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BACKGROUND: In randomized clinical trials, treatment effects may vary, and this possibility is referred to as heterogeneity of treatment effect (HTE). One way to quantify HTE is to partition participants into subgroups based on individual's risk of experiencing an outcome, then measuring treatment effect by subgroup. Given the limited availability of externally validated outcome risk prediction models, internal models (created using the same dataset in which heterogeneity of treatment analyses also will be performed) are commonly developed for subgroup identification. We aim to compare different methods for generating internally developed outcome risk prediction models for subject partitioning in HTE analysis. METHODS: Three approaches were selected for generating subgroups for the 2,441 participants from the United States enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) randomized controlled trial. An extant proportional hazards-based outcomes predictive risk model developed on the overall ASPREE cohort of 19,114 participants was identified and was used to partition United States' participants by risk of experiencing a composite outcome of death, dementia, or persistent physical disability. Next, two supervised non-parametric machine learning outcome classifiers, decision trees and random forests, were used to develop multivariable risk prediction models and partition participants into subgroups with varied risks of experiencing the composite outcome. Then, we assessed how the partitioning from the proportional hazard model compared to those generated by the machine learning models in an HTE analysis of the 5-year absolute risk reduction (ARR) and hazard ratio for aspirin vs. placebo in each subgroup. Cochran's Q test was used to detect if ARR varied significantly by subgroup. RESULTS: The proportional hazard model was used to generate 5 subgroups using the quintiles of the estimated risk scores; the decision tree model was used to generate 6 subg

IMPORTANCE: Age-related hearing loss is common in an aging population, affecting communication and contributing to a worsened quality of life. It occurs as a result of cochlear degeneration and may be further exacerbated by inflammation and microvascular changes, as observed in animal models. OBJECTIVE: To compare the effect of daily low-dose aspirin vs placebo on the progression of age-related hearing loss in healthy older adults. DESIGN, SETTING, AND PARTICIPANTS: A prespecified secondary analysis was conducted of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized clinical trial. Participants were 279 healthy community-dwelling individuals living in Australia who were aged 70 years or older and free of overt cardiovascular diseases, dementia, and life-limiting illnesses. Participants were recruited between January 1, 2010, and December 31, 2014, and followed up over 3 years. Statistical analysis was completed from June to December 2023. INTERVENTION: A 100-mg daily dose of enteric-coated aspirin or matching placebo. MAIN OUTCOMES AND MEASURES: Hearing measures were air conduction audiometry and binaural speech perception in noise. Assessments were conducted at baseline, 18 months, and 3 years. The change from baseline hearing measures were analyzed using an intention to treat approach. Aspirin and placebo were compared using mixed linear regression models adjusting for age, sex, diabetes, and smoking. RESULTS: Of 279 participants, 154 (55%) were male, and the median age at baseline was 73.1 years (IQR, 71.5-76.2 years). A total of 98 of 138 participants (71%) in the aspirin group and 94 of 141 participants (67%) in the placebo group reported experiencing hearing loss at baseline. Compared with placebo, aspirin did not affect the changes in mean (SD) 4-frequency average hearing threshold from baseline to year 3 (aspirin: baseline, 27.8 [13.3] dB; year 3, 30.7 [13.7] dB; difference, 3.3 [3.9] dB; placebo: baseline, 27.5 [12.6] dB; year 3, 30.9 [13.8]

