| 1. |
- Ferencz, Beata, et al.
(author)
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The Benefits of Staying Active in Old Age : Physical Activity Counteracts the Negative Influence of PICALM, BIN1, and CLU Risk Alleles on Episodic Memory Functioning
- 2014
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In: Psychology and Aging. - : American Psychological Association (APA). - 0882-7974 .- 1939-1498. ; 29:2, s. 440-449
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Journal article (peer-reviewed)abstract
- PICALM, BIN1, CLU, and APOE are top candidate genes for Alzheimer's disease, and they influence episodic memory performance in old age. Physical activity, however, has been shown to protect against age-related decline and counteract genetic influences on cognition. The aims of this study were to assess whether (a) a genetic risk constellation of PICALM, BIN1, and CLU polymorphisms influences cognitive performance in old age; and (b) if physical activity moderates this effect. Data from the SNAC-K population-based study were used, including 2,480 individuals (age range = 60 to 100 years) free of dementia at baseline and at 3- to 6-year follow-ups. Tasks assessing episodic memory, perceptual speed, knowledge, and verbal fluency were administered. Physical activity was measured using self-reports. Individuals who had engaged in frequent health-or fitness-enhancing activities within the past year were compared with those who were inactive. Genetic risk scores were computed based on an integration of risk alleles for PICALM (rs3851179 G allele, rs541458 T allele), BIN1 (rs744373 G allele), and CLU (rs11136000 T allele). High genetic risk was associated with reduced episodic memory performance, controlling for age, education, vascular risk factors, chronic diseases, activities of daily living, and APOE gene status. Critically, physical activity attenuated the effects of genetic risk on episodic memory. Our findings suggest that participants with high genetic risk who maintain a physically active lifestyle show selective benefits in episodic memory performance.
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| 2. |
- Ferencz, Beata, et al.
(author)
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The influence of APOE and TOMM40 polymorphisms on hippocampal volume and episodic memory in old age
- 2013
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In: Frontiers in Human Neuroscience. - : Frontiers Media SA. - 1662-5161. ; 7
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Journal article (peer-reviewed)abstract
- Mitochondrial dysfunction is implicated in neurodegenerative disorders, such as Alzheimer's disease (AD). Translocase of outer mitochondrial membrane 40 (TOMM40) may be influential in this regard by influencing mitochondrial neurotoxicity. Little is known about the influence of the TOMM40 gene on hippocampal (HC) volume and episodic memory (EM), particularly in healthy older adults. Thus, we sought to discern the influence of TOMM40 single nucleotide polymorphisms (SNPs), which have previously been associated with medial temporal lobe integrity (rs11556505 and rs2075650), on HC volume and EM. The study sample consisted of individuals from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) who were free of dementia and known neurological disorders, and 6087 years of age (n = 424). EM was measured by using a 16-item word list with a 2-min free recall period and delineation of the HC was performed manually. The influence of Apolipoprotein E (APOE) and TOMM40 was assessed by 2 x 2 ANOVAs and partial correlations. There was no effect of APOE and TOMM40 on EM performance and HC volume. However, partial correlations revealed that HC volume was positively associated with free recall performance (r = 0.21, p < 0.01, r(2) = 0.04). When further stratified for TOMM40, the observed association between HC volume and free recall in APOE epsilon 4 carriers was present in combination with TOMM40 rs11556505 any T (r = 0.28, p < 0.01, R-2 = 0.08) and rs2075650 any G (r = 0.28, p < 0.01, R-2 = 0.08) risk alleles. This pattern might reflect higher reliance on HC volume for adequate EM performance among APOE epsilon 4 carriers with additional TOMM40 risk alleles suggesting that the TOMM40 gene cannot merely be considered a marker of APOE genotype. Nevertheless, neither APOE nor TOMM40 influenced HC volume or EM in this population-based sample of cognitively intact individuals over the age of 60.
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| 3. |
- Ferreira, Daniel, et al.
(author)
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The interactive effect of demographic and clinical factors on hippocampal volume : A multicohort study on 1958 cognitively normal individuals
- 2017
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In: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 27:6, s. 653-667
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Journal article (peer-reviewed)abstract
- Alzheimer's disease is characterized by hippocampal atrophy. Other factors also influence the hippocampal volume, but their interactive effect has not been investigated before in cognitively healthy individuals. The aim of this study is to evaluate the interactive effect of key demographic and clinical factors on hippocampal volume, in contrast to previous studies frequently investigating these factors in a separate manner. Also, to investigate how comparable the control groups from ADNI, AIBL, and AddNeuroMed are with five population-based cohorts. In this study, 1958 participants were included (100 AddNeuroMed, 226 ADNI, 155 AIBL, 59 BRC, 295 GENIC, 279 BioFiNDER, 398 PIVUS, and 446 SNAC-K). ANOVA and random forest were used for testing between-cohort differences in demographic-clinical variables. Multiple regression was used to study the influence of demographic-clinical variables on hippocampal volume. ANCOVA was used to analyze whether between-cohort differences in demographic-clinical variables explained between-cohort differences in hippocampal volume. Age and global brain atrophy were the most important variables in explaining variability in hippocampal volume. These variables were not only important themselves but also in interaction with gender, education, MMSE, and total intracranial volume. AddNeuroMed, ADNI, and AIBL differed from the population-based cohorts in several demographic-clinical variables that had a significant effect on hippocampal volume. Variability in hippocampal volume in individuals with normal cognition is high. Differences that previously tended to be related to disease mechanisms could also be partly explained by demographic and clinical factors independent from the disease. Furthermore, cognitively normal individuals especially from ADNI and AIBL are not representative of the general population. These findings may have important implications for future research and clinical trials, translating imaging biomarkers to the general population, and validating current diagnostic criteria for Alzheimer's disease and predementia stages.
