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Background The risk–benefit balance of statin use in healthy older people is uncertain. We describe the baseline characteristics of the STAREE (Statins in Reducing Events in the Elderly) trial, which is a randomized, double‐blind, placebo‐controlled trial among community‐dwelling older people; the trial evaluated the effect of atorvastatin 40 mg for the prevention of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke), and on disability‐free survival (survival free of both dementia and persistent physical disability). Methods and Results STAREE enrolled people aged ≥70 years from 1583 general practices across Australia with no history of clinical cardiovascular disease, diabetes, or dementia. Baseline data collected included demographic, clinical, cognitive (Modified Mini‐Mental State Examination), psychological (Center for Epidemiologic Studies Short Depression Scale), lifestyle, medical, physical, blood and urine measures, and quality of life. Demographic and clinical characteristics of study participants were then compared with publicly available landmark statin trials. A total of 9971 participants were recruited (mean±SD age 74.7±4.5 years, 4023 (40%) ≥75 years, 52% women) between July 2015 and March 2023. The mean low‐density lipoprotein cholesterol was 3.27 mmol/L (SD=0.72; 126 mg/dL). Hypertension was reported by 43% of participants and the mean blood pressure was 136/80 mm Hg. Compared with previous landmark statin trials that included primary prevention cohorts, STAREE is unique in including such a large number of older (≥75 years) independent‐living people. Conclusions STAREE is the largest primary prevention trial of statins powered to address the important clinical outcomes of major cardiovascular events, disability‐free survival, and cognition in older people. Registration https://www.clinicaltrials.gov; Unique identifier: NCT02099123.

Abstract Introduction Maternal stress and trauma during pregnancy have been shown to influence cortisol levels and epigenetic patterns, including DNA methylation, in the offspring. This study aimed to determine whether a tailor‐made family intervention could help reduce cortisol levels in children born to traumatized mothers, and to determine whether it effected offspring DNA methylation. The secondary aim was to determine whether the family intervention influenced DNA methylation aging, a marker of biological aging. Methods A needs‐based family intervention was designed to help address relational difficulties and family functioning, and included a focus on family strengths and problem‐solving patterns. Women survivors of sexual violence during the Kosovar war in 1998–1999, and their families (children with or without partners) were randomly assigned to 10 sessions of a family therapy over a 3–5‐month period, or to a waitlist control group. Both mothers and children completed assessments prior to and after the intervention phase. Children's blood samples collected at these two time points were used to measure cortisol and epigenome‐wide DNA methylation patterns (Illumina EPIC array). Cortisol levels, and genome‐wide DNA methylation changes pre‐/postintervention were compared between children in the intervention and the waitlist groups. DNA methylation age and accelerated biological aging were calculated. Results Sixty‐two women–child dyads completed the study, 30 were assigned first to the intervention group, and 32 to the waitlist control group. In adjusted linear regression, the family intervention was associated with a significant decline in cortisol levels compared to the waitlist control (β = −124.72, 95% confidence interval [CI]: −197.4 to −52.1, p = .001). Children in the intervention group, compared to the waitlist control group, showed >1% differential methylation degree at 5819 CpG (5'—C—phosphate—G—3') sites across the genome (p

Abstract Background Cognitive impairment is common after stroke, and a large proportion of stroke patients will develop dementia. However, there have been few large prospective studies which have assessed cognition both prior to and after stroke. This study aims to determine the extent to which incident stroke impacts different domains of cognitive function in a longitudinal cohort of older community-dwelling individuals. Methods 19,114 older individuals without cardiovascular disease or major cognitive impairment were recruited and followed over a maximum 11 years. Stroke included ischaemic and haemorrhagic stroke and was adjudicated by experts. Cognitive function was assessed regularly using Modified Mini-Mental State Examination (3MS), Hopkins Verbal Learning Test–Revised (HVLT-R), Symbol Digit Modalities Test (SDMT), and Controlled Oral Word Association Test (COWAT). Linear mixed models were used to investigate the change in cognition at the time of stroke and decline in cognitive trajectories following incident stroke. Results During a median follow-up period of 8.4 [IQR: 7.2, 9.6] years, 815 (4.3%) participants experienced a stroke. Over this time, there was a general decline observed in 3MS, HVLT-R delayed recall, and SDMT scores across participants. However, for individuals who experienced a stroke, there was a significantly greater decline across all cognitive domains immediately after the event immediately after the event (3MS: -1.03 [95%CI: -1.45, -0.60]; HVLT-R: -0.47 [-0.70, -0.24]; SDMT: -2.82 [-3.57, -2.08]; COWAT: -0.67 [-1.04, -0.29]) and a steeper long-term decline for three of these domains (3MS -0.62 [-0.88, -0.35]; COWAT: -0.30 [-0.46, -0.14]); HVLT-R: -0.12 [95%CI, -0.70, -0.24]). However individuals with stroke experienced no longer-term decline in SDMT compared to the rest of the participants. Conclusions These findings highlight the need for comprehensive neuropsychology assessments for ongoing monitoring of cognition following incident stroke; and potential early intervention.

Abstract INTRODUCTION This study investigated whether epigenetic age acceleration (AA) is associated with the change in cognitive function and the risk of incident dementia over 9 years, separately in males and females. METHODS Six epigenetic AA measures, including GrimAge, were estimated in baseline blood samples from 560 Australians aged ≥70 years (50.7% female). Cognitive assessments included global function, episodic memory, executive function, and psychomotor speed. Composite cognitive scores were also generated. Dementia (Diagnostic and Statistical Manual for Mental Disorders – IV [DSM‐IV] criteria) was adjudicated by international experts. RESULTS Associations between epigenetic AA and cognitive performance over‐time varied by sex. In females only, GrimAA/Grim2AA was associated with worse delayed recall, composite cognition, and composite memory (adjusted‐beta ranged from –0.1372 to –0.2034). In males only, GrimAA/Grim2AA was associated with slower processing speed (adjusted‐beta, –0.3049) and increased dementia risk (adjusted hazard ratios [HRs], 1.78 and 2.00, respectively). DISCUSSION Epigenetic AA is associated with cognitive deterioration in later life but with evidence of sex‐specific associations. Highlights Epigenetic age acceleration was associated with cognitive deterioration over time. However, these associations differed by sex. In females, accelerated GrimAge appeared to be a better marker of decline in memory. In males, accelerated GrimAge was associated with slower processing speed over time. Association between accelerated GrimAge and dementia risk was found only in males.

