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Causal Associations of Cognitive Reserve and Hierarchical Aging-Related Outcomes: A Two-Sample Mendelian Randomization Study
Abstract
Purpose
Two-sample Mendelian randomization methods were used to explore the causal effects of cognitive reserve proxies, such as educational attainment, occupational attainment, and physical activity (PA), on biological (leukocyte telomere length), phenotypic (sarcopenia-related features), and functional (frailty index and cognitive performance) aging levels.
Results
Educational attainment had a potential protective effect on the telomere length ( β = 0.10, 95% CI: 0.08–0.11), sarcopenia-related features ( β = 0.04–0.24, 95% CI: 0.02–0.27), frailty risk ( β = −0.31, 95% CI: −0.33 to −0.28), cognitive performance ( β = 0.77, 95% CI: 0.75–0.80). Occupational attainment was causally related with sarcopenia-related features ( β = 0.07–0.10, 95% CI: 0.05–0.14), and cognitive performance ( β = 0.30, 95% CI: 0.24–0.36). Device-measured PA was potentially associated with one sarcopenia-related feature ( β = 0.14, 95% CI: 0.03–0.25).
Conclusions
Our findings support the potential causality of educational attainment on biological, phenotypic, and functional aging outcomes, of occupational attainment on phenotypic and functional aging-related outcomes, and of PA on phenotypic aging-related outcomes.
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Physical activity and cognitive functioning are strongly intertwined. However, the causal relationships underlying this association are still unclear. Physical activity can enhance brain functions, but healthy cognition may also promote engagement in physical activity. Here, we assessed the bidirectional relationships between physical activity and general cognitive functioning using Latent Heritable Confounder Mendelian Randomization (LHC-MR). Association data were drawn from two large-scale genome-wide association studies (UK Biobank and COGENT) on accelerometer-measured moderate, vigorous, and average physical activity (N = 91,084) and cognitive functioning (N = 257,841). After Bonferroni correction, we observed significant LHC-MR associations suggesting that increased fraction of both moderate (b = 0.32, CI95% = [0.17,0.47], P = 2.89e − 05) and vigorous physical activity (b = 0.22, CI95% = [0.06,0.37], P = 0.007) lead to increased cognitive functioning. In contrast, we found no evidence of a causal effect of average physical activity on cognitive functioning, and no evidence of a reverse causal effect (cognitive functioning on any physical activity measures). These findings provide new evidence supporting a beneficial role of moderate and vigorous physical activity (MVPA) on cognitive functioning.
Background
Previous studies have reported an association between sarcopenia and type 2 diabetes mellitus (T2DM), but causation was prone to confounding factors. A more robust research approach is urgently required to investigate the causal relationship between sarcopenia and T2DM.
Methods
The bi-directional two-sample MR study was carried out in two stages: Sarcopenia-related traits were investigated as exposure while T2DM was investigated as an outcome in the first step, whereas the second step was reversed. The GWAS summary data for hand-grip strength (n = 256,523), appendicular lean mass (ALM, n = 450,243), and walking pace (n = 459,915) were obtained from the UK Biobank. T2DM data were obtained from one of the biggest case-control studies on diabetes (DIAGRAM; n = 180,834 cases and 492,191 controls), which was published in 2022. The inverse-variance weighted (IVW) approach was used to obtain MR estimates, and various sensitivity analysis was also performed.
Results
Low hand-grip strength had a potential causal relationship with an increased incidence of T2DM (OR = 1.109; 95% CI, 1.008–1.222; p = 0.0350). T2DM risk was reduced by increasing ALM and walking pace: A 1 kg/m² increase in ALM decreased the risk of T2DM by 10.2% (OR = 0.898; 95% CI, 0.830–0.952; p < 0.001). A 1 m/s increase in walking pace decreased the risk of T2DM by 90.0% (OR = 0.100; 95% CI, 0.053–0.186; p < 0.001). The relationship was bidirectional, with T2DM as a causative factor of sarcopenia-related traits (p < 0.05) except for ALM (β = 0.018; 95% CI, −0.008 to −0.044; p = 0.168).
Conclusions
Hand-grip strength and T2DM had a potential bidirectional causal relationship, as did walking pace and T2DM. We suggest that sarcopenia and T2DM may mutually have a significant causal effect on each other.
BACKGROUND
Education, intelligence, and cognition are associated with hypertension, but which one plays the most prominent role in the pathogenesis of hypertension and which modifiable risk factors mediate the causal effects remains unknown.
METHODS
Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted 2-sample multivariable Mendelian randomization to estimate the independent effects of education, intelligence, or cognition on hypertension (FinnGen study, 70 651 cases/223 663 controls; UK Biobank, 77 723 cases/330 366 controls) and blood pressure (International Consortium of Blood Pressure, 757 601 participants), and used 2-step Mendelian randomization to evaluate 25 potential mediators of the association and calculate the mediated proportions.
RESULTS
Meta-analysis of inverse variance weighted Mendelian randomization results from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was associated with 44% (95% CI: 0.40–0.79) decreased hypertension risk and 1.682 mm Hg lower systolic and 0.898 mm Hg lower diastolic blood pressure, independently of intelligence and cognition. While the causal effects of intelligence and cognition on hypertension were not independent of education, 6 out of 25 cardiometabolic risk factors were identified as mediators of the association between education and hypertension, ranked by mediated proportions, including body mass index (mediated proportion: 30.1%), waist-to-hip ratio (22.8%), body fat percentage (14.1%), major depression (7.0%), high-density lipoprotein cholesterol (4.7%), and triglycerides (3.4%). These results were robust to sensitivity analyses.
CONCLUSIONS
Our findings illustrated the causal, independent impact of education on hypertension and blood pressure and outlined cardiometabolic mediators as priority targets for prevention of hypertension attributable to low education.
Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.
Background
Frailty is the most complicated expression of aging that is related to disability or multi-morbidity. The aim of the present study was to estimate the prevalence of frailty and its associated factors among community-dwelling aged population.
Methods
A total of 1529 eligible community- dwelling older adults (≥ 60 years) were enrolled in the baseline phase of Birjand Longitudinal Aging Study (BLAS) from 2019 to 2020. Their frailty status was assessed using the Fried’s frailty phenotype and frailty index. Sociodemographic factors, including sex, age, marital status, and education level, were collected. Health status assessment included the history of hypertension, diabetes mellitus, cardiovascular disease, Alzheimer’s diseases and dementia, and other health conditions. Furthermore, functional assessment (ADL, IADL) and anthropometric measurements including height, weight, waist, calf, and mid-arm circumference were made and the body mass index was calculated. The nutrition status and polypharmacy (use 3 or more medication) were also evaluated.