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| 4. |
- Kalpouzos, Grégoria, et al.
(author)
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Telomerase Gene (hTERT) and Survival : Results From Two Swedish Cohorts of Older Adults
- 2016
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In: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press (OUP). - 1079-5006 .- 1758-535X. ; 71:2, s. 188-195
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Journal article (peer-reviewed)abstract
- Telomere length has been associated with longevity. As telomere length is partly determined by the human telomerase reverse transcriptase (hTERT), we investigated the association between an hTERT polymorphism located in its promoter region ((-) (1327)T/C) and longevity in two cohorts of older adults. Participants from the Kungsholmen project (KP; n = 1,205) and the Swedish National study of Aging and Care in Kungsholmen (SNAC-K; n = 2,764) were followed for an average period of 7.5 years. The main outcomes were hazard ratios (HR) of mortality and median age at death. In both cohorts, mortality was lower in female T/T carriers, aged 75+ years in KP (HR = 0.8, 95% CI: 0.5-0.9) and 78+ years in SNAC-K (HR = 0.6, 95% CI: 0.4-0.8) compared with female C/C carriers. T/T carriers died 1.8-3 years later than the C/C carriers. This effect was not present in men, neither in SNAC-K women aged 60-72 years. The association was not modified by presence of cancer, cardiovascular diseases, number of chronic diseases, or markers of inflammation, and did not interact with APOE genotype or estrogen replacement therapy. The gender-specific increased survival in T/T carriers can be due to a synergistic effect between genetic background and the life-long exposure to endogenous estrogen.
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| 5. |
- Laukka, Erika J., et al.
(author)
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Microstructural White Matter Properties Mediate the Association between APOE and Perceptual Speed in Very Old Persons without Dementia
- 2015
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Journal article (peer-reviewed)abstract
- Background Reduced white matter integrity, as indicated by lower fractional anisotropy (FA) and higher mean diffusivity (MD), has been related to poorer perceptual speed (PS) performance. As the epsilon 4 allele has been associated with lower white matter integrity in old age, this represents a potential mechanism through which APOE may affect PS. Objective To examine whether the association between APOE and PS is mediated by white matter microstructure in very old persons without dementia. Method Participants were selected from the population-based SNAC-K study. After excluding persons with dementia, preclinical dementia, and other neurological disorders, 652 persons (age range 78-90) were included in the study, of which 89 had data on diffusion tensor imaging (DTI). We used structural equation modeling to form seven latent white matter factors (FA and MD) and one latent PS factor. Separate analyses were performed for FA and MD and mediational analyses were carried out for tracts where significant associations were observed to both APOE and PS. Results APOE was associated with white matter microstructure in 2 out of 14 tracts; e4 carriers had significantly lower FA in forceps major and higher MD in the cortico-spinal tract. Allowing the white matter microstructure indicators in these tracts to mediate the association between APOE and PS resulted in a markedly attenuated association between these variables. Bootstrapping statistics in the subsample with DTI data (n = 89) indicated that FA in forceps major significantly mediated the association between APOE and PS (indirect effect: -0.070, 95% bias corrected CIs -0.197 to -0.004). Conclusion Lower white matter integrity may represent one of several mechanisms through which APOE affects PS performance in elderly persons free of dementia and preclinical dementia.
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| 6. |
- Papenberg, Goran, et al.
(author)
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Magnified effects of the COMT gene on white-matter microstructure in very old age
- 2015
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In: Brain Structure and Function. - : Springer Science and Business Media LLC. - 1863-2653 .- 1863-2661. ; 220:5, s. 2927-2938
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Journal article (peer-reviewed)abstract
- Genetic factors may partly account for between-person differences in brain integrity in old age. Evidence from human and animal studies suggests that the dopaminergic system is implicated in the modulation of white-matter integrity. We investigated whether a genetic variation in the Catechol-O-Methyltransferase (COMT) Val158Met polymorphism, which influences dopamine availability in prefrontal cortex, contributes to interindividual differences in white-matter microstructure, as measured with diffusion-tensor imaging. In a sample of older adults from a population-based study (60-87 years; n = 238), we found that the COMT polymorphism affects white-matter microstructure, indexed by fractional anisotropy and mean diffusivity, of several white-matter tracts in the oldest age group (81-87 years), although there were no reliable associations between COMT and white-matter microstructure in the two younger age groups (60-66 and 72-78 years). These findings extend previous observations of magnified genetic effects on cognition in old age to white-matter integrity.
