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BackgroundSocial prescribing (SP) enables healthcare professionals to link patients with non-medical interventions available in the community to address underlying socioeconomic and behavioural determinants. We synthesised the evidence to understand the effectiveness of SP for chronic disease prevention.MethodsA systematic literature search was conducted using five databases and two registries. Eligible studies included randomised controlled trials of SP among community-dwelling adults recruited from primary care or community setting, investigating any chronic disease risk factors defined by the WHO (behavioural factors: smoking, physical inactivity, unhealthy diet and excessive alcohol consumption; metabolic factors: raised blood pressure, overweight/obesity, hyperlipidaemia and hyperglycaemia). Random effect meta-analyses were performed at two time points: completion of intervention and follow-up after trial.ResultsWe identified nine reports from eight trials totalling 4621 participants. All studies evaluated SP exercise interventions which were highly heterogeneous regarding the content, duration, frequency and length of follow-up. Majority of studies had some concerns for risk of bias. Meta-analysis revealed that SP likely increased physical activity (completion: mean difference (MD) 21 min/week, 95% CI 3 to 39, I2=0%; follow-up ≤12 months: MD 19 min/week, 95% CI 8 to 29, I2=0%). However, SP may not improve markers of adiposity, blood pressure, glucose and serum lipid. There were no eligible studies that primarily target unhealthy diet, smoking and excessive alcohol drinking behaviours.ConclusionsSP exercise interventions probably increased physical activity slightly; however, no benefits were observed for metabolic factors. Determining whether SP is effective in modifying the determinants of chronic diseases and promotes sustainable healthy behaviours is limited by the current evidence of quantification and uncertainty, warranting further rigorous studies.PROSPERO registration numberCRD42022346687.

We sought to determine the association between heart failure (HF) and cognitive change and dementia.Systematic search of three electronic databases was performed and 29 eligible studies involving approximately 3 million participants were identified. Twelve studies examined dementia and 20 cognitive change, but only a subset of studies could be included in the meta-analysis. These findings indicated that HF was not significantly associated with dementia (n = 8, hazard ratio 1.18, 95% confidence interval 0.93-1.50), but increased the risk of cognitive impairment (n = 3, hazard ratio 1.80, 95% confidence interval 1.14-2.86) . Additionally, HF was associated with poorer mean cognitive performance in global cognition (Hedges' g -0.73, 95% confidence interval -1.12 to -0.35), memory (Hedges' g -0.57, 95% confidence interval -0.72 to -0.42), executive function (Hedges' g -0.58, 95% confidence interval -0.72 to -0.43), attention/speed (Hedges' g -0.50, 95% confidence interval -0.63 to -0.37) and language (Hedges' g -0.61, 95% confidence interval -1.05 to -0.17).Patients with HF perform worse on all cognitive tests and have an increased risk of cognitive impairment. These findings highlight the need for clinicians to consider cognition as part of routine care for patients with HF.

Background: Cognitive test-retest reliability measures can be used to evaluate meaningful changes in scores. Objective: This analysis aimed to develop a comprehensive set of test-retest reliability values and minimal detectable change (MDC) values for a cognitive battery for community-dwelling older individuals in Australia and the U.S., for use in clinical practice. Methods: Cognitive scores collected at baseline and year 1, in the ASPirin in Reducing Events in the Elderly clinical trial were used to calculate intraclass correlation coefficients (ICC) for four tests: Modified Mini-Mental State examination (3MS), Hopkins Verbal Learning Test-Revised (HVLT-R), single-letter Controlled Oral Word Association Test (COWAT-F), and Symbol Digit Modalities Test (SDMT). 16,956 participants aged 70 years and over (65 years and over for U.S. minorities) were included. ICCs were used to calculate MDC values for eight education and ethno-racial subgroups. Results: All four cognitive tests had moderate (ICC > 0.5) to good (ICC > 0.7) test-retest reliability. ICCs ranged from 0.53 to 0.63 (3MS), 0.68 to 0.77 (SDMT), 0.56 to 0.64 (COWAT-F), 0.57 to 0.69 (HVLT-R total recall), and 0.57 to 0.70 (HVLT-R delayed recall) across the subgroups. MDC values ranged from 6.60 to 9.95 (3MS), 12.42 to 15.61 (SDMT), 6.34 to 8.34 (COWAT-F), 8.13 to 10.85 (HVLT-R total recall), and 4.00 to 5.62 (HVLT-R delayed recall). Conclusion: This large cohort of older individuals provides test-retest reliability and MDC values for four widely employed tests of cognitive function. These results can aid interpretation of cognitive scores and decline instead of relying on cross-sectional normative data alone.