Background Walking for transport may prolong survival in younger and middle-aged adults; however, evidence for older adults is scarce. We examined a prospective relationship between transport-related walking and all-cause mortality among adults aged 70 years and over.Methods Community-dwelling, apparently healthy older adults (n=11 539; mean age 75.1 years, 53.1% females), participants of the ASPirin in Reducing Events in the Elderly Longitudinal Study of Older Persons, reported their frequency of transport-related walking (never, rarely/once a week, more than once a week or every day). All-cause mortality was verified by two independent sources. Cox proportional-hazards models (HR and 95% CI) assessed the association between transport-related walking and all-cause mortality.Results Of participants, 44.1% reported walking every day, 31.5% more than once a week, 21.7% rarely or once a week and 2.7% never engaged in transport-related walking. During the median follow-up of 8.6 years (IQR: 7.4–10.1), 1599 participants (13.9%) died. Compared with those who reported never walking for transport, the risk of all-cause mortality was lower for those walking rarely or once a week (HR 0.73, 95% CI 0.56 to 0.96); more than once a week (HR 0.76, 95% CI 0.59 to 0.99) and every day (HR 0.74, 95% CI 0.57 to 0.96). Analyses were adjusted for age, sex, education, smoking, alcohol consumption, living status, rurality, household income, socioeconomic status, chronic conditions, body mass index and overall physical activity levels.Conclusions Engaging in any weekly transport-related walking helps older adults prolong survival. Public health campaigns and urban planning should promote and support transport-related walking to boost physical activity levels of older adults and support healthier ageing.

Abstract Background Posttraumatic Stress Disorder (PTSD) could potentially increase the risk of mortality, and there is a need for a meta-analysis to quantify this association. This study aims to determine the extent to which PTSD is a predictor of mortality. Methods EMBASE, MEDLINE, and PsycINFO were searched systematically on 12th February 2020, with updated searches conducted in July 2021, and December 2022 (PROSPERO CRD42019142971). Studies involving community-dwelling participants with a diagnosis of PTSD or PTSD symptoms, and a comparator group of individuals without PTSD, and which assessed mortality risk, were included. A random-effects meta-analysis was conducted on studies reporting Odds Ratio (OR), Hazard Ratio (HR), and Risk Ratio (RR), and subgroup analysis was also performed by age, sex, type of trauma experienced, PTSD diagnosis, and cause of death. Results A total of 30 eligible studies of mostly good methodological quality were identified, with a total of more than 2.1 million participants with PTSD. The majority of studies involved male-dominated, veteran populations. PTSD was associated with a 47% (95% CI: 1.06–2.04) greater risk of mortality across six studies that reported OR/RR, and a 32% increased risk across 18 studies which reported time to death (HR: 1.32, 95% CI: 1.10–1.59). There was very high study heterogeneity (I2 > 94%) and this was not explained by the prespecified subgroup analysis. Conclusion PTSD is associated with increased mortality risk, however further research is required amongst civilians, involving women, and in individuals from underdeveloped countries.

Introduction Cerebrovascular disease and neurodegeneration are causes of cognitive decline and dementia, for which primary prevention options are currently lacking. Statins are well-tolerated and widely available medications that potentially have neuroprotective effects. The STAREE-Mind Imaging Study is a randomised, double-blind, placebo-controlled clinical trial that will investigate the impact of atorvastatin on markers of neurovascular health and brain atrophy in a healthy, older population using MRI. This is a nested substudy of the ‘Statins for Reducing Events in the Elderly’ (STAREE) primary prevention trial.Methods Participants aged 70 years or older (n=340) will be randomised to atorvastatin or placebo. Comprehensive brain MRI assessment will be undertaken at baseline and up to 4 years follow-up, including structural, diffusion, perfusion and susceptibility imaging. The primary outcome measures will be change in brain free water fraction (a composite marker of vascular leakage, neuroinflammation and neurodegeneration) and white matter hyperintensity volume (small vessel disease). Secondary outcomes will include change in perivascular space volume (glymphatic drainage), cortical thickness, hippocampal volume, microbleeds and lacunae, prefrontal cerebral perfusion and white matter microstructure.Ethics and dissemination Academic publications from this work will address the current uncertainty regarding the impact of statins on brain structure and vascular integrity. This study will inform the utility of repurposing these well-tolerated, inexpensive and widely available drugs for primary prevention of neurological outcomes in older individuals. Ethics approval was given by Monash University Human Research Ethics Committee, Protocol 12206.Trial registration number ClinicalTrials.gov Identifier: NCT05586750.

Background: Stress can have adverse impacts on health, particularly when it is chronic or resulting from major adverse events. Our study investigated whether relatively common adverse events in older individuals were associated with an increased risk of death, as well as cause-specific death and potential gender differences. Methods: Participants were 12896 community-dwelling Australians aged ≥70 years at enrolment into the ASPREE (ASPirin in Reducing Events in the Elderly) study and without known life-limiting disease. A questionnaire administered in the year after enrolment, collected information on ten adverse events experienced in the past year. Mortality status was verified by multiple sources including health records and the National Death Index across a maximum of 10 years. Underlying causes of death were determined using clinical information by two adjudicators. Cox-proportional hazards regression models were used to estimate mortality risk. Results: Two of the ten adverse events were associated with an increased risk of mortality in fully adjusted models. A 69% increased risk of mortality was observed in participants who reported their spouse/partner had recently died (95% CI: 1.19–2.39, P

Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Addressing social determinants of health (SDoH) may be the next forefront of reducing the enormous burden of CVD. SDoH can be defined as any social, economic, or environmental factor that influences a health outcome. Comprehensive evidence of the role of SDoH in CVD is lacking, nevertheless. This umbrella review aims to give a comprehensive overview of the role of SDoH in CVD. We searched systematic reviews (with or without meta‐analyses) using 8 databases and included review reference lists. Four themes (economic circumstances, social/community context, early childhood development, and neighbourhood/built environment) and health literacy in the health/health care theme were considered. Seventy reviews were eligible. Despite the quality of the included reviews being low or critically low, there was consistent evidence that factors relating to economic circumstances and early childhood development themes were associated with an increased risk of CVD and CVD mortality. We also found evidence that factors in the social/community context and neighbourhood/built environment themes, such as social isolation, fewer social roles, loneliness, discrimination, ethnicity, neighborhood socioeconomic status, violence, and environmental attributes, had a role in CVD. SDoH factors without (or with minimal) evidence synthesis for CVD were also identified. In sum, this umbrella review offers evidence that SDoH, especially economic circumstance and early childhood development, play a significant role in CVD. This calls for the strengthening of nonmedical interventions that address multiple factors simultaneously and the inclusion of SDoH in future CVD risk prediction models. Registration URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42022346994.

Background: Increasing evidence suggests that stress could be a risk factor for dementia but this might vary by gender. This study investigated whether adverse life events were associated with cognitive decline and dementia in later-life, separately in men and women. Methods: Participants were 12,789 community-dwelling Australians aged ≥ 70 years. Ten common adverse events in later-life were self-reported. Cognitive decline was defined as a 1.5 SD decline from participants’ baseline score in tests of global cognition, psychomotor speed, episodic memory, and executive functioning, which were assessed regularly over a maximum of 10.3 years. Dementia was diagnosed according to DSM-IV criteria. Results: An increased risk of dementia was observed in participants who experienced the death of a spouse/partner (HR: 1.72, 95% CI: 1.17 – 2.52) and for individuals who experienced major financial problems (HR: 1.53, 95% CI: 1.05 – 2.23). The latter also increased the risk of cognitive decline in men specifically (HR: 1.43, 95% CI: 1.10 – 1.86). In contrast, some events for women were associated with a reduced risk of dementia (e.g. close family or friends lost their job/retired (HR: 0.62, 95% CI: 0.40–0.95)). Limitations: Events including major money problems may result from prodromal dementia symptoms, thus reverse causation needs to be considered. Conclusions: Adverse life events may influence dementia risk in older adults, but associations vary depending on the nature of the event, and across genders. These findings support the need for early interventions in older people who have experienced adversities, particularly for the death of a loved one.