Results
The prevalence of frailty was 21.69% according to the frailty phenotype and 23.97% according to the frailty index. A multiple logistic regression model showed a strong association between low physical activity and frailty phenotype (OR = 36.31, CI = 16.99–77.56, P < 0.01), and frailty index (OR = 15.46, CI = 5.65–42.34, P < 0.01). Other factors like old age (≥80), female sex, malnutrition, polypharmacy, obesity, and arthritis were also associated with frailty. The Kappa coefficient of the agreement between these two instruments was 0.18.
Conclusion
It seems that low physical activity is the most important determinant of frailty. Low physical activity and some other factors may be preventable or modifiable and thus serve as clinically relevant targets for intervention.
Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in ‘biological age’ than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL. The authors measured blood cell telomere length in 474,074 participants of UK Biobank providing a major resource for assessing the role of this proposed marker of biological age in human health and disease.
Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.
Background: Both leisure activities and the ε4 allele of the apolipoprotein E ( APOE ε4) have been shown to affect cognitive health. We aimed to determine whether engagement in leisure activities protects against APOE ε4-related cognitive decline.
Methods: We used the cohort data from the Chinese Longitudinal Healthy Longevity Survey. A total of 3,017 participants (mean age of 77.0 years, SD = 9.0; 49.3% female) from 23 provinces of China were recruited in 2008 and were reinterviewed in 2014. We assessed cognitive function using the Mini-Mental State Examination (MMSE). We calculated cognitive decline using subtraction of the MMSE score of each participant in 2008 and 2014. We genotyped a number of APOE ε4 alleles for each participant at baseline and determined the Index of Leisure Activities (ILAs) by summing up the frequency of nine types of typical activities in productive, social, and physical domains. We used ordinal logistic regression models to estimate the effects of leisure activities, APOE ε4, and their interaction on cognitive decline, statistically adjusted for a range of potential confounders.
Results: There were significant associations between APOE ε4 and faster cognitive decline, independent of potential confounders, and between leisure activities and mitigated cognitive decline. The odds ratios were 1.25 (95% CI: 1.03, 1.53) and 0.93 (95% CI: 0.89, 0.97), respectively. We found significant interactions of APOE ε4 with leisure activities with a P -value of 0.018. We also observed interactive effects of subtypes of leisure activities: participants who regularly engaged in productive activities were more likely to reduce the risk of APOE ε4-related cognitive decline.
Conclusion: Our findings provide support for the indication that participating in leisure activities reduces the risk of APOE ε4-related cognitive decline.
Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60–70 years) and Swedish TwinGene participants (n = 10,616, 41–87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10⁻⁸). Many FI-associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on pathways in the brain.
Leukocyte telomere length (LTL) represents a key integrating component of the cumulative effects of environmental, lifestyle, and genetic factors. A question, however, remains on whether LTL can be considered predictive for a longer and healthier life. Within the elderly prospective TRELONG cohort (n = 612), we aimed to investigate LTL as a predictor of longevity and identify the main determinants of LTL among many different factors (physiological and lifestyle characteristics, physical performance and frailty measures, chronic diseases, biochemical measurements and apolipoprotein E genotyping). We found an ever-increasing relationship between LTL quartiles and survival. Hazard ratio analysis showed that for each unit increase in LTL and Short Physical Performance Battery (SPPB) scores, the mortality risk was reduced by 22.41% and 8.78%, respectively. Conversely, male gender, Charlson Comorbidity Index, and age threatened survival, with mortality risk growing by 74.99%, 16.57% and 8.5%, respectively. Determinants of LTL elongation were SPPB scores (OR = 1.1542; p = 0.0066) and years of education (OR = 1.0958; p = 0.0065), while male gender (OR = 0.4388; p = 0.0143) and increased Disease Count Index (OR = 0.6912; p = 0.0066) were determinants of LTL attrition. Longer LTL predicts a significant survival advantage in elderly people. By identifying determinants of LTL elongation, we provided additional knowledge that could offer a potential translation into prevention strategies.
Appendicular lean mass (ALM) is a heritable trait associated with loss of lean muscle mass and strength, or sarcopenia, but its genetic determinants are largely unknown. Here we conducted a genome-wide association study (GWAS) with 450,243 UK Biobank participants to uncover its genetic architecture. A total of 1059 conditionally independent variants from 799 loci were identified at the genome-wide significance level (p < 5 × 10⁻⁹), all of which were also significant at p < 5 × 10–5 in both sexes. These variants explained ~15.5% of the phenotypic variance, accounting for more than one quarter of the total ~50% GWAS-attributable heritability. There was no difference in genetic effect between sexes or among different age strata. Heritability was enriched in certain functional categories, such as conserved and coding regions, and in tissues related to the musculoskeletal system. Polygenic risk score prediction well distinguished participants with high and low ALM. The findings are important not only for lean mass but also for other complex diseases, such as type 2 diabetes, as ALM is shown to be a protective factor for type 2 diabetes.
Cognitive abilities are important predictors of educational and occupational performance, socioeconomic attainment, health, and longevity. Declines in cognitive abilities are linked to impairments in older adults’ everyday functions, but people differ from one another in their rates of cognitive decline over the course of adulthood and old age. Hence, identifying factors that protect against compromised late-life cognition is of great societal interest. The number of years of formal education completed by individuals is positively correlated with their cognitive function throughout adulthood and predicts lower risk of dementia late in life. These observations have led to the propositions that prolonging education might (a) affect cognitive ability and (b) attenuate aging-associated declines in cognition. We evaluate these propositions by reviewing the literature on educational attainment and cognitive aging, including recent analyses of data harmonized across multiple longitudinal cohort studies and related meta-analyses. In line with the first proposition, the evidence indicates that educational attainment has positive effects on cognitive function. We also find evidence that cognitive abilities are associated with selection into longer durations of education and that there are common factors (e.g., parental socioeconomic resources) that affect both educational attainment and cognitive development. There is likely reciprocal interplay among these factors, and among cognitive abilities, during development. Education–cognitive ability associations are apparent across the entire adult life span and across the full range of education levels, including (to some degree) tertiary education. However, contrary to the second proposition, we find that associations between education and aging-associated cognitive declines are negligible and that a threshold model of dementia can account for the association between educational attainment and late-life dementia risk. We conclude that educational attainment exerts its influences on late-life cognitive function primarily by contributing to individual differences in cognitive skills that emerge in early adulthood but persist into older age. We also note that the widespread absence of educational influences on rates of cognitive decline puts constraints on theoretical notions of cognitive aging, such as the concepts of cognitive reserve and brain maintenance. Improving the conditions that shape development during the first decades of life carries great potential for improving cognitive ability in early adulthood and for reducing public-health burdens related to cognitive aging and dementia.
