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Preserving cognitive function with age or super-aging greatly contributes to successful aging. Super-aging nonagenarians born in Denmark in either year 1905 or 1915 were classified as Cognitively High-Performing Oldest Old individuals with a five item cognitive composite score, equivalent to or better than mean middle-aged subjects. Cognitively high-performers were more physically active and had a better physical performance on e.g., Activity of Daily Living (p-value < 0.01), gait speed (p-value < 0.01) and grip strength (p-value < 0.05) compared with age-matched peers. Cognitive high-performing was also linked to lower depression symptomatology. When comparing super-agers with semi super-agers classified by Mini Mental State Examination > 27, super-agers were still more physically active and had a better physical performance (p-value < 0.05). Results suggests that physical activity is a lifestyle factor strongly associated with both semi and full cognitive super-aging., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Cognitive ability plays an important role in mental and physical well-beings in the increasingly ageing populations. Here, based on a sample of 30 cognitive function-discordant monozygotic twin pairs, we aimed to detect specific epigenetic variants potentially related to cognitive function by conducting an epigenome-wide association study (EWAS). Association between methylation level of single CpG site with cognitive function score was tested by linear mixed effect model. Functions of cis-regulatory regions and ontology enrichments were predicted by Genomic Regions Enrichment of Annotations Tool (GREAT). Differentially methylated regions (DMRs) were detected by comb-p python library. A list of 28 CpG sites were identified to reach the level of P < 1 × 10 -4 , and the strongest association (cor = 0.138, P = 2.549 × 10 -6 ) was detected for DNA CpG site (Chr17: 40,700,490 bp) located at HSD17B1P1. The identified 14,065 genomic CpG sites (P < 0.05) were mapped to 2646 genes, especially HSD17B1P1, CUL4A, INTS8, GFI1B, ZNF467, CDH15, and PSMA1. GREAT ontology enrichments mainly highlighted nicotine pharmacodynamics pathway, GABA-B receptor II/nicotinic acetylcholine receptor/hedgehog/endothelin/Wnt signaling pathways, Parkinson disease, Huntington disease, glycolysis, neuronal system, and toll-like receptor binding. We detected 15 DMRs located at/near 16 genes, especially LINC01551, LINC02282, and FAM32A. And 32 cognitive function-associated differentially methylated genes could be replicated, such as SHANK2, ABCA2, PRDM16, NCOR2, and INPP5A. Our EWAS in monozygotic twins identify specific epigenetic variations which are significantly involved in functional genes, biological function and pathways that mediate cognitive function. The findings provide clues to further identify new diagnostic biomarkers and therapeutic targets for cognitive dysfunction., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cognitive function is a substantially heritable trait related to numerous important life outcomes. Several genome-wide association studies of cognitive function have in recent years led to the identification of thousands of significantly associated loci and genes. Individuals included in these studies have rarely been nonagenarians and centenarians, and since cognitive function is an important component of quality of life for this rapidly expanding demographic group, there is a need to explore genetic factors associated with individual differences in cognitive function at advanced ages. In this study, we pursued this by performing a genome-wide association study of cognitive function in 490 long-lived Danes (age range 90.1-100.8 years). While no genome-wide significant SNPs were identified, suggestively significant SNPs (P < 1 × 10 -5 ) were mapped to several interesting genes, including ZWINT, CELF2, and DNAH5, and the glutamate receptor genes GRID2 and GRM7. Additionally, results from a gene set over-representation analysis indicated potential roles of gene sets related to G protein-coupled receptor (GPCR) signaling, interaction between L1 and ankyrins, mitogen-activated protein kinase (MAPK) signaling, RNA degradation, and cell cycle. Larger studies are needed to shed further light on the possible importance of these suggestive genes and pathways in cognitive function in nonagenarians and centenarians., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Despite a strong genetic background in cognitive function only a limited number of single nucleotide polymorphisms (SNPs) have been found in genome-wide association studies (GWASs). We hypothesize that this is partially due to mis-specified modeling concerning phenotype distribution as well as the relationship between SNP dosage and the level of the phenotype. To overcome these issues, we introduced an assumption-free method based on generalized correlation coefficient (GCC) in a GWAS of cognitive function in Danish and Chinese twins to compare its performance with traditional linear models. The GCC-based GWAS identified two significant SNPs in Danish samples (rs71419535, p = 1.47e-08; rs905838, p = 1.69e-08) and two significant SNPs in Chinese samples (rs2292999, p = 9.27e-10; rs17019635, p = 2.50e-09). In contrast, linear models failed to detect any genome-wide significant SNPs. The number of top significant genes overlapping between the two samples in the GCC-based GWAS was higher than when applying linear models. The GCC model identified significant genetic variants missed by conventional linear models, with more replicated genes and biological pathways related to cognitive function. Moreover, the GCC-based GWAS was robust in handling correlated samples like twin pairs. GCC is a useful statistical method for GWAS that complements traditional linear models for capturing genetic effects beyond the additive assumption.