Introduction The world is undergoing a demographic transition to an older population. Preventive healthcare has reduced the burden of chronic illness at younger ages but there is limited evidence that these advances can improve health at older ages. Statins are one class of drug with the potential to prevent or delay the onset of several causes of incapacity in older age, particularly major cardiovascular disease (CVD). This paper presents the protocol for the STAtins in Reducing Events in the Elderly (STAREE) trial, a randomised double-blind placebo-controlled trial examining the effects of statins in community dwelling older people without CVD, diabetes or dementia.Methods and analysis We will conduct a double-blind, randomised placebo-controlled trial among people aged 70 years and over, recruited through Australian general practice and with no history of clinical CVD, diabetes or dementia. Participants will be randomly assigned to oral atorvastatin (40 mg daily) or matching placebo (1:1 ratio). The co-primary endpoints are disability-free survival defined as survival-free of dementia and persistent physical disability, and major cardiovascular events (cardiovascular death or non-fatal myocardial infarction or stroke). Secondary endpoints are all-cause death, dementia and other cognitive decline, persistent physical disability, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, heart failure, atrial fibrillation, fatal and non-fatal cancer, all-cause hospitalisation, need for permanent residential care and quality of life. Comparisons between assigned treatment arms will be on an intention-to-treat basis with each of the co-primary endpoints analysed separately in time-to-first-event analyses using Cox proportional hazards regression models.Ethics and dissemination STAREE will address uncertainties about the preventive effects of statins on a range of clinical outcomes important to older people. Institutional ethics approval has been obtained. All research outputs will be disseminated to general practitioner co-investigators and participants, published in peer-reviewed journals and presented at national and international conferences.Trial registration number NCT02099123.

Study objective: This study examined the association between frailty and incident cardiovascular disease (CVD) events, major adverse cardiovascular events (MACE), and CVD-related mortality. Design: Longitudinal cohort study. Setting: The ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial in Australia and the United States. Participants: 19,114 community-dwelling older adults (median age 74.0 years; 56.4 % females). Interventions: Pre-frailty and frailty were assessed using a modified Fried phenotype and a deficit accumulation Frailty Index (FI) at baseline. Main outcome measures: CVD was defined as a composite of CVD death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure; MACE included all except heart failure. Cox proportional hazards regression was used to analyze the association between frailty and CVD outcomes over a median follow-up of 4.7 years. Results: Baseline pre-frail and frail groups had a higher risk of incident CVD events (Hazard Ratio (HR): 1.31; 95 % Confidence Interval (CI): 1.14–1.50 for pre-frail and HR: 1.63; 95 % CI: 1.15–2.32 for frail) and MACE (pre-frail HR: 1.26; 95 % CI: 1.08–1.47 and frail HR: 1.51; 95 % CI: 1.00–2.29) than non-frail participants according to Fried phenotype after adjusting for traditional CVD risk factors. Effect sizes were similar or larger when frailty was assessed with FI; similar results for men and women. Conclusion: Frailty increases the likelihood of developing CVD, including MACE, in community-dwelling older men and women without prior CVD events. Screening for frailty using Fried or FI method could help identify community-dwelling older adults without prior CVD events who are more likely to develop CVD, including MACE, and may facilitate targeted preventive measures to reduce their risk.

Studies have shown that the effects of early-life stress and trauma can be enduring, with long-term negative effects on health. Epigenetics, including DNA methylation, have been implicated as a potential mechanism for these effects. Brain-derived neurotropic factor (BDNF) is a neurotransmitter involved in learning and memory, and altered BDNF promoter methylation measured in peripheral tissue has been found with early-life stress. However, whether such methylation differences remain stable into later life, is unknown. This study aimed to investigate the association between childhood adversity and BDNF promoter methylation in adults aged 65 years and over. Data came from a large study of older community-dwelling individuals in France (ESPRIT). Information on three major childhood adverse events, namely abuse/maltreatment, war/natural disaster, and financial difficulties/poverty, was obtained by retrospective reporting from participants of ESPRIT study. BDNF promoter I and IV methylation was assessed in blood and buccal tissue. Linear regression analysis was performed, adjusting for age, sex, education, depression, and morbidity. Among 927 participants, there was no strong evidence that childhood abuse/maltreatment or financial difficulties/poverty were associated with BDNF methylation in older individuals. For war/natural disaster, differential methylation at four of twenty-nine CpG sites was observed, however, these would not have remained significant after correction for multiple testing. Together, these findings do not support a long-term association between adverse childhood events and BDNF methylation in older age, but further large prospective studies are needed, which do not target specific genes, but consider DNA methylation across the genome.

Abstract Introduction This study investigated whether grip strength and gait speed predict cognitive aging trajectories and examined potential sex‐specific associations. Methods Community‐dwelling older adults (n = 19,114) were followed for up to 7 years, with regular assessment of global function, episodic memory, psychomotor speed, and executive function. Group‐based multi‐trajectory modeling identified joint cognitive trajectories. Multinomial logistic regression examined the association of grip strength and gait speed at baseline with cognitive trajectories. Results High performers (14.3%, n = 2298) and low performers (4.0%, n = 642) were compared to the average performers (21.8%, n = 3492). Grip strength and gait speed were positively associated with high performance and negatively with low performance (P‐values

IntroductionNeuroimaging-based ‘brain age’ can identify individuals with ‘advanced’ or ‘resilient’ brain aging. Brain-predicted age difference (brain-PAD) is predictive of cognitive and physical health outcomes. However, it is unknown how individual health and lifestyle factors may modify the relationship between brain-PAD and future cognitive or functional performance. We aimed to identify health-related subgroups of older individuals with resilient or advanced brain-PAD, and determine if membership in these subgroups is differentially associated with changes in cognition and frailty over three to five years.MethodsBrain-PAD was predicted from T1-weighted images acquired from 326 community-dwelling older adults (73.8 ± 3.6 years, 42.3% female), recruited from the larger ASPREE (ASPirin in Reducing Events in the Elderly) trial. Participants were grouped as having resilient (n=159) or advanced (n=167) brain-PAD, and latent class analysis (LCA) was performed using a set of cognitive, lifestyle, and health measures. We examined associations of class membership with longitudinal change in cognitive function and frailty deficit accumulation index (FI) using linear mixed models adjusted for age, sex and education.ResultsSubgroups of resilient and advanced brain aging were comparable in all characteristics before LCA. Two typically similar latent classes were identified for both subgroups of brain agers: class 1 were characterized by low prevalence of obesity and better physical health and class 2 by poor cardiometabolic, physical and cognitive health. Among resilient brain agers, class 1 was associated with a decrease in cognition, and class 2 with an increase over 5 years, though was a small effect that was equivalent to a 0.04 standard deviation difference per year. No significant class distinctions were evident with FI. For advanced brain agers, there was no evidence of an association between class membership and changes in cognition or FI.ConclusionThese results demonstrate that the relationship between brain age and cognitive trajectories may be influenced by other health-related factors. In particular, people with age-resilient brains had different trajectories of cognitive change depending on their cognitive and physical health status at baseline. Future predictive models of aging outcomes will likely be aided by considering the mediating or synergistic influence of multiple lifestyle and health indices alongside brain age.