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| 7. |
- Wang, Rui, et al.
(author)
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Effects of vascular risk factors and APOE epsilon 4 on white matter integrity and cognitive decline
- 2015
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In: Neurology. - 0028-3878 .- 1526-632X. ; 84:11, s. 1128-1135
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Journal article (peer-reviewed)abstract
- Objective:To investigate the effects of vascular risk factors and APOE status on white matter microstructure, and subsequent cognitive decline among older people.Methods:This study included 241 participants (age 60 years and older) from the population-based Swedish National Study on Aging and Care in Kungsholmen in central Stockholm, Sweden, who were free of dementia and stroke at baseline (2001-2004). We collected data through interviews, clinical examinations, and laboratory tests. We measured fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging, and estimated volume of white matter hyperintensities using automatic segmentation. We assessed global cognitive function with the Mini-Mental State Examination at baseline and at 3- and/or 6-year follow-up. We analyzed the data using multivariate linear regression and linear mixed models.Results:Heavy alcohol consumption, hypertension, and diabetes were significantly associated with lower FA or higher MD (p < 0.05). When aggregating heavy alcohol consumption, hypertension, and diabetes together with current smoking, having an increasing number of these 4 factors concurrently was associated with decreasing FA and increasing MD (p(trend) < 0.01), independent of white matter hyperintensities. Vascular risk factors and APOE epsilon 4 allele interacted to negatively affect white matter microstructure; having multiple (2) vascular factors was particularly detrimental to white matter integrity among APOE epsilon 4 carriers. Lower tertile of FA and upper tertile of MD were significantly associated with faster Mini-Mental State Examination decline.Conclusions:Vascular risk factors are associated with reduced white matter integrity among older adults, which subsequently predicted faster cognitive decline. The detrimental effects of vascular risk factors on white matter microstructure were exacerbated among APOE epsilon 4 carriers.
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| 8. |
- Xu, Wei-Li, et al.
(author)
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HHEX_23 AA Genotype Exacerbates Effect of Diabetes on Dementia and Alzheimer Disease : A Population-Based Longitudinal Study
- 2015
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In: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 12:7
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Journal article (peer-reviewed)abstract
- Background Research has suggested that variations within the IDE/HHEX gene region may underlie the association of type 2 diabetes with Alzheimer disease (AD). We sought to explore whether IDE genes play a role in the association of diabetes with dementia, AD, and structural brain changes using data from two community-based cohorts of older adults and a subsample with structural MRI. Methods and Findings The first cohort, which included dementia-free adults aged >= 75 y (n = 970) at baseline, was followed for 9 y to detect incident dementia (n = 358) and AD (n = 271) cases. The second cohort (for replication), which included 2,060 dementia-free participants aged >= 60 y at baseline, was followed for 6 y to identify incident dementia (n = 166) and AD (n = 121) cases. A subsample (n = 338) of dementia-free participants from the second cohort underwent MRI. HHEX_23 and IDE_9 were genotyped, and diabetes (here including type 2 diabetes and prediabetes) was assessed. In the first cohort, diabetes led to an adjusted hazard ratio (HR) of 1.73 (95% CI 1.19-2.32) and 1.66 (95% CI 1.06-2.40) for dementia and AD, respectively, among all participants. Compared to people carrying the GG genotype without diabetes, AA genotype carriers with diabetes had an adjusted HR of 5.54 (95% CI 2.407.18) and 4.81 (95% CI 1.88-8.50) for dementia and AD, respectively. There was a significant interaction between HHEX_23-AA and diabetes on dementia (HR 4.79, 95% CI 1.63-8.90, p = 0.013) and AD (HR 3.55, 95% CI 1.45-9.91, p = 0.025) compared to the GG genotype without diabetes. In the second cohort, the HRs were 1.68 (95% CI 1.04-2.99) and 1.64 (1.02-2.33) for the diabetes-AD and dementia-AD associations, respectively, and 4.06 (95% CI 1.06-7.58, p = 0.039) and 3.29 (95% CI 1.02-8.33, p = 0.044) for the interactions, respectively. MRI data showed that HHEX_23-AA carriers with diabetes had significant structural brain changes compared to HHEX_23-GG carriers without diabetes. No joint effects of IDE_9 and diabetes on dementia were shown. As a limitation, the sample sizes were small for certain subgroups. Conclusions A variant in the HHEX_23 gene interacts with diabetes to be associated with a substantially increased risk of dementia and AD, and with structural brain changes among dementia-free elderly people.
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