Only few studies have investigated the genomewide transcriptome of normative cognitive aging. We therefore aimed at investigating blood gene expression patterns associated with cognitive aging using a population-based sample of 235 middle-aged monozygotic twin pairs with longitudinal data on cognitive function. This unique setup enabled examination of gene expression differences associated with individual and intrapair differences in cognitive level and change while controlling for underlying genetic variation and shared early environment. Overall, increased expression of several gene sets was found to strongly correlate with a lower cognitive level and cognitive decline. The most significantly correlated gene sets were related to protein metabolism, translation, RNA metabolism, infectious disease, and the immune system, which are all processes previously linked to transcription signatures of pathological and normal brain aging, and aging in blood. The results of our study thus suggest that gene expression patterns of cognitive level and decline in our sample mirror those seen in cognitively impaired individuals, which could point toward a more generic response to cognitive aging and aging in general., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To estimate the effects of baseline grip strength and cognition on the trajectory of functional limitation over time., Design: Longitudinal study of older adults participating in the Survey of Health, Ageing and Retirement in Europe (SHARE)., Setting: Urban and rural households in 11 European countries and Israel., Participants: Individuals aged 50 and older from SHARE (2004-2015) (N=14,073; 52.5% female)., Measurements: Outcomes were functional limitation scores from five panel wave. Main exposure variables were grip strength and cognitive measures including memory, verbal fluency, and numeracy at baseline. Basic demographic characteristics, life habits, and health status were considered as potential confounders. Mixed-effect linear regression models were fitted., Results: Functional limitation increased significantly over time (follow-up range 0.9-11.6 years) (β = 0.051, P < .001). Mixed-effect linear regression models identified significant interactions between grip strength (β = -0.001, P < .001), numeracy (β = -0.012, P < .001), verbal fluency (β = -0.003, P < .001), word recall (β = -0.006, P < .001) and time on functional limitation., Conclusion: Stronger baseline grip strength and better cognition predicted a slower rate of increase in functional limitation over time in older adults. Grip strength and cognitive function appeared to be useful indicators of the functional limitation process and attested to their value in monitoring functional change in European older adults. J Am Geriatr Soc 67:93-99, 2019., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

Neurobiology is regulated by miRNA. Here circulating plasma miRNAs were assayed on a 754 miRNA OpenArray platform using 90 monozygotic elderly twins (73-95 year of age) and associated with mini mental state examination (MMSE) and a five-component cognitive score (CCS) in an explorative study. Both ordinary individual and twin-pair analyses were performed with level of cognitive scores. Candidate miRNAs were further associated with cognitive decline over 10 years using up to six repeated assessments. A total of 278 miRNAs were expressed in plasma from at least ten participants and 23 miRNAs were nominally associated (i.e., at an uncorrected p < 0.05) with CCS or MMSE in the paired analyses. Generally, elderly individuals with poor cognitive function had increase miRNA expression compared with equivalent individuals who performed better on the cognitive scale. Three miRNAs, miR-151a-3p, miR-212-3p and miR-1274b were associated with CCS both in the paired and the individual analysis. Four miRNAs found to be associated with CCS in cross-sectional analysis were also found to show an association in longitudinal analysis such that increase miRNA expression was associated with steeper cognitive decline. We propose a shared biological path underlies dementia and normative cognitive aging.

Aim: To explore the genetic and environmental influences on cardiovascular risk factors (CVRF) and cognitive function in the world's largest and rapidly aging Chinese population., Methods: Cognitive function and CVRF, including body mass index, systolic blood pressure, diastolic blood pressure, pulse pressure, glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDLC) and low-density lipoprotein cholesterol were measured in 379 complete twin pairs. Univariate and bivariate twin models were fitted to estimate the genetic and environmental components in the variance and covariance of CVRF and cognition., Results: Mild-to-high heritability was estimated for CVRF and cognition (0.27-0.74). Unique environmental factors showed low-to-moderate contributions (0.23-0.56). Only HDLC presented significant common environmental contribution (0.50). Bivariate analysis showed significantly negative genetic correlations (r G ) between cognition and systolic blood pressure (r G = -0.56), diastolic blood pressure (r G = -0.42), pulse pressure (r G = -0.45), and positive genetic correlations between cognition and total cholesterol (r G = 0.33), triglyceride (r G = 0.23) and HDLC (r G = 0.41). HDLC and cognition presented a unique environmental correlation (r E = -0.13), but in the opposite direction., Conclusions: Cognitive function was genetically related to systolic blood pressure, diastolic blood pressure, pulse pressure, total cholesterol, triglyceride and HDLC with a negative or positive direction. Cognition and HDLC might share part of a similar unique environmental factor. Geriatr Gerontol Int 2018; 18: 352-359., (© 2017 Japan Geriatrics Society.)