Abstract Background Poor social health is associated with increased risk of cardiovascular disease (CVD). Recent research suggests that different social health domains should be considered separately as the implications for health and possible interventions may differ. Aim To assess social isolation, low social support and loneliness as predictors of CVD. Methods Secondary analysis of 11,486 community-dwelling, Australians, aged 70 years and over, free of CVD, dementia, or significant physical disability, from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Social isolation, social support (Revised Lubben Social Network Scale), and loneliness were assessed as predictors of CVD using Cox proportional-hazard regression. CVD events included fatal CVD, heart failure hospitalization, myocardial infarction and stroke. Analyses were adjusted for established CVD risk factors. Results Individuals with poor social health were 42 % more likely to develop CVD (p = 0.01) and twice as likely to die from CVD (p = 0.02) over a median 4.5 years follow-up. Interaction effects indicated that poorer social health more strongly predicted CVD in smokers (HR 4.83, p = 0.001, p-interaction = 0.01), major city dwellers (HR 1.94, p

Purpose The Australian Temperament Project Generation 3 Study (ATPG3) was established to examine the extent to which offspring social and emotional development is shaped in the decades prior to conception, in parent and grandparent histories of psychosocial adjustment (eg, emotional regulation, relationship quality and prosociality) and maladjustment (eg, depressive symptoms, substance use and antisociality).Participants The Australian Temperament Project (ATP) commenced in 1983 as a population representative survey of the social and emotional health of 2443 young Australians (Generation 2: 4–8 months old) and their parents (Generation 1). Since then, families have been followed from infancy to young adulthood (16 waves). Between 2012 and 2018, the cohort was screened biannually for pregnancies (Generation 3), with assessments conducted in the third trimester of pregnancy, and at 8 weeks and 1 year postpartum.Findings to date A total of 1167 offspring (607 female) born to 703 Generation 2 parents (400 mothers) were recruited into the ATPG3 Study. Findings to date highlight: (1) strong continuities in depressive symptoms and substance use from adolescence through to becoming a parent; (2) a role for persistent preconception mental health problems in risk for parent–child bonding difficulties, as well as infant emotional reactivity and behaviour problems; (3) the importance of secure attachments in adolescence in reducing long-term risk for postpartum mental health problems; and (4) the protective nature of perceived social support, both preconception and postpartum, in strengthening relationship quality and social support during the COVID-19 pandemic.Future plans Assessments of ATPG3 families in preschool and middle childhood are currently funded and underway. We intend to maintain the offspring cohort through childhood, adolescence, young adulthood and into parenthood. Data will be used to map preconception determinants of emotional health, and enhance approaches to population monitoring and targeted intervention over the life course and across generations.

Objective: To identify the socio-demographic, lifestyle, and clinical characteristics associated with self-reported weight status in early (age 18 years) and late (age ≥ 70 years) adulthood. Methods: The number of participants was 11,288, who were relatively healthy community-dwelling Australian adults aged ≥70 years (mean age 75.1 ± 4.2 years) in the Aspirin in Reducing Events in the Elderly (ASPREE) Longitudinal Study of Older Persons (ALSOP) sub-study. Self-reported weight at the study baseline (age ≥ 70 years) and recalled weight at age 18 years were collected. Height measured at baseline was used to calculate the BMI at both time points. Individuals were categorised into one of five ‘lifetime’ weight status groups: healthy weight (at both age 18 year and ≥70 years), overweight (at either or both times), non-obese (age 18 year) to obesity (age ≥70 years), obesity (age 18 years) to non-obese (age ≥ 70 years), and early and later life obesity (at age 18 years and ≥70 years). Results: Participants who experienced obesity in early and/or late adulthood were at a higher risk of adverse clinical characteristics. Obesity in late adulthood (regardless of early adulthood weight status) was associated with high proportions of hypertension, diabetes, and dyslipidaemia, whereas obesity in early adulthood (regardless of late adulthood weight status) was associated with lower cognitive scores (on all four measures). Discussion/Conclusion: Healthy or overweight weight status in early and later adulthood was associated with more favourable socioeconomic, lifestyle, and clinical measures. Obesity in early adulthood was associated with lower cognitive function in later adulthood, whereas obesity in later adulthood was associated with hypertension, diabetes, and dyslipidaemia.

Abstract Background Brain age is a biomarker that predicts chronological age using neuroimaging features. Deviations of this predicted age from chronological age is considered a sign of age-related brain changes, or commonly referred to as brain ageing. The aim of this systematic review is to identify and synthesize the evidence for an association between lifestyle, health factors and diseases in adult populations, with brain ageing. Methods This systematic review was undertaken in accordance with the PRISMA guidelines. A systematic search of Embase and Medline was conducted to identify relevant articles using search terms relating to the prediction of age from neuroimaging data or brain ageing. The tables of two recent review papers on brain ageing were also examined to identify additional articles. Studies were limited to adult humans (aged 18 years and above), from clinical or general populations. Exposures and study design of all types were also considered eligible. Results A systematic search identified 52 studies, which examined brain ageing in clinical and community dwelling adults (mean age between 21 to 78 years, ~ 37% were female). Most research came from studies of individuals diagnosed with schizophrenia or Alzheimer’s disease, or healthy populations that were assessed cognitively. From these studies, psychiatric and neurologic diseases were most commonly associated with accelerated brain ageing, though not all studies drew the same conclusions. Evidence for all other exposures is nascent, and relatively inconsistent. Heterogenous methodologies, or methods of outcome ascertainment, were partly accountable. Conclusion This systematic review summarised the current evidence for an association between genetic, lifestyle, health, or diseases and brain ageing. Overall there is good evidence to suggest schizophrenia and Alzheimer’s disease are associated with accelerated brain ageing. Evidence for all other exposures was mixed or limited. This was mostly due to a lack of independent replication, and inconsistency across studies that were primarily cross sectional in nature. Future research efforts should focus on replicating current findings, using prospective datasets. Trial registration A copy of the review protocol can be accessed through PROSPERO, registration number CRD42020142817 .

