Educational Influences on Late-Life Health: Genetic Propensity and Attained Education.

OBJECTIVES: The educational gradient in late-life health is well established. Despite this, there are still ambiguities concerning the role of underlying confounding by genetic influences and gene-environment (GE) interplay. Here, we investigate the role of educational factors (attained and genetic propensities) on health and mortality in late life using genetic propensity for educational attainment (as measured by a genome-wide polygenic score, PGSEdu) and attained education. METHODS: By utilizing genetically informative twin data from the Swedish Twin Registry (n = 14,570), we investigated influences of the educational measures, familial confounding as well as the possible presence of passive GE correlation on both objective and subjective indicators of late-life health, that is, the Frailty Index, Multimorbidity, Self-rated health, cardiovascular disease, and all-cause mortality. RESULTS: Using between-within models to adjust for shared familial factors, we found that the relationship between educational level and health and mortality later in life persisted despite controlling for familial confounding. PGSEdu and attained education both uniquely predicted late-life health and mortality, even when mutually adjusted. Between-within models of PGSEdu on the health outcomes in dizygotic twins showed weak evidence for passive GE correlation (prGE) in the education-health relationship. DISCUSSION: Both genetic propensity to education and attained education are (partly) independently associated with health in late life. These results lend further support for a causal education-health relationship but also raise the importance of genetic contributions and GE interplay.

Is Frailty Different in Younger Adults Compared to Old? Prevalence, Characteristics, and Risk Factors of Early-Life and Late-Life Frailty in Samples from Sweden and UK.

INTRODUCTION: Although frailty is commonly considered as a syndrome of old individuals, recent studies show that it can affect younger adults, too. Whether and how frailty differs in younger adults compared to old is however unknown. To this end, we analyzed the prevalence, characteristics, and risk factors of early-life (aged <65) and late-life (aged ≥65) frailty. METHODS: We analyzed individuals in the UK Biobank (N = 405,123) and Swedish Screening Across the Lifespan Twin (SALT; N = 43,641) study. Frailty index (FI) scores ≥0.21 were used to demarcate frailty. Characteristics of early-life versus late-life frailty were analyzed by collating the FI items (deficits) into domains and comparing the domain scores between younger and older frail individuals. Logistic regression was used to assess the risk factors of frailty. RESULTS: The pooled prevalence rates of frailty were 10.3% (95% confidence interval [CI]: 2.7-32.7), 14.4% (95% CI: 4.5-37.2), 19.2% (95% CI: 2.5-68.5) in individuals aged ≤55, 55-64, 65-74, respectively. Younger frail adults (aged <65) had higher scores in immunological, mental wellbeing, and pain-related domains, whereas older frail adults (aged ≥65) had higher scores in cardiometabolic, cancer, musculoskeletal, and sensory-related domains. Higher age, female sex, smoking, lower alcohol consumption, lower education, obesity, overweight, low income, and maternal smoking were similarly associated with the risk of early-life and late-life frailty. CONCLUSION: Frailty is prevalent also in younger age groups (aged <65) but differs in some of its characteristics from the old. The risk factors of frailty are nevertheless largely similar for early-life and late-life frailty.

Impact of the COVID-19 pandemic on Swedish adults aged 77 years and older: Age differences in lifestyle changes.

AIMS: This study aimed to describe the impact of the COVID-19 pandemic on lifestyle and social activities among older adults in Sweden, with a special focus on differences between the 'younger old' (aged 77-84) and 'older old' (aged 85-109). METHODS: This study is based on a nationally representative sample of older adults (aged ⩾77 years) in Sweden (SWEOLD). Data were collected between May 2021 and April 2022, when many recommendations were removed but the virus was still classified as a public health disease. We studied occurrences and differences between the two age groups in several lifestyle factors and social activities. RESULTS: The younger old displayed larger changes in lifestyles because of the pandemic than the older old. Most changes were found in social interactions with family. CONCLUSIONS: Our results highlight the large heterogeneity within the Swedish population aged ⩾77 years, and that the younger old experienced a bigger lifestyle change than the older old. Previous activity levels might be important to consider in order to understand how regulations may affect the older population. Finally, our findings indicate large age differences in Internet use, which require attention to prevent digital exclusion of an already vulnerable group.

Influences of genetically predicted and attained education on geographic mobility and their association with mortality.