Multiple loci or genes have been identified using genome-wide association studies mainly in western countries but with inconsistent results. No similar studies have been conducted in the world's largest and rapidly aging Chinese population. The paper aimed to identify the specific genetic variants associated with cognitive function in middle and old-aged Chinese dizygotic twins (DZ). Cognitive function was measured on 139 pairs of DZ by Montreal Cognitive Assessment. The subjects were genotyped at 1048575 SNP positions. Regression-based mixed-effect kinship model of GWAS was conducted to test the SNPs. Gene-based analysis was performed on VEGAS2. The statistically significant genes were then subject to gene set enrichment analysis to further identify the specific biological pathways associated with cognitive function. No SNPs reached genome-wide significance although there were 13 SNPs of suggestive significance (P < 10 -5 ). Gene-based analysis found 823 significant genes topped by TNRC18P1 (P = 1.00 × 10 -6 ), FGFR1OP2 (P = 6.00 × 10 -6 ), and AKR1D1 (P = 2.30 × 10 -5 ). Enrichment analysis identified 46 biological pathways, mainly involving in signaling transmission, metabolic process and Alzheimer's disease. Analysis of SNPs involved in the regulatory motif detected cell-type specific enhancers involving aorta and colon smooth muscle both have been reported to implicate in cognition. We conclude that genetic variations are significantly involved in functional genes, biological pathways and the regulatory domain that mediate cognitive performances.

The genetic and environmental impacts on correlations between hearing and cognitive functions have not been well studied. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA). Hearing function was assessed by audiometric pure-tone hearing thresholds at different frequencies, including 0.5 kHz, 1 kHz, 2 kHz, 4 kHz, 8 kHz, and 12.5 kHz, with the lower hearing thresholds indicating better hearing function. Cognitive and hearing functions were measured on 379 complete twin pairs (240 monozygotic and 139 dizygotic pairs) with a median age of 50 years (range: 40-80 years). Bivariate twin models were fitted to quantify the genetic and environmental components of the correlations between hearing and cognitive functions. The analysis showed significantly high genetic correlation between 2 kHz of hearing and cognition (r G = -1.00, 95% CI [-1.00, -0.46]) and moderate genetic correlation between 4 kHz of hearing and cognition (r G = -0.62, 95% CI [-1.00, -0.14]). We found no significant genetic correlations between low as well as high frequencies of hearing and cognition. Low to moderate common and unique environmental correlations were shown between low frequencies of hearing and cognition (-0.13 to -0.39) and the common environmental correlation between 8 kHz, one of the high frequencies of hearing, and cognition (-0.22). The middle frequencies of hearing and cognitive functions may have a shared genetic basis. Low frequencies of hearing and cognition may share similar common and unique environmental factors. At 8 kHz, the high frequency of hearing and cognition may share similar common environment. This twin study detected a significant genetic and environmental basis in the phenotype correlation between cognition and hearing, which differed across frequencies.

Although the correlation between cognition and physical function has been well studied in the general population, the genetic and environmental nature of the correlation has been rarely investigated. We conducted a classical twin analysis on cognitive and physical function, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), handgrip strength, five-times-sit-to-stand test (FTSST), near visual acuity, and number of teeth lost in 379 complete twin pairs. Bivariate twin models were fitted to estimate the genetic and environmental correlation between physical and cognitive function. Bivariate analysis showed mildly positively genetic correlations between cognition and FEV1, r G = 0.23 [95% CI: 0.03, 0.62], as well as FVC, r G = 0.35 [95% CI: 0.06, 1.00]. We found that FTSST and cognition presented very high common environmental correlation, r C = -1.00 [95% CI: -1.00, -0.57], and low but significant unique environmental correlation, r E = -0.11 [95% CI: -0.22, -0.01], all in the negative direction. Meanwhile, near visual acuity and cognition also showed unique environmental correlation, r E = 0.16 [95% CI: 0.03, 0.27]. We found no significantly genetic correlation for cognition with handgrip strength, FTSST, near visual acuity, and number of teeth lost. Cognitive function was genetically related to pulmonary function. The FTSST and cognition shared almost the same common environmental factors but only part of the unique environmental factors, both with negative correlation. In contrast, near visual acuity and cognition may positively share part of the unique environmental factors.