Background
The concept of reserve was established to account for the observation that a given degree of neurodegenerative pathology may result in varying degrees of symptoms in different individuals. There is a large amount of evidence on epidemiological risk and protective factors for neurodegenerative diseases and dementia, yet the biological mechanisms that underpin the protective effects of certain lifestyle and physiological variables remain poorly understood, limiting the development of more effective preventive and treatment strategies. Additionally, different definitions and concepts of reserve exist, which hampers the coordination of research and comparison of results across studies.
Discussion
This paper represents the consensus of a multidisciplinary group of experts from different areas of research related to reserve, including clinical, epidemiological and basic sciences. The consensus was developed during meetings of the working groups of the first International Conference on Cognitive Reserve in the Dementias (24–25 November 2017, Munich, Germany) and the Alzheimer’s Association Reserve and Resilience Professional Interest Area (25 July 2018, Chicago, USA). The main objective of the present paper is to develop a translational perspective on putative mechanisms underlying reserve against neurodegenerative disease, combining evidence from epidemiological and clinical studies with knowledge from animal and basic research. The potential brain functional and structural basis of reserve in Alzheimer’s disease and other brain disorders are discussed, as well as relevant lifestyle and genetic factors assessed in both humans and animal models.
Conclusion
There is an urgent need to advance our concept of reserve from a hypothetical model to a more concrete approach that can be used to improve the development of effective interventions aimed at preventing dementia. Our group recommends agreement on a common dictionary of terms referring to different aspects of reserve, the improvement of opportunities for data sharing across individual cohorts, harmonising research approaches across laboratories and groups to reduce heterogeneity associated with human data, global coordination of clinical trials to more effectively explore whether reducing epidemiological risk factors leads to a reduced burden of neurodegenerative diseases in the population, and an increase in our understanding of the appropriateness of animal models for reserve research.
Physical activity and sleep duration are established risk factors for many diseases, but their aetiology is poorly understood, partly due to relying on self-reported evidence. Here we report a genome-wide association study (GWAS) of device-measured physical activity and sleep duration in 91,105 UK Biobank participants, finding 14 significant loci (7 novel). These loci account for 0.06% of activity and 0.39% of sleep duration variation. Genome-wide estimates of ~ 15% phenotypic variation indicate high polygenicity. Heritability is higher in women than men for overall activity (23 vs. 20%, p = 1.5 × 10⁻⁴) and sedentary behaviours (18 vs. 15%, p = 9.7 × 10⁻⁴). Heritability partitioning, enrichment and pathway analyses indicate the central nervous system plays a role in activity behaviours. Two-sample Mendelian randomisation suggests that increased activity might causally lower diastolic blood pressure (beta mmHg/SD: −0.91, SE = 0.18, p = 8.2 × 10⁻⁷), and odds of hypertension (Odds ratio/SD: 0.84, SE = 0.03, p = 4.9 × 10⁻⁸). Our results advocate the value of physical activity for reducing blood pressure.
Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
Objective:
In line with cognitive reserve theory, higher occupational cognitive complexity is associated with reduced cognitive decline in older adulthood. How and when occupational cognitive complexity first exerts protective effects during the life span remains unclear. We investigated associations between occupational cognitive complexity during early to midadulthood and brain structure and cognition in midlife.
Method:
Participants were 669 adults from the Coronary Artery Risk Development in Young Adults study (aged 18-30 years at baseline, 52% female, 38% Black). We calculated scores reflecting occupational cognitive complexity using Census Occupation Codes (years 10 and 15) and Occupational Information Network (O*NET) data. At year 25, participants had structural brain magnetic resonance imaging, diffusion tensor imaging, and cognitive testing (Rey Auditory Verbal Learning Test, Digit Symbol Substitution Test, Stroop). In adjusted mixed models, we examined associations between occupational cognitive complexity during early to midadulthood and midlife brain structure, specifically gray matter volume and white matter fractional anisotropy, and cognition in midlife (all outcomes converted to z-scores).
Results:
Higher occupational cognitive complexity was associated with greater white matter fractional anisotropy (estimate = 0.10, p = .01) but not gray matter volume. Higher occupational cognitive complexity was associated with better Digit Symbol Substitution Test (estimate = 0.13, p < .001) and Stroop (estimate = 0.09, p = .01) performance but not Rey Auditory Verbal Learning Test performance.
Conclusions:
Occupational cognitive complexity earlier in adulthood is associated with better white matter integrity, processing speed, and executive function in midlife. These associations may capture how occupational cognitive complexity contributes to cognitive reserve. (PsycINFO Database Record
Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
A total of 230 670 women and 190 057 men free from prevalent cancer and cardiovascular disease were included from UK Biobank. Usual walking pace was self-defined as slow, steady/average or brisk. Handgrip strength was assessed by dynamometer. Cox-proportional hazard models were adjusted for social deprivation, ethnicity, employment, medications, alcohol use, diet, physical activity, and television viewing time. Interaction terms investigated whether age, body mass index (BMI), and smoking status modified associations. Over 6.3 years, there were 8598 deaths, 1654 from cardiovascular disease and 4850 from cancer. Associations of walking pace with mortality were modified by BMI. In women, the hazard ratio (HR) for all-cause mortality in slow compared with fast walkers were 2.16 [95% confidence interval (CI): 1.68–2.77] and 1.31 (1.08–1.60) in the bottom and top BMI tertiles, respectively; corresponding HRs for men were 2.01 (1.68–2.41) and 1.41 (1.20–1.66). Hazard ratios for cardiovascular mortality remained above 1.7 across all categories of BMI in men and women, with modest heterogeneity in men. Handgrip strength was associated with cardiovascular mortality in men only (HR tertile 1 vs. tertile 3 = 1.38; 1.18–1.62), without differences across BMI categories, while associations with all-cause mortality were only seen in men with low BMI. Associations for walking pace and handgrip strength with cancer mortality were less consistent.
A simple self-reported measure of slow walking pace could aid risk stratification for all-cause and cardiovascular mortality within the general population.
Mendelian randomization-Egger (MR-Egger) is an analysis method for Mendelian randomization using summarized genetic data. MR-Egger consists of three parts: (1) a test for directional pleiotropy, (2) a test for a causal effect, and (3) an estimate of the causal effect. While conventional analysis methods for Mendelian randomization assume that all genetic variants satisfy the instrumental variable assumptions, the MR-Egger method is able to assess whether genetic variants have pleiotropic effects on the outcome that differ on average from zero (directional pleiotropy), as well as to provide a consistent estimate of the causal effect, under a weaker assumption—the InSIDE (INstrument Strength Independent of Direct Effect) assumption. In this paper, we provide a critical assessment of the MR-Egger method with regard to its implementation and interpretation. While the MR-Egger method is a worthwhile sensitivity analysis for detecting violations of the instrumental variable assumptions, there are several reasons why causal estimates from the MR-Egger method may be biased and have inflated Type 1 error rates in practice, including violations of the InSIDE assumption and the influence of outlying variants. The issues raised in this paper have potentially serious consequences for causal inferences from the MR-Egger approach. We give examples of scenarios in which the estimates from conventional Mendelian randomization methods and MR-Egger differ, and discuss how to interpret findings in such cases.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-017-0255-x) contains supplementary material, which is available to authorized users.