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.

Background Evidence for the prognostic implications of hyperglycaemia in older adults is inconsistent. Objective To evaluate disability-free survival (DFS) in older individuals by glycaemic status. Methods This analysis used data from a randomised trial recruiting 19,114 community-based participants aged ≥70 years, who had no prior cardiovascular events, dementia and physical disability. Participants with sufficient information to ascertain their baseline diabetes status were categorised as having normoglycaemia (fasting plasma glucose [FPG] Results We included 18,816 participants (median follow-up: 6.9 years). Compared to normoglycaemia, participants with diabetes had greater risks of DFS loss (weighted HR: 1.39, 95% CI 1.21–1.60), all-cause mortality (1.45, 1.23–1.72), persistent physical disability (1.73, 1.35–2.22), CIND (1.22, 1.08–1.38), MACE (1.30, 1.04–1.63) and cardiovascular events (1.25, 1.02–1.54) but not dementia (1.13, 0.87–1.47). The prediabetes group did not have an excess risk for DFS loss (1.02, 0.93–1.12) or other outcomes. Conclusions Among older people, diabetes was associated with reduced DFS, and higher risk of CIND and cardiovascular outcomes, whereas prediabetes was not. The impact of preventing or treating diabetes in this age group deserves closer attention.

Supplementary Table 1 from The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells

Supplementary Figure Legends 1-4 from The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells

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Supplementary Figure 1 from The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells

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Objectives We provide new evidence on the profiles of social isolation, social support, and loneliness before and after spousal death for older widows. We also examine the moderating effects of gender and financial resources on changes in social health before and after widowhood. Methods We use 19 waves of data from the Household, Income and Labour Dynamics in Australia Survey, including 749 widowed individuals and a comparison group of around 8,000 married individuals. We apply coarsened exact matching weights and control for age and time trends. Local polynomial smoothed plots show the profiles of social health from 3 years pre- to 3 years postspousal death. All analyses were stratified by gender. Results Spousal death was strongly associated with increased loneliness for women and men, but also an increase in interactions with friends and family not living with the bereaved. For men, financial resources (both income and asset wealth) provided some protection against loneliness. Spousal death was not associated with changes in social support or participation in community activities. Discussion We demonstrate that loneliness is a greater challenge of widowhood than social isolation or a lack of social support. Our findings suggest that interventions focusing only on increasing social interactions are unlikely to alleviate loneliness following spousal death. Moreover, policies that reduce the cost of formal social participation may have limited effectiveness in tackling loneliness, particularly for women. Alternative strategies, such as helping the bereaved form a new sense of identity and screening for loneliness around widowhood by health care workers, could be beneficial.

BACKGROUND: CKD is a risk factor for cognitive impairment (CI), but reports of individual associations of eGFR and albuminuria with CI and incident dementia in healthier, older, longitudinal populations are lacking. Our goal was to estimate these associations in a large cohort of older healthy persons. METHODS: In a longitudinal cohort study of older persons without prior cardiovascular disease, we estimated the associations between baseline eGFR (in ml/min per 1.73 m(2)) and albuminuria, measured as urine albumin-creatinine ratio (UACR; in mg/mmol) and cognitive test scores, declines in cognitive test scores, and incident dementia using adjusted linear and linear mixed models. Cox proportional hazards regression models assessed the association between baseline kidney function and incident CI no dementia (CIND) or dementia at a median of 4.7 years. RESULTS: At baseline, among 18,131 participants, median age was 74 years, eGFR was 74 (IQR, 63–84) ml/min per 1.73 m(2), UACR was 0.8 (IQR, 0.5–1.5) mg/mmol (7.1 [4.4–13.3] mg/g), and 56% were female. Baseline eGFR was not associated with performance on any cognitive tests in cross-sectional analysis, nor was incident CIND or dementia over a median follow-up of 4.7 years. However, baseline UACR ≥3 mg/mmol (≥26.6 mg/g) was significantly associated with lower baseline scores and larger declines on the Modified Mini-Mental State Exam, verbal memory and processing speed tests, and with incident CIND (hazard ratio [HR], 1.19; 95% CI, 1.07 to 1.33) and dementia (HR, 1.32; 95% CI, 1.06 to 1.66). CONCLUSION: Mild albuminuria was associated with worse baseline cognitive function, cognitive decline, and increased risk for incident CIND and dementia. Screening global cognitive tests for older persons with UACR ≥3 mg/mmol could identify those at elevated risk of cognitive decline and dementia.

