greater number applied only to women. Sex-specific mechanisms and intervention targets are implied.
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Affiliation(s)
| | - G Peggy McFall
- Neuroscience and Mental Health Institute.,Department of Psychology, University of Alberta, Edmonton, Canada
| | - Shea J Andrews
- Centre for Research on Ageing, Health and Wellbeing, The Australian National University, Canberra, Australia
| | - Kaarin J Anstey
- Centre for Research on Ageing, Health and Wellbeing, The Australian National University, Canberra, Australia
| | - Roger A Dixon
- Neuroscience and Mental Health Institute.,Department of Psychology, University of Alberta, Edmonton, Canada
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Thibeau S, McFall GP, Wiebe SA, Anstey KJ, Dixon RA. Genetic factors moderate everyday physical activity effects on executive functions in aging: Evidence from the Victoria Longitudinal Study. Neuropsychology 2016; 30:6-17. [PMID: 26710092 DOI: 10.1037/neu0000217] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE Everyday physical activity (EPA) is an important modifiable contributor to age-related variability in executive functioning (EF). However, its role may be moderated by nonmodifiable genetic factors. We tested independent and interactive effects of brain-derived neurotrophic factor (BDNF rs6265) and insulin degrading enzyme (IDE rs6583817) on EF and EPA-EF relationships. METHOD The sample consisted of genotyped older adults (N = 577; M age = 70.47 years) over 3 waves (∼9 years) of the Victoria Longitudinal Study. Analyses included (a) confirmatory factor analysis establishing a single latent EF factor from 4 standard EF tasks, (b) latent growth modeling over a 40-year band of aging (ages 53 to 95), and (c) structural regression to investigate the independent and interactive effects of BDNF, IDE, and EPA. RESULTS First, higher levels of EPA were associated with better EF performance at the centering age (75 years) and less EF decline. Second, IDE G+ (protective) carriers exhibited better EF performance at Age 75 than their G- (nonprotective) peers. Third, within the IDE G+ carrier group, those with higher EPA exhibited better EF performance and slower decline over time than those with lower EPA. Fourth, for the BDNF homozygote Val group, higher EPA was associated with better EF performance and more gradual EF change; however, this beneficial effect was not seen for Met carriers. CONCLUSION The effect of modifiable physical health factors on EF is moderated by biological mechanisms associated with risk-protection genetic polymorphisms.
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Affiliation(s)
| | | | | | - Kaarin J Anstey
- Centre for Research on Ageing, Health and Wellbeing, Australian National University
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McFall GP, Sapkota S, McDermott KL, Dixon RA. Risk-reducing Apolipoprotein E and Clusterin genotypes protect against the consequences of poor vascular health on executive function performance and change in nondemented older adults. Neurobiol Aging 2016; 42:91-100. [PMID: 27143425 DOI: 10.1016/j.neurobiolaging.2016.02.032] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 02/24/2016] [Accepted: 02/29/2016] [Indexed: 02/06/2023]
Abstract
We examined independent and cumulative effects of 2 Alzheimer's-related genetic polymorphisms, Apolipoprotein E (APOE) and Clusterin (CLU), in relation to the deleterious effects of poor vascular health (pulse pressure [PP]) on executive function (EF) performance and change in nondemented older adults. Using a sample (n = 593; age range = 53-95 years) from the Victoria Longitudinal Study, we applied latent growth modeling to test the effect of PP, as moderated by APOE and CLU, on an EF latent variable. EF was affected by higher levels of PP but differentially less so for carriers of low-risk alleles (APOE ɛ2+; CLU TT) than for moderate- or high-risk alleles (APOE ɛ2-; CLU C+). The cumulative genetic risk of APOE plus CLU provided similar moderation of PP level effects on EF. Future research may focus on how APOE and CLU might provide different but complementary contributions to predicting EF level and change. Vascular health risk in synergistic association with risk-related polymorphisms can elucidate the neurobiological underpinnings of cognitive trajectories in nondemented aging.
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Affiliation(s)
- G Peggy McFall
- Department of Psychology, University of Alberta, Edmonton, Canada; Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada
| | - Shraddha Sapkota
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada
| | - Kirstie L McDermott
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada
| | - Roger A Dixon
- Department of Psychology, University of Alberta, Edmonton, Canada; Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada.