# Background Optimism is a psychosocial asset associated with healthy ageing. Coronavirus disease 2019 (COVID-19) tremendously impacts people's lives and health. This study explored what optimism means to older Australians and how the pandemic may have affected their perceptions. # Methods Eleven adults (55% female), aged 68-74 years, living in metropolitan and regional areas of Australia participated in semi-structured interviews via video-conferencing. Participants' perceptions of optimism, lived experience, and potential impacts of the pandemic on optimism were explored. Data were evaluated using reflective thematic analysis. # Findings The themes identified were: (i) the essence, beliefs and meaning of optimism, (ii) personality and disposition in shaping optimism through the life course, and (iii) the effects and aftermath of a stressor. Genetics and family history, gratitude and hopefulness, life-course development and the life journey shaped optimism. Pragmatic beliefs and attitudes, being solution-focused, and positivity contributed to the lifelong development of optimism. Optimism promoted proactive coping strategies and acceptance of difficulties during the pandemic. # Conclusions The overall meaning of optimism was a generalised positive outlook shaped by the dynamic interaction of attributes. Optimism was not impacted by the pandemic stressor. Rather, optimism helped individuals handle this stressful time. Optimism may aid older individuals' recovery from the effects of COVID-19.

ObjectiveThere is variability across individuals in cognitive aging. To investigate the associations of several modifiable factors with high and low cognitive performance.MethodsData came from 17,724 community-dwelling individuals aged 65–98 years. Global cognition, verbal fluency, episodic memory, and psychomotor speed were assessed over up to seven years. Group-based multi-trajectory modeling identified distinct cognitive trajectories. Structural equation modeling examined the direct/indirect associations of social/behavioral factors and several chronic conditions with cognitive trajectories.ResultsSeven trajectory subgroups were identified. In the structural equation modeling we compared two subgroups-participants with the highest (14.2%) and lowest (4.1%) cognitive performance with the average subgroup. Lower education, never alcohol intake, and frailty directly predicted increased risk of low performance, and decreased likelihood of high performance. Hypertension (RR: 0.69, 95%CI: 0.60–0.80), obesity (RR: 0.84, 95%CI: 0.73–0.97), diabetes (RR: 0.69, 95%CI: 0.56–0.86) and depression (RR: 0.68, 95%CI: 0.54–0.85) only predicted lower likelihood of high cognitive performance, while dyslipidemia was only associated with low performance (RR: 1.30, 95%CI: 1.07–1.57). Living alone predicted increased risk of low cognitive performance and several comorbidities. Smoking did not predict cognitive trajectories but was associated with increased risk of diabetes, obesity and frailty. Findings were similar when examining the direct associations between modifiable risk factors and all seven cognitive subgroups.ConclusionsAlthough several modifiable factors were associated with high performance, and reversely with low performance, this was not observed for obesity, hypertension and dyslipidemia. Further, health behaviors may affect cognitive function indirectly, via geriatric conditions. This indicates that strategies to promote healthy cognitive aging, may be distinct from those targeting dementia prevention.

ObjectiveThe inter-individual variability in cognitive changes may be early indicators of major health events. We aimed to determine whether late-life cognitive trajectories were associated with incident dementia, persistent physical disability and all-cause mortality.MethodsData came from a cohort of older community-dwelling individuals aged 70 years or above in Australia and the United States. Global cognition, verbal fluency, episodic memory and psychomotor speed were assessed regularly at up to seven waves between 2010 and 2017. Dementia, disability in activities of daily living, and death were adjudicated between 2017 and 2020. Latent classes of cognitive trajectories over seven years were determined using group-based trajectory modeling. Multivariable logistic regression was used for the prospective associations between cognitive trajectories and these outcomes.ResultsCognitive trajectories were defined for 16,174 participants (mean age: 78.9 years; 56.7% female) who were alive and without incident dementia or disability by 2017, among which 14,655 participants were included in the association analysis. Between three and five trajectory classes were identified depending on the cognitive test. Cognitive trajectories were strongly associated with the risk of dementia. For example, compared to those in the highest-functioning trajectory, the worst performers of episodic memory had a 37-fold increased risk of dementia (95% CI: 17.23–82.64). The lowest trajectories of both global cognition and episodic memory also predicted increased mortality risk (OR: 1.80, 95% CI: 1.28–2.52; OR: 1.61, 95% CI: 1.09–2.36, respectively), while only slow psychomotor speed was marginally associated with physical disability (OR: 2.39, 95% CI: 0.99–5.77).ConclusionsIn older individuals, cognitive trajectories appear to be early indicators of clinically relevant health outcomes. Systematic cognitive assessments as part of routine geriatric evaluation may facilitate early identification and interventions for those individuals at highest risk.

Abstract Objectives A feature of late-life depression is alterations of the stress hormone system. The CYP21A2 gene encodes for the steroid 21-hydroxylase enzyme which is required for the biosynthesis of mineralocorticoids and glucocorticoids, two main components of the stress response in humans. Variants in the CYP21A2 gene could influence risk of late-life depression, but this has not been examined. This study investigated possible associations between five variants in the CYP21A2 gene and late-life depression in 1007 older community-dwelling men and women. Results In multivariate logistic regression model, significant associations were found between three single-nucleotide polymorphisms (rs389883, rs437179, and rs630379) and depression in women specifically (OR ranging from 1.51 to 1.68, p-values 0.025 to 0.0045), and the two latter remained significant after correction for multiple testing. Variants of the CYP21A2 gene appear as susceptibility factors for late-life depression in a sex-specific manner, independently of somatic and neuropsychiatric comorbidity.

Methylation levels at the hypoxia-inducible factor 3α gene (HIF3A) in blood have been linked to body mass index (BMI) in adults. Despite evidence implicating HIF3A in angiogenesis and metabolism, no studies have examined links between HIF3A methylation in early life and cardiovascular health. Here, we investigated the relationship between HIF3A methylation in blood at birth and 12 months of age with cardiovascular measures at 4 years. We also examined influences of prenatal exposures, birth outcomes, and genetic variation. Methylation of two HIF3A promoter regions in cord blood was measured using Sequenom EpiTYPER mass-spectrometry. The first promoter region was also measured in 12-month blood. Four-year cardiovascular measures included blood pressure, pulse wave velocity, and aortic and carotid intima-media thickness. Associations were tested using partial correlation tests and linear regression modelling. Methylation of the first HIF3A promoter in cord and 12-month blood was not associated with four-year measures. There was modest evidence of an association between DNA methylation at the second HIF3A promoter in cord blood and four-year systolic blood pressure (n = 353, r = 0.12, p = 0.03). In sex-stratified analysis, methylation of the second promoter was modestly associated with systolic and diastolic blood pressure (r = 0.16, p = 0.03 for both) in males only. In conclusion, HIF3A methylation at birth shows some evidence of an association with later blood pressure in childhood. Further work should determine whether this relationship persists into later childhood, and should assess potential functional links between HIF3A methylation and cardiovascular health more generally.