Brain age is a neuroimaging-based biomarker of aging. This study examined whether the difference between brain age and chronological age (brain-PAD) is associated with cognitive function at baseline and longitudinally. Participants were relatively healthy, predominantly white community-dwelling older adults (n = 531, aged ≥70 years), with high educational attainment (61% ≥12 years) and socioeconomic status (59% ≥75th percentile). Brain age was estimated from T1-weighted magnetic resonance images using an algorithm by Cole et al., 2018. After controlling for age, gender, education, depression and body mass index, brain-PAD was negatively associated with psychomotor speed (Symbol Digit Modalities Test) at baseline (Bonferroni p < 0.006), but was not associated with baseline verbal fluency (Controlled Oral Word Association Test), delayed recall (Hopkins Learning Test Revised), or general cognitive status (Mini-Mental State Examination). Baseline brain-PAD was not associated with 3-year change in cognition (Bonferroni p > 0.006). These findings indicate that even in relatively healthy older people, accelerated brain aging is associated with worse psychomotor speed, but future longitudinal research into changes in brain-PAD is needed.

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.

Purpose: Recent epidemiological evidence has suggested that use of lipid-lowering medications, particularly statins, was associated with reduced cardiovascular disease (CVD) events and persistent physical disability in healthy older adults. However, the comparative efficacy of different statins in this group remains unclear. This study aimed to compare different forms of statins in their associations with CVD and physical disability in healthy older adults. Methods: This post hoc analysis included data from 5981 participants aged ≥ 70 years (≥ 65 if US minorities; median age:74.0) followed for a median of 4.7 years, who had no prior CVD events or physical disability and reported using a statin at baseline. The incidence of the composite and components of major adverse cardiovascular events and persistent physical disability were compared across different statins according to their type, potency, and lipophilicity using multivariable Cox proportional-hazards models. Results: Atorvastatin was the most used statin type at baseline (37.9%), followed by simvastatin (29.6%), rosuvastatin (25.5%), and other statins (7.0%, predominantly pravastatin). In comparisons of specific statins according to type and lipophilicity (lipophilic vs. hydrophilic statin), observed differences in all outcomes were small and not statistically significant (all p values > 0.05). High-potency statin use (atorvastatin and rosuvastatin) was marginally associated with lower risk of fatal CVD events compared with low-/moderate-potency statin use (hazard ratio: 0.59; 95% confidence interval: 0.35, 1.00). Conclusion: There were minimal differences in CVD outcomes and no significant difference in persistent physical disability between various forms of statins in healthy older adults. Future investigations are needed to confirm our results.

Gerontology and ageing research are increasingly focussing on healthy life span (healthspan), the period of life lived free of serious disease and disability. Late-life depression (LLD) is believed to impact adversely on physical health. However, no studies have examined its effect on healthspan. This study investigated the effect of LLD and subthreshold depression on disability-free survival, a widely accepted measure of healthspan.This prospective cohort study used data from the ASPirin in Reducing Events in the Elderly study. Participants were aged ≥70 years (or ≥65 years for African-American and Hispanic participants) and free of dementia, physical disability and cardiovascular disease. Depressive symptoms were measured using the 10-item Centre for Epidemiological Studies Depression Scale (CES-D-10). LLD and subthreshold depression were defined as CES-D-10 scores ≥8 and 3-7, respectively. Disability-free survival was defined as survival free of dementia and persistent physical disability.A total of 19,110 participants were followed up for a maximum of 7.3 years. In female participants, LLD was associated with lower disability-free survival adjusting for sociodemographic and lifestyle factors, medical comorbidities, polypharmacy, physical function and antidepressant use (HR, 1.50; 95% CI, 1.23-1.82). In male participants, LLD was associated with lower disability-free survival adjusting for sociodemographic and lifestyle factors (HR, 1.30; 95% CI, 1.03-1.64). Subthreshold depression was also associated with lower disability-free survival in both sexes.LLD may be a common and important risk factor for shortened healthspan.

Background: Biological aging may be a robust biomarker of dementia or cognitive performance. This systematic review synthesized the evidence for an association between epigenetic aging and dementia, mild cognitive impairment and cognitive function. Methods: A systematic search was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: 30 eligible articles were included. There was no strong evidence that accelerated epigenetic aging was associated with dementia/mild cognitive impairment (n = 7). There was some evidence of an association with poorer cognition (n = 20), particularly with GrimAge acceleration, but this was inconsistent and varied across cognitive domains. A meta-analysis was not performed due to high study heterogeneity. Conclusion: There is insufficient evidence to indicate that current epigenetic aging clocks can be clinically useful biomarkers of dementia or cognitive aging.