A substantial loss of muscle mass and strength (sarcopenia), a decreased regenerative capacity, and a compromised physical performance are hallmarks of aging skeletal muscle. These changes are typically accompanied by impaired muscle metabolism, including mitochondrial dysfunction and insulin resistance. A challenge in the field of muscle aging is to dissociate the effects of chronological aging per se on muscle characteristics from the secondary influence of lifestyle and disease processes. Remarkably, physical activity and exercise are well-established countermeasures against muscle aging, and have been shown to attenuate age-related decreases in muscle mass, strength, and regenerative capacity, and slow or prevent impairments in muscle metabolism. We posit that exercise and physical activity can influence many of the changes in muscle during aging, and thus should be emphasized as part of a lifestyle essential to healthy aging.
Introduction:
Recognition that an older person has sarcopenia is important because this condition is linked to a range of adverse outcomes. Sarcopenia becomes increasingly common with age, and yet there are few data concerning its descriptive epidemiology in the very old (aged 85 years and above). Our aims were to describe risk factors for sarcopenia and estimate its prevalence and incidence in a British sample of the very old.
Methods:
We used data from two waves (2006/07 and 2009/10) of the Newcastle 85+ Study, a cohort born in 1921 and registered with a Newcastle/North Tyneside general practice. We assessed sarcopenia status using the European Working Group on Sarcopenia in Older People (EWGSOP) definition. Grip strength was measured using a Takei digital dynamometer (Takei Scientific Instruments Ltd., Niigata, Japan), gait speed was calculated from the Timed Up and Go test, and lean mass was estimated using a Tanita-305 body fat analyzer. We used logistic regression to examine associations between risk factors for prevalent sarcopenia at baseline and incident sarcopenia at follow-up.
Results:
European Working Group on Sarcopenia in Older People sarcopenia was present in 21% of participants at baseline [149/719 participants, mean age 85.5 (0.4) years]. Many participants had either slow gait speed or weak grip strength (74.3%), and hence measurement of muscle mass was frequently indicated by the EWGSOP definition. Incidence data were available for 302 participants, and the incident rate was 3.7 cases per 100 person years at risk. Low Standardized Mini-Mental State Examination, lower occupational social class, and shorter duration of education were associated with sarcopenia at baseline, while low muscle mass was associated with incident sarcopenia. Low body mass index (BMI) was a risk factor for both in a graded fashion, with each unit decrease associated with increased odds of prevalent [odds ratio (OR) 1.29, 95% confidence interval (CI): 1.21, 1.37] and incident (OR 1.20, 95% CI: 1.08, 1.33) sarcopenia.
Conclusions:
To our knowledge, this is the first study to describe prevalence and incidence of EWGSOP sarcopenia in the very old. Low BMI was a risk factor for both current and future sarcopenia; indeed, there was some evidence that low BMI may be a reasonable proxy for low lean mass. Overall, the high prevalence of sarcopenia among the very old suggests that this group should be a focus for future research.
Mendelian randomization analyses are often performed using summarized data. The causal estimate from a one-sample analysis (in which data are taken from a single data source) with weak instrumental variables is biased in the direction of the observational association between the risk factor and outcome, whereas the estimate from a two-sample analysis (in which data on the risk factor and outcome are taken from non-overlapping datasets) is less biased and any bias is in the direction of the null. When using genetic consortia that have partially overlapping sets of participants, the direction and extent of bias are uncertain. In this paper, we perform simulation studies to investigate the magnitude of bias and Type 1 error rate inflation arising from sample overlap. We consider both a continuous outcome and a case-control setting with a binary outcome. For a continuous outcome, bias due to sample overlap is a linear function of the proportion of overlap between the samples. So, in the case of a null causal effect, if the relative bias of the one-sample instrumental variable estimate is 10% (corresponding to an F parameter of 10), then the relative bias with 50% sample overlap is 5%, and with 30% sample overlap is 3%. In a case-control setting, if risk factor measurements are only included for the control participants, unbiased estimates are obtained even in a one-sample setting. However, if risk factor data on both control and case participants are used, then bias is similar with a binary outcome as with a continuous outcome. Consortia releasing publicly available data on the associations of genetic variants with continuous risk factors should provide estimates that exclude case participants from case-control samples.
Resistance exercise training is known to be effective in increasing muscle mass in older people. Acute measurement of protein metabolism data has indicated that the magnitude of response may differ between sexes. We compared adaptive responses in muscle mass and function to 18 weeks resistance exercise training in a cohort of older (>65 years) men and women. Resistance exercise training improved knee extensor maximal torque, 4 m walk time, time to complete five chair rises, muscle anatomical cross-sectional area (ACSA) and muscle quality with no effect on muscle fat/water ratio or plasma glucose, insulin, triacylglycerol, IL-6, and TNF-α Differences between sexes were observed for knee extensor maximal torque and muscle quality with greater increases observed in men versus women (P < 0.05). Maximal torque increased by 15.8 ± 10.6% in women and 41.7 ± 25.5% in men, whereas muscle quality increased by 8.8 ± 17.5% in women and by 33.7 ± 25.6% in men. In conclusion, this study has demonstrated a difference in the magnitude of adaptation, of some of the outcome measures employed, in response to 18 weeks of resistance exercise training between men and women. The mechanisms underlying this observation remain to be established.
Higher occupational attainment has previously been associated with increased Alzheimer's disease (AD) neuropathology when individuals are matched for cognitive function, indicating occupation could provide cognitive reserve. We examined whether occupational complexity (OCC) associates with decreased hippocampal volume and increased whole-brain atrophy given comparable cognitive function in middle-aged adults at risk for AD. Participants (n = 323) underwent structural MRI, cognitive evaluation, and work history assessment. Three complexity ratings (work with data, people, and things) were obtained, averaged across up to 3 reported jobs, weighted by years per job, and summed to create a composite OCC rating. Greater OCC was associated with decreased hippocampal volume and increased whole-brain atrophy when matched for cognitive function; results remained substantively unchanged after adjusting for several demographic, AD risk, vascular, mental health, and socioeconomic characteristics. These findings suggest that, in people at risk for AD, OCC may confer resilience to the adverse effects of neuropathology on cognition.
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Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.