Abstract Background Quality of life (QoL) is multi-dimensional concept of an individual’ general well-being status in relation to their value, environment, cultural and social context in which they live. This study aimed to quantitatively synthesise available evidence on the association between QoL and mortality in the general population. Methods An electronic search was conducted using three bibliographic databases, MEDLINE, EMBASE and PsycINFO. Inclusion criteria were studies that assessed QoL using standardized tools and examined mortality risk in a non-patient population. Qualitative data synthesis and meta-analyses using a random-effects model were performed. Results Of 4184 articles identified, 47 were eligible for inclusion, involving approximately 1,200,000 participants. Studies were highly heterogeneous in terms of QoL measures, population characteristics and data analysis. In total, 43 studies (91.5%) reported that better QoL was associated with lower mortality risk. The results of four meta-analyses indicated that higher health-related QoL (HRQoL) is associated with lower mortality risk, which was consistent for overall HRQoL (HR 0.633, 95% CI: 0.514 to 0.780), physical function (HR 0.987, 95% CI: 0.982 to 0.992), physical component score (OR 0.950, 95% CI: 0.935 to 0.965), and mental component score (OR 0.980, 95% CI: 0.969 to 0.992). Conclusion These findings provide evidence that better QoL/HRQoL was associated with lower mortality risk. The utility of these measures in predicting mortality risk indicates that they should be considered further as potential screening tools in general clinical practice, beyond the traditional objective measures such as body mass index and the results of laboratory tests.

Study objective: The aim of this study was to identify whether physical component score (PCS) of health-related quality of life trajectories over 4.7-years predicted subsequent risk of incident fatal and non-fatal CVD events, and all-cause mortality. Methods: This study included 16,871 community-dwelling people aged ≥65 years enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) trial. PCS was assessed annually using the SF-12 (version-2) over a median 4.7-years (i.e. from baseline (2010–2014) till June 2017). Incident CVD events and all-cause mortality occurring after June 2017 until the second-year after the end of the trial were considered. Growth mixture and logistic regression modelling were used. Results: Four PCS trajectories were identified: high (66.5%), intermediate (13.3%), decline (13.8%), and low (6.5%), and there was subsequently a total of 406 (2.50%) incident CVD events, 197 (1.17%) fatal CVD, and 751 (4.45%) deaths. The declining PCS trajectory group had the highest risk of incident CVD (adjusted OR, 1.51; 95%CI 1.14, 1.99), while the low PCS trajectory group had the greatest risk of fatal CVD (adjusted OR, 1.74; 95%CI 1.06, 2.85) and all-cause mortality (adjusted OR, 1.83; 95%CI 1.40, 2.40). After further adjustment for the baseline PCS score, only the association between declining PCS trajectory and incident CVD (adjusted OR, 1.51; 95%CI 1.11, 2.07) remained. Conclusion: Our study strengthens the importance of PCS as a predictive measure of CVD and all-cause mortality in older people and also highlights that a declining PCS trajectory could be considered an early predictor of future CVD events.

Background Blood pressure variability (BPV) in midlife increases risk of late‐life dementia, but the impact of BPV on the cognition of adults who have already reached older ages free of major cognitive deficits is unknown. We examined the risk of incident dementia and cognitive decline associated with long‐term, visit‐to‐visit BPV in a post hoc analysis of the ASPREE (Aspirin in Reducing Events in the Elderly) trial. Methods and Results ASPREE participants (N=19 114) were free of dementia and significant cognitive impairment at enrollment. Measurement of BP and administration of a standardized cognitive battery evaluating global cognition, delayed episodic memory, verbal fluency, and processing speed and attention occurred at baseline and follow‐up visits. Time‐to‐event analysis using Cox proportional hazards regression models were used to calculate hazard ratios (HR) and corresponding 95% CI for incident dementia and cognitive decline, according to tertile of SD of systolic BPV. Individuals in the highest BPV tertile compared with the lowest had an increased risk of incident dementia and cognitive decline, independent of average BP and use of antihypertensive drugs. There was evidence that sex modified the association with incident dementia (interaction P=0.02), with increased risk in men (HR, 1.68; 95% CI, 1.19–2.39) but not women (HR, 1.01; 95% CI, 0.72–1.42). For cognitive decline, similar increased risks were observed for men and women (interaction P=0.15; men: HR, 1.36; 95% CI, 1.16–1.59; women: HR, 1.14; 95% CI, 0.98–1.32). Conclusions High BPV in older adults without major cognitive impairment, particularly men, is associated with increased risks of dementia and cognitive decline. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583; isrctn.com. Identifier: ISRCTN83772183.

Abstract Background Maternal alcohol consumption in pregnancy may have adverse effects on child gross motor (GM) development. There have been few human studies on this topic, particularly ones examining low exposure. This study examined the association between prenatal alcohol exposure (PAE) and infant GM development at 12-months of age. Methods Participants were 1324 women recruited from antenatal clinics in Sydney and Perth, Australia. Maternal and paternal alcohol use was assessed in pregnancy via interview; offspring GM development was measured at 12-months with the Bayley Scales of Infant Development (BSID-III). Results Any alcohol use in pregnancy was common: 56.1%, of pregnant women drank early in Trimester one (0–6 weeks), however this reduced to 27.9% on average thereafter and at predominantly low levels. However, infant BSID GM scale scores were not found to differ significantly as a function of PAE in the first 6-weeks (low, moderate, binge or heavy PAE), nor with low PAE across pregnancy. Conclusions We found no evidence to suggest that low PAE is associated with measurable impairment in infant GM development at 12-months. Further research is needed to examine potential PAE impacts on GM development in heavier exposure groups and through the childhood years when subtle GM deficits may be more detectable.

Abstract Background Ageing is one of the principal risk factors for many chronic diseases. However, there is considerable between-person variation in the rate of ageing and individual differences in their susceptibility to disease and death. Epigenetic mechanisms may play a role in human ageing, and DNA methylation age biomarkers may be good predictors of age-related diseases and mortality risk. The aims of this systematic review were to identify and synthesise the evidence for an association between peripherally measured DNA methylation age and longevity, age-related disease, and mortality risk. Methods A systematic search was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using relevant search terms, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and PsychINFO databases were searched to identify articles meeting the inclusion criteria. Studies were assessed for bias using Joanna Briggs Institute critical appraisal checklists. Data was extracted from studies measuring age acceleration as a predictor of age-related diseases, mortality or longevity, and the findings for similar outcomes compared. Using Review Manager 5.3 software, two meta-analyses (one per epigenetic clock) were conducted on studies measuring all-cause mortality. Results Twenty-three relevant articles were identified, including a total of 41,607 participants. Four studies focused on ageing and longevity, 11 on age-related disease (cancer, cardiovascular disease, and dementia), and 11 on mortality. There was some, although inconsistent, evidence for an association between increased DNA methylation age and risk of disease. Meta-analyses indicated that each 5-year increase in DNA methylation age was associated an 8 to 15% increased risk of mortality. Conclusion Due to the small number of studies and heterogeneity in study design and outcomes, the association between DNA methylation age and age-related disease and longevity is inconclusive. Increased epigenetic age was associated with mortality risk, but positive publication bias needs to be considered. Further research is needed to determine the extent to which DNA methylation age can be used as a clinical biomarker.