PurposeThe 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).ParticipantsThe 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 dateA 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 plansAssessments 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.

Frailty and chronic kidney disease (CKD) both increase with age and are prevalent in older adults. However, studies in older adults examining the relationship between frailty and milder impairments of kidney function are relatively sparse. We examined the cross-sectional association of baseline estimated glomerular filtration rate (eGFR), albuminuria and CKD ([eGFR60 ml/min/1.73 m

Frailty is a state of heightened vulnerability and susceptibility to physiologic stressors that increases with age. It has shown increasing utility in predicting a range of adverse health outcomes. Here, we characterize a 67-item deficit-accumulation frailty index (FI) in 19 110 community-dwelling individuals in the ASPirin in Reducing Events in the Elderly clinical trial. Participants aged 65–98 years were recruited from the United States and Australia and were without diagnosed dementia and cardiovascular disease, and major physical disability. The median FI score was .10 (interquartile range: .07–.14) at baseline, and the prevalence of frailty (FI > .21) increased from 8.1% to 17.4% after 6 years. FI was positively associated with age, and women had significantly higher scores than men at all ages. The FI was negatively correlated with gait speed (r = −.31) and grip strength (r = −.46), and strongly associated with a modified Fried’s frailty phenotype (p < .0001, for all comparisons). Frailty was associated with the primary composite outcome capturing independent life lived free of major disability and dementia, and increased the rate of persistent physical disability (hazard ratio: 21.3, 95% confidence interval: 15.6–28.9). It added significantly to the predictive capacity of these outcomes above age, sex, and ethnicity alone. The FI is thus a useful biomarker of aging even among relatively healthy older individuals and provides important information about an individual’s vulnerability to and risk of disease.

Background: The neurocognitive effect of statins in older adults remain uncertain. Objectives: The aim of this study was to investigate the associations of statin use with cognitive decline and incident dementia among older adults. Methods: This analysis included 18,846 participants ≥65 years of age in a randomized trial of aspirin, who had no prior cardiovascular events, major physical disability, or dementia initially and were followed for 4.7 years. Outcome measures included incident dementia and its subclassifications (probable Alzheimer's disease, mixed presentations); mild cognitive impairment (MCI) and its subclassifications (MCI consistent with Alzheimer's disease, other MCI); and changes in domain-specific cognition, including global cognition, memory, language and executive function, psychomotor speed, and the composite of these domains. Associations of baseline statin use versus nonuse with dementia and MCI outcomes were examined using Cox proportional hazards models and with cognitive change using linear mixed-effects models, adjusting for potential confounders. The impact of statin lipophilicity on these associations was further examined, and effect modifiers were identified. Results: Statin use versus nonuse was not associated with dementia, MCI, or their subclassifications or with changes in cognitive function scores over time (p > 0.05 for all). No differences were found in any outcomes between hydrophilic and lipophilic statin users. Baseline neurocognitive ability was an effect modifier for the associations of statins with dementia (p for interaction Conclusions: In adults ≥65 years of age, statin therapy was not associated with incident dementia, MCI, or declines in individual cognition domains. These findings await confirmation from ongoing randomized trials.

Aim: To investigate the association between maternal post-traumatic stress disorder (PTSD) during pregnancy and offspring DNA methylation and cortisol levels. Materials & methods: Blood genome-wide DNA methylation and cortisol was measured in the youngest child of 117 women who experienced sexual violence/torture during the Kosovo war. Results: Seventy-two percent of women had PTSD symptoms during pregnancy. Their children had higher cortisol levels and differential methylation at candidate genes ( NR3C1, HTR3A and BNDF) . No methylation differences reached epigenome-wide corrected significance levels. Conclusion: Identifying the biological processes whereby the negative effects of trauma are passed across generations and defining groups at high risk is a key step to breaking the intergenerational transmission of the effects of mental disorders.

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.