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Clinical and Sociodemographic Factors Associated with Cognitive Impairment and Neuroprotection in Diabetes Patients. SPANISH JOURNAL OF PSYCHOLOGY 2015; 18:E65. [DOI: 10.1017/sjp.2015.61] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AbstractThe aim of this study is to analyze the potential impact of factors (clinical and demographic variables and comorbidities) associated with Diabetes Mellitus (DM) on certain mental processes related to cognitive impairment, with special attention to the analysis of parameters that define processing speed and executive function. Neuropsychological examination of elderly Spanish patients (N = 59, 33 females, Mage 70.98 years) diagnosed with DM, in addition to application of an ad hoc questionnaire to collect information on comorbidities and other relevant demographic variables. Based on a cross-sectional design, correlational analysis was carried out. Cognitive performance showed an inverse relationship to age and cardiopathology while years of schooling and regular physical activity appeared as neuroprotective factors. DM is an illness which, linked to other variables, can be regarded as a risk factor for the development of cognitive impairment. Certain factors (physical activity and cognitive stimulation) have the potential to mitigate this tendency. There is a need to further our understanding of the neurobiological mechanisms involved.
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12
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DeCarlo CA, MacDonald SWS, Vergote D, Jhamandas J, Westaway D, Dixon RA. Vascular Health and Genetic Risk Affect Mild Cognitive Impairment Status and 4-Year Stability: Evidence From the Victoria Longitudinal Study. J Gerontol B Psychol Sci Soc Sci 2015; 71:1004-1014. [PMID: 26362601 DOI: 10.1093/geronb/gbv043] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 05/16/2015] [Indexed: 01/12/2023] Open
Abstract
OBJECTIVES Mild cognitive impairment (MCI) is a high-risk condition for progression to Alzheimer's disease (AD). Vascular health is a key mechanism underlying age-related cognitive decline and neurodegeneration. AD-related genetic risk factors may be associated with preclinical cognitive status changes. We examine independent and cross-domain interactive effects of vascular and genetic markers for predicting MCI status and stability. METHOD We used cross-sectional and 2-wave longitudinal data from the Victoria Longitudinal Study, including indicators of vascular health (e.g., reported vascular diseases, measured lung capacity and pulse rate) and genetic risk factors-that is, apolipoprotein E (APOE; rs429358 and rs7412; the presence vs absence of ε4) and catechol-O-methyltransferase (COMT; rs4680; met/met vs val/val). We examined associations with objectively classified (a) cognitive status at baseline (not impaired congnitive (NIC) controls vs MCI) and (b) stability or transition of cognitive status across a 4-year interval (stable NIC-NIC vs chronic MCI-MCI or transitional NIC-MCI). RESULTS Using logistic regression, indicators of vascular health, both independently and interactively with APOE ε4, were associated with risk of MCI at baseline and/or associated with MCI conversion or MCI stability over the retest interval. DISCUSSION Several vascular health markers of aging predict MCI risk. Interactively, APOE ε4 may intensify the vascular health risk for MCI.
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Affiliation(s)
- Correne A DeCarlo
- Department of Psychology, University of Victoria, British Columbia, Canada.
| | | | | | - Jack Jhamandas
- Department of Medicine (Neurology).,Neuroscience and Mental Health Institute
| | - David Westaway
- Neuroscience and Mental Health Institute.,Centre for Prions and Protein Folding Diseases
| | - Roger A Dixon
- Neuroscience and Mental Health Institute.,Department of Psychology, University of Alberta, Edmonton, Canada
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Alzheimer's Genetic Risk Intensifies Neurocognitive Slowing Associated with Diabetes in Non-Demented Older Adults. ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING 2015; 1:395-402. [PMID: 26665159 PMCID: PMC4671298 DOI: 10.1016/j.dadm.2015.08.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Introduction We examine interactive and intensification effects of type 2 diabetes (T2D) with APOE and an Alzheimer's disease genetic risk score (GRS) on neurocognitive speed performance and change in nondemented older adults. Methods In an accelerated longitudinal design, we used latent growth modeling to test moderators of level and change in a neurocognitive speed latent variable for 628 adults (baseline median age = 69.0) followed over 9 years. The GRS was compiled using the cumulative risk of APOE, CLU, CR1, and PICALM. Results First, T2D predicted slower speed performance at centering age (75). Second, no predictive effects were associated with APOE or GRS. Third, a significant interaction showed that high risk from both T2D and GRS was selectively associated with steeper longitudinal slowing than all comparison cross-domain risk groups. Discussion Higher AD-related genetic risk intensified deleterious effects of diabetes on neurocognitive slowing in nondemented aging beyond the independent influence of APOE.