Abstract Introduction This study aimed to investigate cognitive aging trajectories, the associated sociodemographic characteristics, and the association of these trajectories with dementia. Methods Generally healthy older adults (n = 19,114) were followed for up to 7 years, with regular cognitive assessments. Group‐based trajectory modeling identified distinct cognitive trajectories. Results Four to seven trajectories were identified per cognitive domain. Stable trajectories were observed across domains. Improvement in verbal fluency and minor psychomotor slowing were common. Substantial decline in global cognition and episodic memory were observed in a small proportion of individuals. Older, less educated participants and men were more common in lower‐functioning trajectories (p

Abstract Introduction Diversity in cognition among apolipoprotein E (APOE) ε4 homozygotes can range from early‐onset Alzheimer's disease (AD) to a lifetime with no symptoms. Methods We evaluated a phenotypic extreme polygenic risk score (PRS) for AD between cognitively healthy APOE ε4 homozygotes aged ≥75 years (n = 213) and early‐onset APOE ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity. Results The PRS for AD was significantly higher in APOE ε4 homozygote AD cases compared to older cognitively healthy APOE ε4/ε4 controls (odds ratio [OR] 8.39; confidence interval [CI] 2.0–35.2; P = .003). The difference in the same PRS between APOE ε3/ε3 extremes was not as significant (OR 3.13; CI 0.98–9.92; P = .053) despite similar numbers and power. There was no statistical difference in an educational attainment PRS between these age extreme case‐controls. Discussion A PRS for AD contributes to modified cognitive expression of the APOE ε4/ε4 genotype at phenotypic extremes of risk.

Background: Findings on structural brain alterations following trauma are inconsistent due probably to heterogeneity in imaging studies and population, clinical presentations, genetic vulnerability, and selection of controls. This study examines whether trauma and re-experiencing symptoms are associated with specific alterations in grey matter volumes and if this varies according to 5-HTTLPR genotype. Methods: Structural MRI was used to acquire anatomical scans from 377 community-dwelling older adults. Quantitative regional estimates of 22 subregional volumes were derived using FreeSurfer software. Lifetime trauma was assessed using the validated Watson’s PTSD inventory, which evaluates the most severe trauma experienced according to DSM criteria. Analyses adjusted for age, sex, total brain volume, head injury, and comorbidities. Results: Of the 212 participants reporting lifetime trauma, 35.4% reported re-experiencing symptoms and for 1.9%, this was severe enough to meet criteria for full threshold PTSD. In participants with the SS 5-HTTLPR genotype only, re-experiencing symptoms were associated with smaller volumes in middle and superior temporal, frontal (lateral orbital, rostral and caudal middle) and parietal (precuneus, inferior and superior) regions. The trauma-exposed participants without re-experiencing symptoms were not significantly different from the non-trauma-exposed participants except for smaller precuneus and superior parietal region in traumatized participants and a larger amygdala in traumatized women specifically. Conclusions: In the non-clinical sample, lifetime trauma and re-experiencing symptoms were associated with smaller volume in prefrontal, temporal and parietal cortex subregions, and this varied according to serotonergic genetic vulnerability, 5-HTTLPR SS individuals being most susceptible.

Abstract Introduction This study determined whether blood DNA methylation (DNAm) patterns differentiate individuals with presymptomatic dementia compared to controls. Methods DNAm was measured in 73 individuals prior to dementia diagnosis and 87 cognitively healthy controls matched for age, sex, smoking, education, and baseline cognition. DNAm was also measured at 3 years follow‐up in 25 dementia cases, and 24 controls. Results Cases and controls differed in DNAm (unadjusted P

Abstract Background Disrupted serotonergic signaling is often a feature of depression and the role of the serotonin transporter gene (SLC6A4), responsible for serotonin re-uptake, has received much attention in this regard. Most studies have focused on the polymorphic 5-HTTLPR upstream repeat, or DNA methylation at the promoter CpG island. Few studies have explored the influence of genetic variation across the gene on DNA methylation, and their combined association with depression risk. The aim of this study was to determine whether genetic variation in the SLC6A4 gene influences promoter DNA methylation, and whether these are associated with depression status. Method The ESPRIT study involves a community-based population of older individuals (> 65 years of age). Major depressive disorder (MDD) was diagnosed according to DSM-IV (American Psychiatric Association, 1994) criteria, and severe depressive symptoms assessed by the Centre for Epidemiological Studies Depression (CES-D) Scale. Sequenom MassARRAY was used to measure SLC6A4 methylation status (n = 302). Results Nominally significant associations were observed between SLC6A4 genetic variants (5-HTTLPR, rs140700, rs4251417, rs6354, rs25528, rs25531) and DNA methylation at several CpG sites. In multivariate regression, DNA methylation was associated with depression status, but only in the presence of specific genotypes. In individuals homozygous for the short 5-HTTLPR and 5-HTTLPR/r25531 alleles, lower methylation at two CpGs was associated with depression (β = − 0.44 to β = − 0.31; p = 0.001 to p = 0.038). Conclusion We present evidence for genotype-dependent associations between SLC6A4 methylation and depression. Genetic variants may also play a role in influencing promoter methylation levels and its association with depression.

Abstract Background The neuropeptide Oxytocin (OXT) plays a central role in birthing, mother-infant bonding and a broad range of related social behaviours in mammals. More recently, interest has extended to epigenetic programming of genes involved in oxytocinergic neurotransmission. This review brings together early findings in a rapidly developing field of research, examining relationships between DNA methylation (DNAm) of the Oxytocin Receptor Gene (OXTR) and social and emotional behaviour in human populations. Method A systematic search across Web of Knowledge/Science, Scopus, Medline and EMBASE captured all published studies prior to June 2017 examining the association between OXTR DNAm and human social and emotional outcomes. Search terms included ‘oxytocin gene’ or ‘oxytocin receptor gene’ and ‘epigenetics’ or ‘DNA methylation’. Any article with a focus on social and emotional functioning was then identified from this set by manual review. Results Nineteen studies met eligibility criteria. There was considerable heterogeneity of study populations, tissue samples, instrumentation, measurement, and OXTR site foci. Only three studies examined functional consequences of OXTR DNAm on gene expression and protein synthesis. Increases in OXTR DNAm were associated with callous-unemotional traits in youth, social cognitive deficits in Autistic Spectrum Disorder (ASD), rigid thinking in anorexia nervosa, affect regulation problems, and problems with facial and emotional recognition. In contrast, reductions in DNAm were associated with perinatal stress, postnatal depression, social anxiety and autism in children. Conclusions Consistent with an emerging field of inquiry, there is not yet sufficient evidence to draw conclusions about the role of OXTR DNAm in human social and emotional behaviour. However, taken together, findings point to increased OXTR DNAm in general impairments in social, cognitive and emotional functioning, and decreased OXTR DNAm in specific patterns of impairment related to mood and anxiety disorders (but not in all). Future progress in this field would be enhanced by adequately powered designs, greater phenotypic precision, and methodological improvements including longitudinal studies with multiple time-points to facilitate causal inference.