High office blood pressure variability (OBPV) in midlife increases the risk of cardiovascular disease (CVD), but the impact of OBPV in older adults without previous CVD is unknown. We conducted a post hoc analysis of ASPREE trial (Aspirin in Reducing Events in the Elderly) participants aged 70-years and older (65 for US minorities) without history of CVD events at baseline, to examine risk of incident CVD associated with long-term, visit-to-visit OBPV. CVD was a prespecified, adjudicated secondary end point in ASPREE. We estimated OBPV using within-individual SD of mean systolic BP from baseline and first 2 annual visits. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% CI for associations with CVD events. In 16 475 participants who survived to year 2 without events, those in the highest tertile of OBPV had increased risk of CVD events after adjustment for multiple covariates, when compared with participants in the lowest tertile (HR, 1.36 [95% CI, 1.08–1.70]; P =0.01). Similar increased risk was observed for ischemic stroke (HR, 1.56 [95% CI, 1.04–2.33]; P =0.03), heart failure hospitalization, or death (HR, 1.73 [95% CI, 1.07–2.79]; P =0.02), and all-cause mortality (HR, 1.27 [95% CI, 1.04–1.54]; P =0.02). Findings were consistent when stratifying participants by use of antihypertensive drugs, while sensitivity analyses suggested the increased risk was especially for individuals whose BP was uncontrolled during the OBPV estimation period. Our findings support increased OBPV as a risk factor for CVD events in healthy older adults with, or without hypertension, who have not had such events previously. Registration— URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT01038583; URL: https://www.isrctn.com ; Unique identifiers: ISRCTN83772183.

BACKGROUND Polypharmacy and frailty are two common geriatric syndromes. We examined the association between polypharmacy and frailty and if, together, they predicted disability-free survival (DFS), defined as time to the first event of dementia, persistent physical disability or death. METHODS We included 19,114 participants from the "ASPirin in Reducing Events in the Elderly" (ASPREE) clinical trial. Polypharmacy was defined as regular, concomitant use of five or more prescription medications. Frailty was assessed using a modified Fried phenotype and a deficit accumulation frailty index (FI) of 66 items. The association between polypharmacy and frailty was assessed by multinomial logistic regression. In addition, Cox regression was used to determine the association between polypharmacy-exposed frailty and DFS. RESULTS Individuals with polypharmacy (vs. < 5 medications) were 55% more likely to be pre-frail (Relative Risk Ratio or RRR: 1.55; 95%Confidence Interval or CI:1.44, 1.68) and three times more likely to be frail (RRR: 3.34; 95%CI: 2.64, 4.22) according to Fried phenotype. Frail individuals had a two-fold reduction in their survival free of dementia/disability (Hazard ratio or HR: 2.16; 95%CI: 1.56, 2.99), whereas frail individuals with polypharmacy had a four-fold reduction (HR: 4.24; 95%CI: 3.28, 5.47). Effect sizes were more prominent when frailty was assessed using the FI than when assessed by Fried phenotype. CONCLUSION Polypharmacy was significantly associated with pre-frailty/frailty. Polypharmacy-exposed pre-frailty/frailty increased the risk of death, dementia or physical disability among older adults. Addressing polypharmacy in older people could ameliorate the impact of frailty on individuals’ functional status, cognition and survival.

BACKGROUND Frailty is associated with adverse outcomes, but whether it independently increases cardiovascular disease (CVD) risk requires clarification. METHODS This study examined the association between frailty in a cohort with no previous CVD events and subsequent CVD outcomes in 19,114 community-dwelling older people from the ASPREE trial. Frailty was assessed using the modified Fried phenotype, comprising weakness, exhaustion, low body mass index (BMI), slowness and low physical activity, and a deficit accumulation frailty index (FI) of 66 items. CVD event was defined as a composite of CVD death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for heart failure. Results Over a median 4.7-years of follow-up (interquartile range: 3.6 to 5.7 years), pre-frail/frail participants were more likely to develop CVD events (Hazard ratio (HR): 1.33; 95% Confidence Interval (CI): 1.16, 1.53 for pre-frail and HR: 1.68; 95% CI: 1.19, 2.38 for frail participants) according to Fried phenotype. Subtypes of CVD (fatal/non-fatal myocardial infarction and heart failure hospitalization) similarly increased HRs except fatal or non-fatal stroke. These effect sizes were more prominent when frailty was assessed using the FI than that assessed by Fried phenotype. CONCLUSION Pre-frail and frail participants were at significantly increased risk of developing CVD and its sub-types (particularly fatal/non-fatal myocardial infarction and hospitalization for heart failure). Addressing pre-frailty and frailty in older people could contribute to CVD prevention strategies.