Genome-wide association studies, which typically report regression coefficients summarizing the associations of many genetic variants with various traits, are potentially a powerful source of data for Mendelian randomization investigations. We demonstrate how such coefficients from multiple variants can be combined in a Mendelian randomization analysis to estimate the causal effect of a risk factor on an outcome. The bias and efficiency of estimates based on summarized data are compared to those based on individual-level data in simulation studies. We investigate the impact of gene-gene interactions, linkage disequilibrium, and 'weak instruments' on these estimates. Both an inverse-variance weighted average of variant-specific associations and a likelihood-based approach for summarized data give similar estimates and precision to the two-stage least squares method for individual-level data, even when there are gene-gene interactions. However, these summarized data methods overstate precision when variants are in linkage disequilibrium. If the P-value in a linear regression of the risk factor for each variant is less than 1×10-5, then weak instrument bias will be small. We use these methods to estimate the causal association of low-density lipoprotein cholesterol (LDL-C) on coronary artery disease using published data on five genetic variants. A 30% reduction in LDL-C is estimated to reduce coronary artery disease risk by 67% (95% CI: 54% to 76%). We conclude that Mendelian randomization investigations using summarized data from uncorrelated variants are similarly efficient to those using individual-level data, although the necessary assumptions cannot be so fully assessed.
The European Working Group on Sarcopenia in Older People (EWGSOP) developed a practical clinical definition and consensus diagnostic criteria for age-related sarcopenia. EWGSOP included representatives from four participant organisations, i.e. the European Geriatric Medicine Society, the European Society for Clinical Nutrition and Metabolism, the International Association of Gerontology and Geriatrics—European Region and the International Association of Nutrition and Aging. These organisations endorsed the findings in the final document.
The group met and addressed the following questions, using the medical literature to build evidence-based answers: (i) What is sarcopenia? (ii) What parameters define sarcopenia? (iii) What variables reflect these parameters, and what measurement tools and cut-off points can be used? (iv) How does sarcopenia relate to cachexia, frailty and sarcopenic obesity?
For the diagnosis of sarcopenia, EWGSOP recommends using the presence of both low muscle mass + low muscle function (strength or performance). EWGSOP variously applies these characteristics to further define conceptual stages as ‘presarcopenia’, ‘sarcopenia’ and ‘severe sarcopenia’. EWGSOP reviewed a wide range of tools that can be used to measure the specific variables of muscle mass, muscle strength and physical performance. Our paper summarises currently available data defining sarcopenia cut-off points by age and gender; suggests an algorithm for sarcopenia case finding in older individuals based on measurements of gait speed, grip strength and muscle mass; and presents a list of suggested primary and secondary outcome domains for research.
Once an operational definition of sarcopenia is adopted and included in the mainstream of comprehensive geriatric assessment, the next steps are to define the natural course of sarcopenia and to develop and define effective treatment.
The concept of reserve has been proposed to account for the disjunction between the degree of brain damage and its clinical outcome. This paper attempts to produce a coherent theoretical account the reserve in general and of cognitive reserve in particular. It reviews epidemiologic data supporting the concept of cognitive reserve, with a particular focus of its implications for aging and dementia. It then focuses on methodologic issues that are important when attempting to elucidate the neural underpinnings of cognitive reserve using imaging studies, and reviews some of our group's work in order to demonstrate these issues.
Frailty can be measured in relation to the accumulation of deficits using a frailty index. A frailty index can be developed from most ageing databases. Our objective is to systematically describe a standard procedure for constructing a frailty index.
This is a secondary analysis of the Yale Precipitating Events Project cohort study, based in New Haven CT. Non-disabled people aged 70 years or older (n = 754) were enrolled and re-contacted every 18 months. The database includes variables on function, cognition, co-morbidity, health attitudes and practices and physical performance measures. Data came from the baseline cohort and those available at the first 18-month follow-up assessment.
Procedures for selecting health variables as candidate deficits were applied to yield 40 deficits. Recoding procedures were applied for categorical, ordinal and interval variables such that they could be mapped to the interval 0-1, where 0 = absence of a deficit, and 1= full expression of the deficit. These individual deficit scores were combined in an index, where 0= no deficit present, and 1= all 40 deficits present. The values of the index were well fit by a gamma distribution. Between the baseline and follow-up cohorts, the age-related slope of deficit accumulation increased from 0.020 (95% confidence interval, 0.014-0.026) to 0.026 (0.020-0.032). The 99% limit to deficit accumulation was 0.6 in the baseline cohort and 0.7 in the follow-up cohort. Multivariate Cox analysis showed the frailty index, age and sex to be significant predictors of mortality.
A systematic process for creating a frailty index, which relates deficit accumulation to the individual risk of death, showed reproducible properties in the Yale Precipitating Events Project cohort study. This method of quantifying frailty can aid our understanding of frailty-related health characteristics in older adults.
The cerebral reserve hypothesis is a heuristic concept used to explain apparent protection from the onset of cerebral disease and/or cognitive decline in old age. A significant obstacle when investigating the reserve hypothesis is the absence of baseline data with which to compare current cognitive status. We tested the influence of three hypothesized proxies of reserve (education, head size and occupational attainment [OCC]) in 92 volunteers born in 1921, whose cognitive function was measured at age 11 and 79 years, and who underwent brain MRI. The association between each proxy and old age cognitive function was tested, adjusting for variance contributed by childhood mental ability and detrimental age-related pathological changes measured using MRI. The results showed that education and OCC, but not total intracranial volume (TICV), contribute to cerebral reserve and help retain cognitive function in old age. Education was found to contribute between 5 and 6% of the variance found in old age memory function but was found to have no significant association with reasoning abilities. OCC was found to contribute around 5% of the variance found in old age memory function and between 6 and 8% of the variance found in old age reasoning abilities. We conclude that the intellectual challenges experienced during life, such as education and occupation, accumulate reserve and allow cognitive function to be maintained in old age.
In conventional epidemiology confounding of the exposure of interest with lifestyle or socioeconomic factors, and reverse causation whereby disease status influences exposure rather than vice versa, may invalidate causal interpretations of observed associations. Conversely, genetic variants should not be related to the confounding factors that distort associations in conventional observational epidemiological studies. Furthermore, disease onset will not influence genotype. Therefore, it has been suggested that genetic variants that are known to be associated with a modifiable (nongenetic) risk factor can be used to help determine the causal effect of this modifiable risk factor on disease outcomes. This approach, mendelian randomization, is increasingly being applied within epidemiological studies. However, there is debate about the underlying premise that associations between genotypes and disease outcomes are not confounded by other risk factors. We examined the extent to which genetic variants, on the one hand, and nongenetic environmental exposures or phenotypic characteristics on the other, tend to be associated with each other, to assess the degree of confounding that would exist in conventional epidemiological studies compared with mendelian randomization studies.