Background: An adverse psychological environment (e.g. stressful events or depression) has been shown to influence basal cortisol levels and cortisol response to stress. This differs depending on the adverse stimuli, but also varies across individuals and may be influenced by genetic predisposition. An insertion/deletion polymorphism in the serotonin transporter gene (5-HTTLPR) is a strong candidate in this regard. Objective: To investigate how stressful life events and depression are associated with diurnal cortisol levels in community-dwelling elderly and determine whether this varies according to genetic variability in the 5-HTTLPR. Methods: This population-based study included 334 subjects aged 65 and older (mean (SD) = 76.5 (6.3)). Diurnal cortisol was measured on two separate days, under quiet (basal) and stressful conditions. The number of recent major stressful events experienced during the past year was assessed from a 12-item validated questionnaire as an index of cumulative recent stressful events. Lifetime trauma was evaluated using the validated Watson's PTSD inventory, which evaluates the most severe traumatic or frightening experience according to DSM criteria. Depression was defined as having a Mini-International Neuropsychiatric Interview (MINI) diagnosis of current major depressive disorder or high levels of depressive symptoms (Center for Epidemiologic Studies-Depression Scale â¥16). 5-HTTLPR genotyping was performed on blood samples. Results: Exposure to stressful life events was associated with lower basal evening cortisol levels overall, and in the participants with the 5-HTTLPR L allele but not the SS genotype. The greatest effects (over 50% decrease, pÂ

Abstract Background It is well established that there is a link between inflammation and depression, with several studies reporting increased circulating levels of the pro-inflammatory cytokine, interleukin-6 (IL6), in depressed individuals. Peripheral epigenetic marks, including DNA methylation, hold promise as biomarkers for a range of complex conditions, with potential to inform diagnosis and tailor interventions. The aim of this study was to determine whether individuals with depression display differential methylation of the IL6 gene promoter compared to individuals without depression. Methods The ESPRIT study of later life neuropsychiatric disorders used a random sampling framework to select non-institutionalised participants aged ≥65 years and over living in the Montpellier region of France. Major depressive disorder (MDD) was assessed using the Mini International Neuropsychiatric Interview (MINI) according to DSM-IV criteria. High levels of depressive symptoms were defined as a score of ≥16 on the Centre for Epidemiologic Studies Depression Scale (CES-D). IL6 promoter DNA methylation was measured on a sub-sample of 380 participants who provided buccal samples. Results Individuals with depression (current MDD or high depressive symptoms) had lower IL6 methylation levels at one of the four sites investigated, however the effect size was small (∆ 2.4%, SE 0.009, p = 0.006). Interestingly, antidepressant use was independently associated with higher IL-6 methylation at the same site (∆ 4.6%, SE 0.019, p = 0.015). In multivariate linear regression analyses adjusting for covariates, including sex and smoking status, these associations remained. There was no effect modification when considering IL6 genotype. Conclusion This study presents evidence that IL6 methylation may be a marker of depression status in older individuals, however further work is now needed to replicate these findings and to assess the association with inflammatory status of individuals.

Dementia can result from a number of distinct diseases with differing etiology and pathophysiology. Even within the same disease, there is considerable phenotypic heterogeneity with varying symptoms and disease trajectories. Dementia diagnosis is thus very complex, time-consuming, and expensive and can only be made definitively post-mortem with histopathological confirmation. These inherent difficulties combined with the overlap of some symptoms and even neuropathological features, present a challenging problem for research in the field. This has likely hampered progress in epidemiological studies of risk factors and preventative interventions, as well as genetic and biomarker research. Resource limitations in large epidemiologically studies mean that limited diagnostic criteria are often used, which can result in phenotypically heterogeneous disease states being grouped together, potentially resulting in misclassification bias. When biomarkers are identified for etiologically heterogeneous diseases, they will have low specificity for any utility in clinical practice, even if their sensitivity is high. We highlight several challenges in in the field which must be addressed for the success of future genetic and biomarker studies, and may be key to the development of the most effective treatments. As a step toward achieving this goal, defining the dementia as a biological construct based on the presence of specific pathological features, rather than clinical symptoms, will enable more precise predictive models. It has the potential to lead to the discovery of novel genetic variants, as well as the identification of individuals at heightened risk of the disease, even prior to the appearance of clinical symptoms.

Following publication of the original article [1], the authors opted to revise the first paragraph of the section “Characteristics associated with maternal drinking in pregnancy”. Below is the updated version.

Objectives: To examine the relationship between psychological and social factors (depression, emotional control, sexual abuse, and parental physical punishment) and adolescent drive for Thinness and Bulimic behaviors in a large community sample, and to investigate possible genetic moderation.Method: Data were drawn from the Australian Temperament Project (ATP), a population-based cohort study that has followed a representative sample of 2443 participants from infancy to adulthood across 16 waves since 1983. A subsample of 650 participants (50.2% female) of Caucasian descent who provided DNA were genotyped for a serotonin transporter promoter polymorphism (5-HTTLPR). Adolescent disordered eating attitudes and behaviors were assessed using the Bulimia and Drive for Thinness scales of the Eating Disorder Inventory-2 (15–16 years). Depression and emotional control were examined at the same age using the Short Mood and Feelings Questionnaire, and an ATP-devised measure of emotional control. History of sexual abuse and physical punishment were assessed retrospectively (23–24 years) in a subsample of 467 of those providing DNA.Results: EDI-2 scores were associated with depression, emotional control, and retrospectively reported parental physical punishment. Although there was statistically significant moderation of the relationship between parental physical punishment and bulimic behaviors by 5-HTTLPR (p = 0.0048), genotypes in this subsample were not in Hardy–Weinberg Equilibrium. No other G×E interactions were significant. Conclusion: Findings from this study affirm the central importance of psychosocial processes in disordered eating patterns in adolescence. Evidence of moderation by 5-HTTLPR was not conclusive; however, genetic moderation observed in a subsample not in Hardy–Weinberg Equilibrium warrants further investigation.

BackgroundThe association between hormone treatment (HT) and mortality remains controversial. This study aimed to determine whether the risk of mortality associated with HT use varies depending on the specific characteristics of treatment and genetic variability in terms of the estrogen receptor.Methodology/principal findingsA prospective, population-based study of 5135 women aged 65 years and older who were recruited from three cities in France and followed over six years. Detailed information related to HT use was obtained and five estrogen receptor polymorphisms were genotyped. The total follow-up was 25,436 person-years and during this time 352 women died. Cancer (36.4%) and cardiovascular disease (19.3%) were the major causes of death. Cox proportional hazards models adjusted for age, education, centre, living situation, comorbidity, depression, physical and mental incapacities, indicated no significant association between HT and mortality, regardless of the type or duration of treatment, or the age at initiation. However, the association between HT and all-cause or cancer-related mortality varied across women, with significant interactions identified with three estrogen receptor polymorphisms (p-values = 0.004 to 0.03) in adjusted analyses. Women carrying the C allele of ESR1 rs2234693 had a decreased risk of all-cause mortality with HT (HR: 0.42, 95% CI: 0.18-0.97), while in stark contrast, those homozygous for the T allele had a significantly increased risk of cancer-related mortality (HR: 3.18, 95% CI: 1.23-8.20). The findings were similar for ESR1 rs9340799 and ESR2 rs1271572.Conclusions/significanceThe risk of mortality was not associated with HT duration, type or age at initiation. It was however not equal across all women, with some women appearing genetically more vulnerable to the effects of HT in terms of their estrogen receptor genotype. These findings, if confirmed in another independent study, may help explain the differential susceptibility of women to the beneficial or adverse effects of HT.