INTRODUCTION: Both educational attainment and genetic propensity to education (PGSEdu) have been associated with geographic mobility. Socioeconomic conditions are, in turn, associated with individuals' health. Geographic mobility could therefore lead to better health for some since it could provide better opportunities, like education. Our aim was to study how attained education and genetic predisposition for higher education are related to geographic mobility, and how they affect the association between geographic mobility and mortality. METHODS: We used data from the Swedish Twin Registry (twins born 1926-1955; n = 14,211) in logistic regression models to test if attained education and PGSEdu predicted geographic mobility. Cox regression models were then performed to test if geographic mobility, attained education, and PGSEdu were associated with mortality. RESULTS: The results show that both attained education and PGSEdu predicted geographic mobility, in both independent and joint effect models, with higher education associated with higher mobility. Geographic mobility was associated with lower mortality in the independent effect model, but joint effect models showed that this association was completely explained by attained education. CONCLUSIONS: To conclude, both attained education and PGSEdu were associated with geographic mobility. Moreover, attained education explained the relationship between geographic mobility and mortality.

Financial strain moderates genetic influences on self-rated health: support for diathesis-stress model of gene-environment interplay.

Data from the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium were used to examine predictions of different models of gene-by-environment interaction to understand how genetic variance in self-rated health (SRH) varies at different levels of financial strain. A total of 11,359 individuals from 10 twin studies in Australia, Sweden, and the United States contributed relevant data, including 2,074 monozygotic and 2,623 dizygotic twin pairs. Age ranged from 22 to 98 years, with a mean age of 61.05 (SD = 13.24). A factor model was used to create a harmonized measure of financial strain across studies and items. Twin analyses of genetic and environmental variance for SRH incorporating age, age2, sex, and financial strain moderators indicated significant financial strain moderation of genetic influences on self-rated health. Moderation results did not differ across sex or country. Genetic variance for SRH increased as financial strain increased, matching the predictions of the diathesis-stress and social comparison models for components of variance. Under these models, environmental improvements would be expected to reduce genetically based health disparities.

Sex differences in genetic and environmental influences on frailty and its relation to body mass index and education.

Frailty is influenced by numerous genetic and environmental factors. However, sex differences in how these factors affect frailty, and the gene-environment interplay among frailty and two of its well-established risk factors, unhealthy body mass index (BMI) and low education, are less clear. In a large sample of 42,994 Swedish twins, we used structural equation models to estimate the genetic (heritability) and environmental sources of variance in frailty, defined as the frailty index (FI), separately in men and women. Genetic and individual-specific environmental factors contributed approximately equally to the FI variance. The heritability of FI was slightly, but significantly, higher in women (52%) than in men (45%), yet we found only weak-to-no indication of different sources of genetic variance influencing frailty across sexes. We observed a small-to-moderate genetic overlap between FI and BMI, and that the correlation between FI and education was largely explained by environmental factors common to twins in a pair. Additionally, genetic factors accounted for more of FI variation at both low and high BMI levels, with similar patterns in both sexes. In conclusion, the twin-based heritability of frailty is higher in women than in men, and different mechanisms may underlie the associations of frailty with BMI and education.

Epigenome-wide association study of level and change in cognitive abilities from midlife through late life.

BACKGROUND: Epigenetic mechanisms are important in aging and may be involved in late-life changes in cognitive abilities. We conducted an epigenome-wide association study of leukocyte DNA methylation in relation to level and change in cognitive abilities, from midlife through late life in 535 Swedish twins. RESULTS: Methylation levels were measured with the Infinium Human Methylation 450 K or Infinium MethylationEPIC array, and all sites passing quality control on both arrays were selected for analysis (n = 250,816). Empirical Bayes estimates of individual intercept (age 65), linear, and quadratic change were obtained from latent growth curve models of cognitive traits and used as outcomes in linear regression models. Significant sites (p < 2.4 × 10-7) were followed up in between-within twin pair models adjusting for familial confounding and full-growth modeling. We identified six significant associations between DNA methylation and level of cognitive abilities at age 65: cg18064256 (PPP1R13L) with processing speed and spatial ability; cg04549090 (NRXN3) with spatial ability; cg09988380 (POGZ), cg25651129 (-), and cg08011941 (ENTPD8) with working memory. The genes are involved in neuroinflammation, neuropsychiatric disorders, and ATP metabolism. Within-pair associations were approximately half that of between-pair associations across all sites. In full-growth curve models, associations between DNA methylation and cognitive level at age 65 were of small effect sizes, and associations between DNA methylation and longitudinal change in cognitive abilities of very small effect sizes. CONCLUSIONS: Leukocyte DNA methylation was associated with level, but not change in cognitive abilities. The associations were substantially attenuated in within-pair analyses, indicating they are influenced in part by genetic factors.