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McFall GP, Wiebe SA, Vergote D, Westaway D, Jhamandas J, Bäckman L, Dixon RA. ApoE and pulse pressure interactively influence level and change in the aging of episodic memory: Protective effects among ε2 carriers. Neuropsychology 2014; 29:388-401. [PMID: 25436424 DOI: 10.1037/neu0000150] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE We tested independent and interactive effects of Apolipoprotein E (ApoE) and pulse pressure (PP) concurrently and longitudinally across 9 years (3 waves) of episodic (EM) and semantic memory (SM) data from the Victoria Longitudinal Study. METHOD We assembled a sample of older adults (n = 570, baseline M age = 71, age range = 53-95) and used latent growth modeling to test 4 research goals. RESULTS First, the best fitting memory model was 2 single latent variables for EM and SM, each exhibiting configural, metric, and partial scalar invariance. This model was analyzed as a parallel process model. Second, baseline level of PP predicted EM performance at centering age (75) and rate of 9-year EM change. Third, we observed no main effects of ApoE on EM or SM. Fourth, EM was affected by higher PP but differentially less so for carriers of the ApoE ε2 allele than the ε3 or ε4 alleles. CONCLUSIONS PP is confirmed as a risk factor for concurrent and changing cognitive health in aging, but the effects operate differently across risk and protective allelic distribution of the ApoE gene.
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Synergistic associations of catechol-O-methyltransferase and brain-derived neurotrophic factor with executive function in aging are selective and modified by apolipoprotein E. Neurobiol Aging 2014; 36:249-56. [PMID: 25107496 DOI: 10.1016/j.neurobiolaging.2014.06.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Revised: 06/16/2014] [Accepted: 06/16/2014] [Indexed: 11/23/2022]
Abstract
Genetic polymorphisms of catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) have shown promising but inconsistent linkages with executive function (EF) in normal aging. We tested (1) independent contributions of COMT and BDNF risk; (2) potential magnification by risk-related interactions or additive effects with age; and (3) effect modification through stratification by apolipoprotein E (APOE) (risk: ε4+). Multiple linear regression models were applied with nondemented older adults (N = 634; range: 53-95 years) for an EF latent variable. No independent effects of BDNF or COMT on EF were observed. Additive (but not interactive) effects of COMT, BDNF, and age showed that older adults with a high-risk allelic combination performed differentially worse. Of 2 tested models of synergistic effects, the additive approach selectively supported a magnification hypothesis, which was qualified by the presence or the absence of APOE ε4.
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McFall GP, Wiebe SA, Vergote D, Jhamandas J, Westaway D, Dixon RA. IDE (rs6583817) polymorphism and pulse pressure are independently and interactively associated with level and change in executive function in older adults. Psychol Aging 2014; 29:418-430. [PMID: 24660790 PMCID: PMC4069225 DOI: 10.1037/a0034656] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
OBJECTIVE We report a gene × environment (health) study focusing on concurrent performance and longitudinal change in a latent-variable executive function (EF) phenotype. Specifically, we tested the independent and interactive effects of a recently identified insulin degrading enzyme genetic polymorphism (IDE rs6583817) and pulse pressure (PP; one prominent aging-related vascular health indicator) across up to 9 years of EF data in a sample of older adults from the Victoria Longitudinal Study. Both factors vary across a continuum of risk-elevating to risk-reducing and have been recently linked to normal and impaired cognitive aging. METHOD We assembled a genotyped and typically aging group of older adults (n = 599, M age = 66 years at baseline), following them for up to 3 longitudinal waves (M interval = 4.4 years). We used confirmatory factor analyses, latent growth modeling, and path analyses to pursue 3 main research goals. RESULTS First, the EF single factor model was confirmed comprising 4 executive function tasks and it demonstrated measurement invariance across the waves. Second, older adults with the major IDE G allele exhibited better EF outcomes than homozygotes for the minor A allele at the centering age of 75 years. Adults with higher PP performed more poorly on EF tasks at age 75 years and exhibited greater EF longitudinal decline. Third, gene × health interaction analyses showed that worsening vascular health (higher PP) differentially affected EF performance in older adults with the IDE G allele. CONCLUSION Genetic interaction analyses can reveal differential and magnifying effects on cognitive phenotypes in aging. In the present case, pulse pressure is confirmed as a risk factor for concurrent and changing cognitive health in aging, but the effects operate differently across the risk and protective allelic distribution of this IDE gene.