Dual decline in gait speed and cognition has been found to be associated with increased dementia risk in previous studies. However, it is unclear if risks are conferred by a decline in domain-specific cognition and gait.To examine associations between dual decline in gait speed and cognition (ie, global, memory, processing speed, and verbal fluency) with risk of dementia.This cohort study used data from older adults in Australia and the US who participated in a randomized clinical trial testing low-dose aspirin between 2010 and 2017. Eligible participants in the original trial were aged 70 years or older, or 65 years or older for US participants identifying as African American or Hispanic. Data analysis was performed between October 2020 and November 2021.Gait speed, measured at 0, 2, 4, and 6 years and trial close-out in 2017. Cognitive measures included Modified Mini-Mental State examination (3MS) for global cognition, Hopkins Verbal Learning Test-Revised (HVLT-R) for memory, Symbol Digit Modalities (SDMT) for processing speed, and Controlled Oral Word Association Test (COWAT-F) for verbal fluency, assessed at years 0, 1, 3, 5, and close-out. Participants were classified into 4 groups: dual decline in gait and cognition, gait decline only, cognitive decline only, and nondecliners. Cognitive decline was defined as membership of the lowest tertile of annual change. Gait decline was defined as a decline in gait speed of 0.05 m/s or greater per year across the study.Dementia (using Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition] criteria) was adjudicated by an expert panel using cognitive tests, functional status, and clinical records. Cox proportional hazard models were used to estimate risk of dementia adjusting for covariates, with death as competing risk.Of 19 114 randomized participants, 16 855 (88.2%) had longitudinal gait and cognitive data for inclusion in this study (mean [SD] age, 75.0 [4.4] years; 9435 women [56.0%], 7558 participants [44.8%] with 12 or more years of education). Compared with nondecliners, risk of dementia was highest in the gait plus HVLT-R decliners (hazard ratio [HR], 24.7; 95% CI, 16.3-37.3), followed by the gait plus 3MS (HR, 22.2; 95% CI, 15.0-32.9), gait plus COWAT-F (HR, 4.7; 95% CI, 3.5-6.3), and gait plus SDMT (HR, 4.3; 95% CI, 3.2-5.8) groups. Dual decliners had a higher risk of dementia than those with either gait or cognitive decline alone for 3MS and HVLT-R.Of domains examined, the combination of decline in gait speed with memory had the strongest association with dementia risk. These findings support the inclusion of gait speed in dementia risk screening assessments.

Purpose: The Australian Temperament Project Generation 3 Cohort (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 (e.g., emotional regulation, relationship quality and prosociality) and maladjustment (e.g., 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) and their parents (Generation 1). Since then, families have been followed from infancy to young adulthood (15 waves). Between 2012 and 2018, the cohort was screened biannually for pregnancies and infants (Generation 3). Assessments were conducted in the third trimester of pregnancy, and at 8 weeks and 1 year postpartum. Findings to date: 1167 offspring (607 female) born to 703 ATP G2 parents (400 mothers) were recruited into the ATPG3 Cohort. 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 the ATPG3 cohort 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: Positive psychosocial factors may protect against cardiovascular disease (CVD). We aimed to determine the association of optimism and pessimism with CVD events in community-dwelling older adults. Methods: 11,651 adults aged 70 years and over, participants of the ASPREE Longitudinal Study of Older Persons (ALSOP), were followed-up for 4.7 years (median). The association of optimism and pessimism (assessed as separate constructs by revised Life Orientation Test) and incident CVD events (composite and components) was assessed by Cox regression adjusted for demographic, socioeconomic and health factors. Results: No association was observed between optimism and pessimism with composite CVD events. Being more pessimistic was associated with a greater risk of fatal coronary heart disease, while being more optimistic was associated with a lower risk of non-fatal myocardial infarction. Conclusions: Optimism and pessimism may shape cardiovascular health of older adults; and we argue these psychosocial factors should be researched as separate constructs.

Background Parental depression and anxiety have been consistently linked to offspring behavior problems across childhood. However, many of the risks for these common mental health problems are established well before pregnancy. This study takes advantage of rare, prospective data to examine relations between parental mental health histories (from adolescence onwards) and next generation offspring behavior problems. Methods Data were drawn from a multi-generational cohort study that has followed Australians from infancy to adulthood since 1983, and 1171 of their offspring assessed prospectively from pregnancy. Generalized estimating equation models were used to estimate associations between parents’ depression/anxiety symptoms in adolescence and young adulthood and offspring behavior problems at 1 year. Results In analyses of 648 mother-infant and 423 father-infant dyads, after adjustment for confounders and concurrent mental health problems, mean behavior problem scores in infants of mothers with a history of mental health problems in both adolescence and young adulthood were over half a standard deviation higher than those of mothers without problems during these periods, B = 2.19, 95% CI 1.21 – 3.17, β = 0.52. No association was observed for fathers. Limitations We only included infants born to participants aged 29–35 years and we assessed behavior problems via parent-report. Conclusions A mother's history of persistent depression and anxiety from adolescence to young adulthood can predict higher levels of behavior problems in her infant. Findings support calls for greater policy and prevention focus on preconception and postnatal mental health, particularly a mother's early emotional health history, prior to parenthood.