We estimated pairwise correlations between nongenetic baseline variables and genetic variables in a cross-sectional study comparing the number of correlations that were statistically significant at the 5%, 1%, and 0.01% level (alpha = 0.05, 0.01, and 0.0001, respectively) with the number expected by chance if all variables were in fact uncorrelated, using a two-sided binomial exact test. We demonstrate that behavioural, socioeconomic, and physiological factors are strongly interrelated, with 45% of all possible pairwise associations between 96 nongenetic characteristics (n = 4,560 correlations) being significant at the p < 0.01 level (the ratio of observed to expected significant associations was 45; p-value for difference between observed and expected < 0.000001). Similar findings were observed for other levels of significance. In contrast, genetic variants showed no greater association with each other, or with the 96 behavioural, socioeconomic, and physiological factors, than would be expected by chance.
These data illustrate why observational studies have produced misleading claims regarding potentially causal factors for disease. The findings demonstrate the potential power of a methodology that utilizes genetic variants as indicators of exposure level when studying environmentally modifiable risk factors.
Introduction:
Lifetime exposure to occupational complexity is linked to late-life cognition, and may affect benefits of preventive interventions.
Methods:
In the 2-year multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), we investigated, through post hoc analyses (N = 1026), the association of occupational complexity with cognition. Occupational complexity with data, people, and substantive complexity were classified through the Dictionary of Occupational Titles.
Results:
Higher levels of occupational complexity were associated with better baseline cognition. Measures of occupational complexity had no association with intervention effects on cognition, except for occupational complexity with data, which was associated with the degree of intervention-related gains for executive function.
Discussion:
In older adults at increased risk for dementia, higher occupational complexity is associated with better cognition. The cognitive benefit of the FINGER intervention did not vary significantly among participants with different levels of occupational complexity. These exploratory findings require further testing in larger studies.
Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive.
We performed a large-scale genome-wide association study of occupational attainment with 248 847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level.
We identified 30 significant loci (P < 5 × 10−8); 12 were novel variants, not associated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986 and rs1627527. The single nucleotide polymorphism-based heritability was estimated to be 8.5% (standard error of the mean = 0.004) and partitioned heritability was enriched in the CNS and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction and neuropsychiatric disorders. In two-sample Mendelian randomization analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.65–0.92 in inverse variance weighted method; OR = 0.73, 95% CI = 0.57–0.92 in the weighted median method]. This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic single nucleotide polymorphisms (OR = 0.72, 95% CI = 0.57–0.91 in the inverse variance weighted method; OR = 0.72, 95% CI = 0.53–0.97 in the weighted median method). Multivariable Mendelian randomization confirmed that occupational attainment had an independent effect on the risk for Alzheimer’s disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54–0.95 in the inverse variance weighted method; OR = 0.68, 95% CI = 0.48–0.97 in the weighted median method).
Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.
The aging of the population has great social and economic effects because it is characterized by a gradual loss in physiological integrity, resulting in functional decline, thereby loss of ability to move independently. Telomeres, the hallmarks of biological aging, play a protective role in both cell death and aging. Critically short telomeres give rise to a metabolically active cell that is unable to repair damage or divide, thereby leading to aging. Lifestyle factors such as physical activity (PA) and nutrition could be associated with telomere length (TL). Indeed, regular PA and healthy nutrition as integral parts of our lifestyle can slow down telomere shortening, thereby delaying aging. In this context, the present comprehensive review summarizes the data from recent literature on the association of PA and nutrition with TL.
Purpose:
Physical activity (PA) is known to improve cognitive and brain function, but debate continues regarding the consistency and magnitude of its effects, populations and cognitive domains most affected, and parameters necessary to achieve the greatest improvements (e.g., dose).
Methods:
In this umbrella review conducted in part for the 2018 Health and Human Services Physical Activity Guidelines for Americans Advisory Committee, we examined whether PA interventions enhance cognitive and brain outcomes across the life span, as well as in populations experiencing cognitive dysfunction (e.g., schizophrenia). Systematic reviews, meta-analyses, and pooled analyses were used. We further examined whether engaging in greater amounts of PA is associated with a reduced risk of developing cognitive impairment and dementia in late adulthood.
Results:
Moderate evidence from randomized controlled trials indicates an association between moderate- to vigorous-intensity PA and improvements in cognition, including performance on academic achievement and neuropsychological tests, such as those measuring processing speed, memory, and executive function. Strong evidence demonstrates that acute bouts of moderate- to vigorous-intensity PA have transient benefits for cognition during the postrecovery period after exercise. Strong evidence demonstrates that greater amounts of PA are associated with a reduced risk of developing cognitive impairment, including Alzheimer's disease. The strength of the findings varies across the life span and in individuals with medical conditions influencing cognition.
Conclusions:
There is moderate-to-strong support that PA benefits cognitive functioning during early and late periods of the life span and in certain populations characterized by cognitive deficits.
Cognitive ageing research examines the cognitive abilities that are preserved and/or those that decline with advanced age. There is great individual variability in cognitive ageing trajectories. Some older adults show little decline in cognitive ability compared with young adults and are thus termed ‘optimally ageing’. By contrast, others exhibit substantial cognitive decline and may develop dementia. Human neuroimaging research has led to a number of important advances in our understanding of the neural mechanisms underlying these two outcomes. However, interpreting the age-related changes and differences in brain structure, activation and functional connectivity that this research reveals is an ongoing challenge. Ambiguous terminology is a major source of difficulty in this venture. Three terms in particular — compensation, maintenance and reserve — have been used in a number of different ways, and researchers continue to disagree about the kinds of evidence or patterns of results that are required to interpret findings related to these concepts. As such inconsistencies can impede progress in both theoretical and empirical research, here, we aim to clarify and propose consensual definitions of these terms.
Several concepts, which in the aggregate get might be used to account for "resilience" against age- and disease-related changes, have been the subject of much research. These include brain reserve, cognitive reserve, and brain maintenance. However, different investigators have use these terms in different ways, and there has never been an attempt to arrive at consensus on the definition of these concepts. Furthermore, there has been confusion regarding the measurement of these constructs and the appropriate ways to apply them to research. Therefore the reserve, resilience, and protective factors professional interest area, established under the auspices of the Alzheimer's Association, established a whitepaper workgroup to develop consensus definitions for cognitive reserve, brain reserve, and brain maintenance. The workgroup also evaluated measures that have been used to implement these concepts in research settings and developed guidelines for research that explores or utilizes these concepts. The workgroup hopes that this whitepaper will form a reference point for researchers in this area and facilitate research by supplying a common language.
Longer human lives have led to a global burden of late-life disease. However, some older people experience little ill health, a trait that should be extended to the general population. Interventions into lifestyle, including increased exercise and reduction in food intake and obesity, can help to maintain healthspan. Altered gut microbiota, removal of senescent cells, blood factors obtained from young individuals and drugs can all improve late-life health in animals. Application to humans will require better biomarkers of disease risk and responses to interventions, closer alignment of work in animals and humans, and increased use of electronic health records, biobank resources and cohort studies.