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Affiliation(s)
- G. Peggy McFall
- Department of Psychology, University of Alberta, Edmonton, Canada
| | - Sandra A. Wiebe
- Department of Psychology, University of Alberta, Edmonton, Canada
- Centre for Neuroscience, University of Alberta, Edmonton, Canada
| | - David Vergote
- Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Canada
| | - Jack Jhamandas
- Centre for Neuroscience, University of Alberta, Edmonton, Canada
- Department of Medicine (Neurology), University of Alberta, Edmonton, Canada
| | - David Westaway
- Centre for Neuroscience, University of Alberta, Edmonton, Canada
- Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Canada
| | - Roger A. Dixon
- Department of Psychology, University of Alberta, Edmonton, Canada
- Centre for Neuroscience, University of Alberta, Edmonton, Canada
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APOE moderates the association between lifestyle activities and cognitive performance: evidence of genetic plasticity in aging. J Int Neuropsychol Soc 2014; 20:478-86. [PMID: 24867440 PMCID: PMC4096557 DOI: 10.1017/s1355617714000356] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The current study examined independent and interactive effects between Apolipoprotein E (APOE) genotype and two types of cognitively-stimulating lifestyle activities (CSLA)-integrated information processing (CSLA-II) and novel information processing (CSLA-NI)-on concurrent and longitudinal changes in cognition. Three-wave data across 6 years of follow-up from the Victoria Longitudinal Study (n=278; ages 55-94) and linear mixed model analyses were used to characterize the effects of APOE genotype and participation in CSLA-II and CSLA-NI in four cognitive domains. Significant CSLA effects on cognition were observed. More frequent participation in challenging activities (i.e., CSLA-NI) was associated with higher baseline scores on word recall, fact recall, vocabulary and verbal fluency. Conversely, higher participation in less cognitively-challenging activities (i.e., CSLA-II) was associated with lower scores on fact recall and verbal fluency. No longitudinal CSLA-cognition effects were found. Two significant genetic effects were observed. First, APOE moderated CSLA-II and CSLA-NI associations with baseline verbal fluency and fact recall scores. Second, APOE non-ɛ4 carriers' baseline performance were more likely to be moderated by CSLA participation, compared to APOE-ɛ4 carriers. Our findings suggest APOE may be a "plasticity" gene that makes individuals more or less amenable to the influence of protective factors such as CSLA.
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de Frias CM, Dixon RA. Lifestyle engagement affects cognitive status differences and trajectories on executive functions in older adults. Arch Clin Neuropsychol 2013; 29:16-25. [PMID: 24323561 DOI: 10.1093/arclin/act089] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The authors first examined the concurrent moderating role of lifestyle engagement on the relation between cognitive status (cognitively elite, cognitively normal [CN], and cognitively impaired [CI]) and executive functioning (EF) in older adults. Second, the authors examined whether baseline participation in lifestyle activities predicted differential 4.5-year stabilities and transitions in cognitive status. Participants (initial N = 501; 53-90 years) were from the Victoria Longitudinal Study. EF was represented by a 1-factor structure. Lifestyle activities were measured in multiple domains of engagement (e.g., cognitive, physical, and social). Two-wave status stability groups included sustained normal aging, transitional early impairment, and chronic impairment. Hierarchical regressions showed that baseline participation in social activities moderated cognitive status differences in EF. CI adults with high (but not low) social engagement performed equivalently to CN adults on EF. Longitudinally, logistic regressions showed that engagement in physical activities was a significant predictor of stability of cognitive status. CI adults who were more engaged in physical activities were more likely to improve in their cognitive status over time than their more sedentary peers. Participation in cognitive activities was a significant predictor of maintenance in a higher cognitive status group. Given that lifestyle engagement plays a detectable role in healthy, normal, and impaired neuropsychological aging, further research in activity-related associations and interventions is recommended.
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Affiliation(s)
- Cindy M de Frias
- School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX, USA
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