ObjectiveTo determine the effect of low-dose aspirin vs placebo on incident all-cause dementia, incident Alzheimer disease (AD), mild cognitive impairment (MCI), and cognitive decline in older individuals.MethodsAspirin in Reducing Events in the Elderly (ASPREE) was a double-blind, placebo-controlled trial of low-dose aspirin. In the United States and Australia, community-dwelling individuals aged ≥70 years (US minorities ≥65 years) and free of cardiovascular disease, physical disability, and diagnosed dementia were enrolled. Participants were randomized 1:1–100 mg daily aspirin or placebo. The Modified Mini-Mental State Examination, Hopkins Verbal Learning Test–Revised, Symbol Digit Modalities Test, and Controlled Oral Word Association Test assessed cognition at baseline and over follow-up. Additional cognitive testing was performed in participants with suspected dementia (“trigger”) based on within-study assessments or clinical history. Dementia was adjudicated according to DSM-IV criteria. National Institute on Aging–Alzheimer’s Association criteria were used for AD and MCI subclassification.ResultsA total of 19,114 participants were followed over a median 4.7 years and 964 triggered further dementia assessments. There were 575 adjudicated dementia cases, and 41% were classified as clinically probable AD. There was no substantial difference in the risk of all dementia triggers (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.91–1.17), probable AD (HR, 0.96; 95% CI, 0.74–1.24), or MCI (HR, 1.12; 95% CI, 0.92–1.37) between aspirin and placebo. Cognitive change over time was similar in the aspirin and placebo groups.ConclusionsThere was no evidence that aspirin was effective in reducing risk of dementia, MCI, or cognitive decline. Follow-up of these outcomes after initial exposure is ongoing.Classification of evidenceThis study provides Class II evidence that for healthy older individuals, low-dose aspirin does not significantly reduce the incidence of dementia, probable AD, MCI, or cognitive decline.Clinicaltrials.gov identifierNCT01038583.

OBJECTIVE: The Hopkins Verbal Learning Test-Revised (HVLT-R) provides a measure of verbal learning and memory. The aim of this study was to provide normative performance data on the HVLT-R for community-dwelling older individuals according to ethno-racial group, age, gender, and years of completed education, in Australia and the U.S. METHOD: The ASPirin in Reducing Events in the Elderly (ASPREE) study recruited 19 114 generally healthy community dwelling individuals aged 70 years and over (65 years and over for U.S minorities), who were without a diagnosis of dementia and scored above 77 on the modified Mini-Mental State (3MS) examination. Included in the analysis presented here were 16 251 white Australians, and in the U.S. 1 082 white, 894 African American and 314 Hispanic/Latino individuals at baseline. RESULTS: Performance on each of the components of the HVLT-R (trials 1–3, total, learning, delayed recall, delayed recognition, percentage retention and recognition discrimination index [RDI]) differed by demographic variables. In country and ethno-racial stratified analyses, female gender, younger age and higher education were significantly associated with better total recall, delayed recall and RDI. Among white Australians these characteristics were also associated with better retention. Age, education and gender-specific reference values across ethno-racial categories were determined. CONCLUSIONS: Ethno-racial, age, gender and education-stratified normative data from this large cohort of community-dwelling older individuals will serve as important reference standards in Australia and the U.S. to assess cognition in older individuals.

There is considerable variability in the rate at which we age biologically, and the brain is particularly susceptible to the effects of aging.We examined the test-retest reliability of brain age at one- and three-year intervals and identified characteristics that predict the longitudinal change in brain-predicted age difference (brain-PAD, defined by deviations of brain age from chronological age).T1-weighted magnetic resonance images were acquired at three timepoints from 497 community-dwelling adults (73.8±3.5 years at baseline, 48% were female). Brain age was estimated from whole brain volume, using a publicly available algorithm trained on an independent dataset. Linear mixed models were used, adjusting for sex, age, and ageExcellent retest reliability of brain age was observed over one and three years. We identified a significant sex difference in brain-PAD, where a faster rate of brain aging (worsening in brain age relative to chronological age) was observed in men, and this finding replicated in secondary analyses. The effect size, however, was relatively weak, equivalent to 0.16 years difference per year. A higher score in physical health related quality of life and verbal fluency were associated with a faster rate of brain aging, while depression was linked to a slower rate of brain aging, but these findings were not robust.Our study provides consistent evidence that older men have slightly faster brain atrophy than women. Given the sparsity of longitudinal research on brain age in older populations, future prospective studies are needed to confirm our findings.