College graduates live much healthier lives than those with less education, but research has yet to document with certainty the sources of this disparity. This study examines why U.S. young adults who earn college degrees exhibit healthier behaviors than those with less education. I use data from the National Longitudinal Study of Adolescent to Adult Health, which offers information on education and health behaviors across adolescence and young adulthood (N = 14,265). Accounting for selection into college, degree attainment substantially reduces the associations between college degree attainment and health behaviors, but college degree attainment demonstrates a strong causal effect on young adult health. Financial, occupational, social, cognitive, and psychological resources explain less than half of the association between college degree attainment and health behaviors. The healthier behaviors of college graduates are the result of sorting into educational attainment, embedding of human capital, and mechanisms other than socioeconomic and psychosocial resources.
Background:
Physical activity (PA) reduces the rate of mobility disability, compared with health education (HE), in at risk older adults. It is important to understand aspects of performance contributing to this benefit.
Objective:
To evaluate intervention effects on tertiary physical performance outcomes.
Design:
The Lifestyle Interventions and Independence for Elders (LIFE) was a multi-centered, single-blind randomized trial of older adults.
Setting:
Eight field centers throughout the United States.
Participants:
1635 adults aged 78.9 ± 5.2 years, 67.2% women at risk for mobility disability (Short Physical Performance Battery [SPPB] <10).
Interventions:
Moderate PA including walking, resistance and balance training compared with HE consisting of topics relevant to older adults.
Outcomes:
Grip strength, SPPB score and its components (balance, 4 m gait speed, and chair-stands), as well as 400 m walking speed.
Results:
Total SPPB score was higher in PA versus HE across all follow-up times (overall P = .04) as was the chair-stand component (overall P < .001). No intervention effects were observed for balance (overall P = .12), 4 m gait speed (overall P = .78), or grip strength (overall P = .62). However, 400 m walking speed was faster in PA versus HE group (overall P =<.001). In separate models, 29% of the rate reduction of major mobility disability in the PA versus HE group was explained by change in SPPB score, while 39% was explained by change in the chair stand component.
Conclusion:
Lower extremity performance (SPPB) was significantly higher in the PA compared with HE group. Changes in chair-stand score explained a considerable portion of the effect of PA on the reduction of major mobility disability-consistent with the idea that preserving muscle strength/power may be important for the prevention of major mobility disability.
In this study, the authors evaluated whether the association between low educational level and increased risk of Alzheimer's disease (AD) and dementia may be explained by occupation-based socioeconomic status (SES). A cohort of 931 nondemented subjects aged ≥75 years from the Kungsholmen Project, Stockholm, Sweden, was followed for 3 years between 1987 and 1993. A total of 101 incident cases of dementia, 76 involving AD, were detected. Less-educated subjects had an adjusted relative risk of developing AD of 3.4 (95% confidence interval: 2.0, 6.0), and subjects with lower SES had an adjusted relative risk of 1.6 (95% confidence interval: 1.0, 2.5). When both education and SES were introduced into the same model, only education remained significantly associated with AD. Combinations of low education with low or high SES were associated with similar increased risks of AD, but well-educated subjects with low SES were not at high risk. Low SES at 20 years of age, even when SES was high at age 40 or 60 years, was associated with increased risk; however, this increase disappeared when education was entered into the model. In conclusion, the association between low education and increased AD risk was not mediated by adult SES or socioeconomic mobility. This suggests that early life factors may be relevant.
Objective
To examine the relation of midlife raised blood pressure and serum cholesterol concentrations to Alzheimer's disease in later life.
Design
Prospective, population based study.
Setting
Populations of Kuopio and Joensuu, eastern Finland.
Participants
Participants were derived from random, population based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average of 21 years' follow up, a total of 1449 (73%) participants aged 65–79 took part in the re-examination in 1998.
Main outcome measures
Midlife blood pressure and cholesterol concentrations and development of Alzheimer's disease in later life.
Results
People with raised systolic blood pressure (≥160 mm Hg) or high serum cholesterol concentration (≥6.5 mmol/l) in midlife had a significantly higher risk of Alzheimer's disease in later life, even after adjustment for age, body mass index, education, vascular events, smoking status, and alcohol consumption, than those with normal systolic blood pressure (odds ratio 2.3, 95% confidence interval 1.0 to 5.5) or serum cholesterol (odds ratio 2.1, 1.0 to 4.4). Participants with both of these risk factors in midlife had a significantly higher risk of developing Alzheimer's disease than those with either of the risk factors alone (odds ratio 3.5, 1.6 to 7.9). Diastolic blood pressure in midlife had no significant effect on the risk of Alzheimer's disease.
Conclusion
Raised systolic blood pressure and high serum cholesterol concentration, and in particular the combination of these risks, in midlife increase the risk of Alzheimer's disease in later life.
What is already known on this topic
What is already known on this topic
Vascular risk factors may play an important part as risk factors for Alzheimer's disease No population based studies have evaluated prospectively the impact of both midlife blood pressure and cholesterol concentration in both men and women on the subsequent development of Alzheimer's disease
What this study adds
What this study adds
Raised systolic blood pressure and high serum cholesterol concentration, and in particular the combination of these risks, in midlife increased the risk of Alzheimer's disease in later life Raised systolic blood pressure and hypercholesterolaemia may have a role in the pathogenesis of Alzheimer's disease; more emphasis should be placed on identification and appropriate treatment of these conditions
To assess the impact of socioeconomic position (SEP) over life on a measure of frailty in old age.
This is a cross-sectional population study of people aged 70 years and more in which 2350 respondents were interviewed in 2008 to 2010. The relationships between different indicators of SEP (childhood standard of living, level of education, occupational class, and current affluence) and quartiles of a frailty index including 43 variables were assessed in ordinal regression models adjusted for potential confounders.
Mean age of the population was 83.3 ± 7.5 years, with 59.4% of women. The mean value of the frailty index was 0.19 ± 0.13, with values ranging between 0 and 0.65. All periods of social disadvantage were associated with increasing frailty in bivariate analysis. In multivariate analysis, a poor level financial security in the old age was the SEP indicator the most strongly associated with frailty (odds ratio [OR]: 2.81, 95% confidence interval [CI]: 2.20-3.59), followed by a low level of education (OR: 1.45, 95% CI: 1.17-1.80) and occupation during active life (OR: 1.38, 95% CI: 1.06-1.79).
Socioeconomic inequalities over life affect health capital in old age. The most important risk factor identified in this study, contemporary financial difficulties, was also the most accessible to prevention.
Copyright © 2015 Elsevier Inc. All rights reserved.
Background:
There is increasing evidence that physical activity supports healthy ageing. Exercise is helpful for cardiovascular, respiratory and musculoskeletal systems, among others. Aerobic activity, in particular, improves cardiovascular fitness and, based on recently reported findings, may also have beneficial effects on cognition among older people.