Background: the genetic and environmental contributions to cognitive function in the old people have been well addressed for the Western populations using twin modelling showing moderate to high heritability. No similar study has been conducted in the world largest and rapidly ageing Chinese population living under distinct environmental condition as the Western populations., Objective: this study aims to explore the genetic and environmental impact on normal cognitive ageing in the Chinese twins., Design/setting: cognitive function was measured on 384 complete twin pairs with median age of 50 years for seven cognitive measurements including visuospatial, linguistic skills, naming, memory, attention, abstraction and orientation abilities. Data were analysed by fitting univariate and bivariate twin models to estimate the genetic and environmental components in the variance and co-variance of the cognitive assessments., Results: intra-pair correlation on cognitive measurements was low to moderate in monozygotic twins (0.23-0.41, overall 0.42) and low in dizygotic twins (0.05-0.30, overall 0.31) with the former higher than the latter for each item. Estimate for heritability was moderate for overall cognitive function (0.44, 95% CI: 0.34-0.53) and low to moderate for visuospatial, naming, attention and orientation abilities ranging from 0.28 to 0.38. No genetic contribution was estimated to linguistic skill, abstraction and memory which instead were under low to moderate control by shared environmental factors accounting for 23-33% of the total variances. In contrast, all cognitive performances showed moderate to high influences by the unique environmental factors., Conclusions: genetic factor and common family environment have a limited contribution to cognitive function in the Chinese adults. Individual unique environment is likely to play a major role in determining the levels of cognitive performance., (© The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Logistic regression analysis based on data from 822 Han Chinese oldest old aged 92+ demonstrated that interactions between carrying FOXO1A-266 or FOXO3-310 or FOXO3-292 and tea drinking at around age 60 or at present time were significantly associated with lower risk of cognitive disability at advanced ages. Associations between tea drinking and reduced cognitive disability were much stronger among carriers of the genotypes of FOXO1A-266 or FOXO3-310 or FOXO3-292 compared with noncarriers, and it was reconfirmed by analysis of three-way interactions across FOXO genotypes, tea drinking at around age 60, and at present time. Based on prior findings from animal and human cell models, we postulate that intake of tea compounds may activate FOXO gene expression, which in turn may positively affect cognitive function in the oldest old population. Our empirical findings imply that the health benefits of particular nutritional interventions, including tea drinking, may, in part, depend upon individual genetic profiles., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The genetic influences on aging-related phenotypes, including cognition and depression, have been well confirmed in the Western populations. We performed the first twin-based analysis on cognitive performance, memory and depression status in middle-aged and elderly Chinese twins, representing the world's largest and most rapidly aging population. The sample consisted of 384 twin pairs with a median age of 50 years. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) scale; memory was assessed using the revised Wechsler Adult Intelligence scale; depression symptomatology was evaluated by the self-reported 30-item Geriatric Depression (GDS-30)scale. Both univariate and multivariate twin models were fitted to the three phenotypes with full and nested models and compared to select the best fitting models. Univariate analysis showed moderate-to-high genetic influences with heritability 0.44 for cognition and 0.56 for memory. Multivariate analysis by the reduced Cholesky model estimated significant genetic (rG = 0.69) and unique environmental (rE = 0.25) correlation between cognitive ability and memory. The model also estimated weak but significant inverse genetic correlation for depression with cognition (-0.31) and memory (-0.28). No significant unique environmental correlation was found for depression with other two phenotypes. In conclusion, there can be a common genetic architecture for cognitive ability and memory that weakly correlates with depression symptomatology, but in the opposite direction.