Drivers of Frailty from Adulthood into Old Age: Results from a 27-Year Longitudinal Population-Based Study in Sweden.

BACKGROUND: Frailty is a strong predictor of adverse outcomes. However, longitudinal drivers of frailty are not well understood. This study aimed at investigating the longitudinal trajectories of a frailty index (FI) from adulthood to late life and identifying the factors associated with the level and rate of change in FI. METHODS: An age-based latent growth curve analysis was performed in the Swedish Adoption/Twin Study of Aging (N = 1,842; aged 29-102 years) using data from up to 15 measurement waves across 27 years. A 42-item FI was used to measure frailty at each wave. RESULTS: A bilinear, two-slope model with a turning point at age 65 best described the age-related change in FI, showing that the increase in frailty was more than twice as fast after age 65. Underweight, obesity, female sex, overweight, being separated from one's co-twin during childhood, smoking, poor social support, and low physical activity were associated with a higher FI at age 65, with underweight having the largest effect size. When tested as time-varying covariates, underweight and higher social support were associated with a steeper increase in FI before age 65, whereas overweight and obesity were associated with less steep increase in FI after age 65. CONCLUSIONS: Factors associated with the level and rate of change in frailty are largely actionable and could provide targets for intervention. As deviations from normal weight showed the strongest associations with frailty, future public health programs could benefit from monitoring of individuals with abnormal BMI, especially those who are underweight.

Replicating associations between DNA methylation and body mass index in a longitudinal sample of older twins.

BACKGROUND: There is an important interplay between epigenetic factors and body weight, and previous work has identified ten sites where DNA methylation is robustly associated with body mass index (BMI) cross-sectionally. However, interpretation of the associations is complicated by the substantial changes in BMI often occurring in late-life, and the fact that methylation is often driven by genetic variation. This study therefore investigated the longitudinal association between these ten sites and BMI from midlife to late-life, and whether associations persist after controlling for genetic factors. METHODS: We used data from 535 individuals (mean age 68) in the Swedish Adoption/Twin Study of Aging (SATSA) with longitudinal measures of both DNA methylation from blood samples and BMI, spanning up to 20 years. Methylation levels were measured with the Infinium Human Methylation 450K or Infinium MethylationEpic array, with seven of the ten sites passing quality control. Latent growth curve models were applied to investigate longitudinal associations between methylation and BMI, and between-within models to study associations within twin pairs, thus adjusting for genetic factors. RESULTS: Baseline DNA methylation levels at five of the seven sites were associated with BMI level at age 65 (cg00574958 [CPT1A]; cg11024682 [SREBF1]), and/or change (cg06192883 [MYO5C]; cg06946797 [RMI2]; cg08857797 [VPS25]). For four of the five sites, the associations remained comparable within twin pairs. However, the effects of cg06192883 were substantially attenuated within pairs. No change in DNA methylation was detected for any of the seven evaluated sites. CONCLUSION: Five of the seven sites investigated were associated with late-life level and/or change in BMI. The effects for four of the sites remained similar when examined within twin pairs, indicating that the associations are mainly environmentally driven. However, the substantial attenuation in the association between cg06192883 and late-life BMI within pairs points to the importance of genetic factors in this association.

Exposure to Antidepressant Medication and the Risk of Incident Dementia.

OBJECTIVE: To test competing hypotheses that monotherapeutic antidepressant exposure is associated with an increased versus a decreased risk of dementia. METHODS: A prospective national matched cohort study from Israel (N = 71,515) without dementia (2002-2012) aged 60 and over were followed up for incident dementia from May 2013 to October 2017. Exposure to antidepressant monotherapy was classified with Anatomical Therapeutic Chemical Codes (N06A) from January 1, 2013 to December 31, 2016. The association between antidepressant monotherapy and the risk of incident dementia was quantified with hazard ratios (HR) and their 95% confidence intervals (CI) obtained from Cox regression models unadjusted and adjusted for 42 covariates. The robustness of the results was tested with 24 sensitivity analyses: 19 analyses restricted to subsamples with plausible differential dementia risks (e.g., anxiety and depression), and 5 analyses across and within antidepressant drug classes. RESULTS: In the primary analysis, the risk of incident dementia for the group exposed to antidepressant monotherapy compared to the group unexposed to antidepressants was estimated with an unadjusted HR = 4.09 (df = 1, 95% Wald CI = 3.64, 4.60) and an adjusted HR = 3.43 (df = 1, 95% Wald CI = 3.04, 3.88). Across the 24 sensitivity analyses the estimated adjusted HR values ranged from 1.99 to 5.47. CONCLUSION: In this study, monotherapeutic antidepressant exposure in old age was associated with increased incident dementia. Clinicians, caregivers, and patients may wish to consider this potentially negative consequence of antidepressant exposure and aim to balance the costs and benefits of treatment.