Objectives:
To assess the effect of aerobic physical activity, aimed at improving cardiorespiratory fitness, on cognitive function in older people without known cognitive impairment.
Search methods:
We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, the Cochrane Controlled Trials Register (CENTRAL) (all years to Issue 2 of 4, 2013), MEDLINE (Ovid SP 1946 to August 2013), EMBASE (Ovid SP 1974 to August 2013), PEDro, SPORTDiscus, Web of Science, PsycINFO (Ovid SP 1806 to August 2013), CINAHL (all dates to August 2013), LILACS (all dates to August 2013), World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch), ClinicalTrials.gov (https://clinicaltrials.gov) and Dissertation Abstracts International (DAI) up to 24 August 2013, with no language restrictions.
Selection criteria:
We included all published randomised controlled trials (RCTs) comparing the effect on cognitive function of aerobic physical activity programmes with any other active intervention, or no intervention, in cognitively healthy participants aged over 55 years.
Data collection and analysis:
Two review authors independently extracted the data from included trials. We grouped cognitive outcome measures into eleven categories covering attention, memory, perception, executive functions, cognitive inhibition, cognitive speed and motor function. We used the mean difference (or standardised mean difference) between groups as the measure of the treatment effect and synthesised data using a random-effects model. We conducted separate analyses to compare aerobic exercise interventions with no intervention and with other exercise, social or cognitive interventions. Also, we performed analyses including only trials in which an increase in the cardiovascular fitness of participants had been demonstrated.
Main results:
Twelve trials including 754 participants met our inclusion criteria. Trials were from eight to 26 weeks in duration.We judged all trials to be at moderate or high risk of bias in at least some domains. Reporting of some risk of bias domains was poor.Our analyses comparing aerobic exercise to any active intervention showed no evidence of benefit from aerobic exercise in any cognitive domain. This was also true of our analyses comparing aerobic exercise to no intervention. Analysing only the subgroup of trials in which cardiorespiratory fitness improved in the aerobic exercise group showed that this improvement did not coincide with improvements in any cognitive domains assessed. Our subgroup analyses of aerobic exercise versus flexibility or balance interventions also showed no benefit of aerobic exercise in any cognitive domain.Dropout rates did not differ between aerobic exercise and control groups. No trial reported on adverse effects.Overall none of our analyses showed a cognitive benefit from aerobic exercise even when the intervention was shown to lead to improved cardiorespiratory fitness.
Authors' conclusions:
We found no evidence in the available data from RCTs that aerobic physical activities, including those which successfully improve cardiorespiratory fitness, have any cognitive benefit in cognitively healthy older adults. Larger studies examining possible moderators are needed to confirm whether or not aerobic training improves cognition.
Morbidity and mortality are greater among socially disadvantaged racial/ethnic groups and those of lower socioeconomic status (SES). Greater chronic stress exposure in disadvantaged groups may contribute to this by accelerating cellular aging, indexed by shorter age-adjusted telomere length. While studies consistently relate shorter leukocyte telomere length (LTL) to stress, the few studies, mostly from the UK, examining associations of LTL with SES have been mixed. The current study examined associations between educational attainment and LTL among 2599 high-functioning black and white adults age 70-79 from the Health, Aging and Body Composition Study. Multiple regression analyses tested associations of race/ethnicity, educational attainment and income with LTL, adjusting for potential confounders. Those with only a high school education had significantly shorter mean LTL (4806basepairs) than those with post-high school education (4926basepairs; B=125, SE=47.6, p=.009). A significant interaction of race and education (B=207.8, SE=98.7, p=.035) revealed more beneficial effects of post-high school education for blacks than for whites. Smokers had shorter LTL than non-smokers, but the association of education and LTL remained significant when smoking was covaried (B=119.7, SE=47.6, p=.012). While higher income was associated with longer LTL, the effect was not significant (p>.10). This study provides the first demonstration of an association between educational attainment and LTL in a US population where higher education appears to have a protective effect against telomere shortening, particularly in blacks.
This was a prospective study of dementia to elucidate mechanisms of disease risk factors amenable to modification and specifically to determine whether midlife cognitive and physical leisure activities are associated with delayed onset or reduced risk of dementia within older male twin pairs.
The co-twin control design used prospectively collected exposure information to predict risk of dementia 20 to 40 years later. The subjects were community-dwelling and nursing home residents living throughout the continental United States. We studied 147 male twin-pairs who were discordant for dementia or age of dementia onset and were members of the National Academy of Sciences-National Research Council Twin Registry of World War II veterans and participants in the Duke Twins Study of Memory in Aging. The main outcome measure was diagnosed dementia by using a two-stage screen and full clinical evaluation. Conditional odds ratios were estimated for the association between midlife leisure activities and late-life dementia.
Greater midlife cognitive activity was associated with a 26% risk reduction for dementia onset. Protective effects were most robust in monozygotic twin pairs, where genetic and early-life influences were most tightly controlled, and for activities that were often cognitive and social in nature. Cognitive activity was particularly protective among monozygotic twin pairs carrying the apolipoprotein E epsilon4 allele, with a 30% risk reduction. Midlife physical activity did not modify dementia risk.
Participation in a range of cognitively and socially engaging activities in midlife reduced risk for dementia and AD in twins discordant for onset, particularly among twin pairs at elevated genetic risk, and might be indicative of an enriched environment.
Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
Observational epidemiological studies suffer from many potential biases, from confounding and from reverse causation, and this limits their ability to robustly identify causal associations. Several high-profile situations exist in which randomized controlled trials of precisely the same intervention that has been examined in observational studies have produced markedly different findings. In other observational sciences, the use of instrumental variable (IV) approaches has been one approach to strengthening causal inferences in non-experimental situations. The use of germline genetic variants that proxy for environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies. The method has been referred to as 'Mendelian randomization', and can be considered as analogous to randomized controlled trials. This paper outlines Mendelian randomization, draws parallels with IV methods, provides examples of implementation of the approach and discusses limitations of the approach and some methods for dealing with these.
Job characteristics may influence dementia risk, but some types of job complexity remain to be examined. Twin studies provide a useful methodology to examine job differences between pairs who share many environmental and genetic influences.
Members of the NAS-NRC Twins Registry of World War II Veterans received a clinical evaluation for dementia and had job ratings from the Dictionary of Occupational Titles.
Cotwin-control models (n = 220 pairs) indicated lower dementia risk with greater job demands of reasoning, mathematics, language, and vocational training, with comparable results in case-control models (n=425 cases). These effects were significant among twin pairs discordant for 6 or more years, but not among those discordant between 3-5 years. Results were similar for Alzheimer's disease, and main effects were not further explained by zygosity or apolipoprotein E genotype.
Jobs that utilize data, academic skills, and extensive vocational training may protect against dementia; however, in twin pairs these effects only emerged among individuals who remained free of dementia several years after onset in their sibling.