Aim: Previous studies have shown that uric acid (UA) has strong anti-oxidant properties, and that high circulating levels of UA are prospectively associated with improved muscle function and cognitive performances in elderly Caucasians. We carried out a replication study in elderly Chinese using cross-sectional design., Methods: Data from 2006 individuals aged 50-74 years who participated in a population-based cross-sectional survey in Qingdao, China, were analyzed. Hand grip strength was measured in kilograms by using an electronic dynamometer. The sit-to-stand (STS) test time was used to represent lower limb strength. The Mini-Mental State Examination (MMSE) was used to estimate the participants' cognitive function. Lifestyle, comorbidities and laboratory measures were considered as potential confounders. Multiple linear regression models and binary logistic regression were fitted to find the association of UA with strength measures and cognitive performances., Results: Participants were grouped according to UA tertiles (<257.75 mmol/L, ≥ 257.75 and ≤ 359.00 mmol/L, >359.00 mmol/L). Hand grip strength significantly increased across UA tertiles (26.4 ± 8.5 kg; 30.1 ± 10.5 kg; 35.0 ± 11.4 kg; P<0.001), and prevalence of cognitive disorder declined across UA tertiles (7.9%, 4.9%, 3.1%; P=0.012). After adjusting for potential confounders, high UA level remained significantly associated with high grip strength (P=0.023) and decreased risk of cognitive disorder with an OR of 1.002 (95% CI 1.000-1.004; P=0.022). However, UA level was not significantly associated with STS time (P=0.780)., Conclusions: Our findings suggested that notwithstanding the associated increased risk of cardiovascular disease, UA might play a protective role in aging-associated decline in muscle strength and cognitive function., (© 2012 Japan Geriatrics Society.)

Leisure activity has been shown to be beneficial to mental health and cognitive aging. The biological basis of the correlation is, however, poorly understood. This study aimed at exploring the genetic and environmental impacts on correlation between leisure activities and cognitive function in the Chinese middle- and old-aged twins. Cognition measured using a screening test (Montreal Cognitive Assessment, MoCA) and leisure activities including intellectual and social activity were investigated on 379 complete twin pairs of middle- and old-aged twins. Univariate and bivariate twin models were fitted to estimate the genetic and environmental components in their variance and covariance. Moderate heritability was estimated for leisure activities and cognition (0.44–0.53) but insignificant for social activity. Common environmental factors accounted for about 0.36 of the total variance to social activity with no significant contribution to leisure activity, intellectual activity and cognition. Unique environmental factors displayed moderate contributions (0.47–0.64) to leisure activities and cognition. Bivariate analysis showed highly and positively genetic correlations between leisure activities and cognition (rG=0.80–0.96). Besides, intellectual activity and cognition presented low but significant unique environmental correlation (rE=0.12). Genetic factor had the moderate contribution to leisure activities and cognition. Cognitive function was highly genetically related to leisure activities. Intellectual activity and cognitive function may share some unique environmental basis. [ABSTRACT FROM AUTHOR]

A complex interrelation exists between change in depression symptomatology and cognitive decline. Studies indicate either that depression is a direct risk factor for cognitive change over time, or vice versa. Longitudinal twin studies provide the possibility to unravel cause and effect of correlated traits. Here, we have applied twin modeling approaches to shed light on the genetic correlation between both level and change of depression symptomatology and cognitive functioning, and to further explore the bidirectionality of any such correlation using assessments of both phenotypes at two occasions 10 years apart. The study included 2,866 Danish twins with a mean age of 56.8 years at intake (range: 45–68 years). Of these, 1,267 were intact pairs. A total number of 1,582 twins (55%), of whom 557 were intact pairs, participated in the follow-up survey. We found stable cross-sectional heritability estimates of approximately 60% for general cognitive abilities and 30% for affective depressive symptoms. There was a considerable decline in the mean cognitive performance over 10 years, whereas the mean affective depression symptoms score was stable and with no genetic contribution to any individual change. Additionally, we saw a small but significant cross-trait correlation at both occasions (-0.11 and -0.09, respectively), but cross-trait cross-occasion analysis revealed no evidence that either of the two traits predicts the other over a 10-year interval. Thus, our study was not able to detect any causal association between change in depressive symptomatology and cognitive decline in middle-aged and elderly people over a 10-year interval. [ABSTRACT FROM PUBLISHER]

Aim: Studies carried out in Western populations have shown age-related changes in multiple health domains together with gender-specific patterns. By focusing on five health domains, self-rated health, hand grip strength, sit-to-stand test, cognitive performance and depression, we examined the age trajectories in general health in a cross-sectional Chinese sample representing the world's largest ethnic population and compare with Danish data that represent Western populations in developed countries. Methods: Multiple regression models were fitted to compare patterns across genders and populations together with gender- and population-specific patterns in age-related decline. Results: Better self-rated health for males than for females was observed in both countries, and Danes reported better health than the Chinese for both genders. For hand grip strength, significant gender differences were shown across countries and significant population differences observed in Danish and Chinese males. There was no population difference in sit-to-stand time across genders. Female Danes outperformed males in cognitive performance. No significant gender differences in depression were observed in both populations. Conclusion: Our cross population analysis identified significant gender and population differences suggesting endogenous biological, physical and social environmental determinants in age-related decline in general health. Geriatr Gerontol Int 2012; 12: 431-439. [ABSTRACT FROM AUTHOR]