Life-course socioeconomic differences and social mobility in preventable and non-preventable mortality: a study of Swedish twins.

BACKGROUND: Despite advances in life expectancy, low socioeconomic status is associated with a shorter lifespan. This study was conducted to investigate socioeconomic differences in mortality by comparing preventable with non-preventable causes of death in 39 506 participants from the Swedish Twin Registry born before 1935. METHODS: Childhood social class, own education, own social class and social mobility were used as separate indicators of socioeconomic status. These data were linked to the Swedish Cause of Death Register. Cause of death was categorized as preventable or non-preventable mortality according to indicators presented in the Avoidable Mortality in the European Union (AMIEHS) atlas. Using Cox proportional hazard models, we tested the association between the socioeconomic measures and all-cause mortality, preventable mortality and non-preventable mortality. Additional co-twin control analyses indicated whether the associations reflected genetic confounding. RESULTS: The social gradient for mortality was most prominent for the adult socioeconomic measures. There was a social gradient in both preventable mortality and non-preventable mortality, but with an indication of a moderately stronger effect in preventable causes of death. In analyses of social mobility, those who experienced life-time low socioeconomic status (SES) or downward social mobility had an increased mortality risk compared with those with life-time high SES and upward social mobility. Adjustments for genetic confounding did not change the observed associations for education, social class or social mobility and mortality. In the co-twin control analyses of reared-apart twins, the association between childhood social class and mortality weakened, indicating possible genetic influences on this association. CONCLUSIONS: Our results indicate that there is an association between low adult socioeconomic status and increased mortality independent of genetic endowment. Thus, we do not find support for indirect social selection as the basis for mortality inequalities in Sweden.

Childhood social class and cognitive aging in the Swedish Adoption/Twin Study of Aging.

In this report we analyzed genetically informative data to investigate within-person change and between-person differences in late-life cognitive abilities as a function of childhood social class. We used data from nine testing occasions spanning 28 y in the Swedish Adoption/Twin Study of Aging and parental social class based on the Swedish socioeconomic index. Cognitive ability included a general factor and the four domains of verbal, fluid, memory, and perceptual speed. Latent growth curve models of the longitudinal data tested whether level and change in cognitive performance differed as a function of childhood social class. Between-within twin-pair analyses were performed on twins reared apart to assess familial confounding. Childhood social class was significantly associated with mean-level cognitive performance at age 65 y, but not with rate of cognitive change. The association decreased in magnitude but remained significant after adjustments for level of education and the degree to which the rearing family was supportive toward education. A between-pair effect of childhood social class was significant in all cognitive domains, whereas within-pair estimates were attenuated, indicating genetic confounding. Thus, childhood social class is important for cognitive performance in adulthood on a population level, but the association is largely attributable to genetic influences.

Validation of abridged mini-mental state examination scales using population-based data from Sweden and USA.

The objective of this study is to validate two abridged versions of the mini-mental state examination (MMSE): one intended for use in face-to-face interviews, and the other developed for telephonic interviews, using data from Sweden and the US to validate the abridged scales against dementia diagnoses as well as to compare their performance to that of the full MMSE scale. The abridged versions were based on eight domains from the original MMSE scale. The domains included in the MMSE-SF were registration, orientation, delayed recall, attention, and visual spatial ability. In the MMSE-SF-C, the visual spatial ability item was excluded, and instead, one additional orientation item was added. There were 794 participants from the Swedish HARMONY study [mean age 81.8 (4.8); the proportion of cognitively impaired was 51 %] and 576 participants from the US ADAMS study [mean age 83.2 (5.7); the proportion of cognitively impaired was 65 %] where it was possible to compare abridged MMSE scales to dementia diagnoses and to the full MMSE scale. We estimated the sensitivity and specificity levels of the abridged tests, using clinical diagnoses as reference. Analyses with both the HARMONY and the ADAMS data indicated comparable levels of sensitivity and specificity in detecting cognitive impairment for the two abridged scales relative to the full MMSE. Receiver operating characteristic curves indicated that the two abridged scales corresponded well to those of the full MMSE. The two abridged tests have adequate validity and correspond well with the full MMSE. The abridged versions could therefore be alternatives to consider in larger population studies where interview length is restricted, and the respondent burden is high.