BACKGROUND: Optimism is a disposition characterised by positive future expectancies, while pessimism is characterised by expecting the worst. High optimism and low pessimism promote the health of older adults and may potentiate full engagement in life. We identified socioeconomic, behavioural, and social factors associated with optimism and pessimism in older adults.METHODS: Participants included 10,146 community-dwelling, apparently healthy Australian adults aged 70 years and over from the ASPREE Longitudinal Study of Older Persons (ALSOP). Optimism and pessimism were measured using the revised Life Orientation Test. Cross-sectional ordinal logistic regression was used to determine the socioeconomic, behavioural, and social health factors associated with optimism and pessimism.RESULTS: Higher education, greater physical activity, lower loneliness, and volunteering were associated with higher optimism and lower pessimism. Low social support was associated with higher pessimism. Higher socioeconomic advantage, greater income, and living alone were associated with lower pessimism. Women were more optimistic and less pessimistic than men. The association of age, smoking status, and alcohol consumption with optimism and pessimism differed for men and women.CONCLUSIONS: Factors associated with higher optimism and lower pessimism were also those demonstrated to support healthy ageing. Health-promotion action at the individual level (e.g., smoking cessation or regular physical activity), health professional level (e.g., social prescribing or improving access and quality of care for all older adults), and community level (e.g., opportunities for volunteer work or low-cost social activities for older adults) may improve optimism and reduce pessimism, possibly also promoting healthy ageing.

Maternal stress during pregnancy is associated with differential DNA methylation in offspring and disrupted cortisol secretion. This study aimed to determine methylation signatures of cortisol levels in children, and whether associations differ based on maternal post-traumatic stress disorder (PTSD). Blood epigenome-wide methylation and fasting cortisol levels were measured in 118 offspring of mothers recruited from the Kosovo Rehabilitation Centre for Torture Victims. Mothers underwent clinically administered assessment for PTSD using Diagnostic and Statistical Manual of Mental Disorders. Correlations between offspring methylation and cortisol levels were examined using epigenome-wide analysis, adjusting for covariates. Subsequent analysis focussed on a priori selected genes involved in the hypothalamic–pituitary–adrenal (HPA) axis stress signalling. Methylation at four sites were correlated with cortisol levels (cg15321696, r = −0.33, cg18105800, r = +0.33, cg00986889, r = −0.25, and cg15920527, r = −0.27). In adjusted multivariable regression, when stratifying based on prenatal PTSD status, significant associations were only found for children born to mothers with prenatal PTSD (p

BACKGROUND: Poor social health is prevalent in older adults and may be associated with worse cognition, and increased dementia risk. The aim of this study was to determine whether social isolation, social support and loneliness are independently associated with cognitive function and incident dementia over 5 years in older adults, and to investigate potential gender differences. METHODS: Participants were 11,498 community-dwelling relatively healthy Australians aged 70–94, in the ASPREE Longitudinal Study of Older Persons (ALSOP). Social isolation, social support, loneliness and cognitive function were assessed through self-report. Outcomes examined were cognitive decline (>1.5 SD decline in cognitive performance since baseline) and incident dementia (adjudicated according to DSM-IV criteria). RESULTS: Most participants self-reported good social health (92%) with very few socially isolated (2%), with low social support (2%) or lonely (5%). Among women, social isolation and low social support were consistently associated with lower cognitive function (e.g., social support and cognition β = −1.17, p < 0.001). No consistent longitudinal associations were observed between baseline social health and cognitive decline (over median 3.1 years) or incident dementia (over median 4.4 years; social isolation: HR = 1.00, p = 0.99; low social support: HR = 1.79, p = 0.11; loneliness: HR = 0.72, p = 0.34 among women and men). CONCLUSION: Our study provides evidence that social isolation and a low social support are associated with worse cognitive function in women, but not men. Social health did not predict incident cognitive decline or dementia, but we lacked power to stratify dementia analyses by gender.