Background Dual decline in gait speed and cognition is associated with an increased risk of dementia. However, it is unclear if risks are conferred by decline in domain‐specific cognition and gait. We aimed to examine associations between dual decline in gait speed and cognition (global cognition, memory, processing speed and verbal fluency) with risk of dementia. Methods Prospective cohort study. Participants were from the ASPREE (ASPirin in Reducing Events in the Elderly) study, a double‐blind, randomized, placebo‐controlled trial of low dose aspirin in older adults (≥70 years; ≥65 if US minority). Of 19,114 randomized participants, 16,855 (88%) had longitudinal gait and cognitive data. Gait speed was measured at 0, 2, 4, 6 years and close‐out. Cognitive measures included Modified Mini‐Mental State examination (3MS, global cognition), Hopkins Verbal Learning Test‐Revised (HVLT‐R, memory), Symbol Digit Modalities (SDMT, processing speed) and Controlled Oral Word Association Test (COWAT‐F, verbal fluency), assessed at years 0, 1, 3, 5, and close‐out. Participants were classified into four groups: 1) dual decline in gait and cognition; 2) gait decline only; 3) cognitive decline only and 4) non‐decliners. Cognitive decline was defined as membership of the lowest tertile of annual change. Gait decline was defined as decline in gait speed ≥0.05 m/s per year across the study. Dementia (DSM‐IV 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. Results The mean age of participants was 75.0 (SD4.4) years. Compared with non‐decliners, risk of dementia was highest in the gait+HVLT‐R decliners (HR 24.7; 95% CI 16.3‐37.3), followed by the gait+3MS (HR 22.2; 95% CI 15.0‐32.9), gait+COWAT‐F (HR 4.66 95%; CI 3.5‐6.3) and gait+SDMT (HR 4.3 95% CI 3.2‐5.8) groups. Dual decliners also had higher risk of d

BACKGROUND: There is considerable variability in the rate at which we age biologically, and the brain is particularly susceptible to the effects of aging. OBJECTIVE: 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). METHODS: 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 age2. RESULTS: Excellent 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. CONCLUSION: 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.

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.

STUDY OBJECTIVE: What is the association between anticholinergic burden and specific domains of cognitive function in older adults who are initially without major cognitive impairment? DESIGN: Post-hoc analysis of longitudinal observational data from the ASPirin in Reducing Events in the Elderly (ASPREE) study. PATIENTS: 19,114 participants from Australia and the United States aged 70 years and older (65 years and older for US minorities) were recruited and followed for a median of 4.7 years. At enrollment, participants were free of known cardiovascular disease, major physical disability, or dementia. MEASUREMENTS: Cognitive assessments administered at baseline and biennially at follow-up visits included the Modified Mini-Mental State examination (3MS), Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall, Controlled Oral Word Association Test (COWAT), and Symbol Digit Modalities Test (SDMT). Anticholinergic burden was calculated at baseline using the Anticholinergic Cognitive Burden (ACB) scale and grouped as scores of 0 (no burden), 1-2 (low to moderate), or 3+ (high). MAIN RESULTS: Linear mixed effects models were used to assess the relationship between ACB score and cognition over time. After adjusting for sex, age, education, minority status, smoking status, hypertension, diabetes, depression, chronic kidney disease, country, and frailty, participants with a high ACB score had worse performance over time for 3MS (Adjusted [Adj] B=-0.092, P=0.034), HVLT-R delayed recall (Adj B=-0.104, P<0.001), COWAT (Adj B=-0.151, P<0.001), and SDMT (Adj B=-0.129, P=0.026), than participants with an ACB score of 0. A low to moderate ACB score was also associated with worse performance over time for HVLT-R delayed recall (Adj B=-0.037, P=0.007) and COWAT (Adj B=-0.065, P=0.003), compared to those with no ACB. CONCLUSIONS: Anticholinergic burden predicts worse cognitive function over time in initially dementia-free older adults, particularly for executive function (COWAT)

OBJECTIVE: The 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. METHODS: Data 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. RESULTS: Cognitive 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). CONCLUSIONS: In 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 iden

OBJECTIVE: There is variability across individuals in cognitive aging. To investigate the associations of several modifiable factors with high and low cognitive performance. METHODS: Data 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. RESULTS: Seven 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. CONCLUSIONS: Although 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 distin

IMPORTANCE: 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. OBJECTIVE: To examine associations between dual decline in gait speed and cognition (ie, global, memory, processing speed, and verbal fluency) with risk of dementia. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: 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. MAIN OUTCOMES AND MEASURES: 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. RESULTS: Of 19 114 randomized participants, 16 855 (88.2%) had longitudinal gait and cog

INTRODUCTION: To determine whether slowed gait and weakened grip strength independently, or together, better identify risk of cognitive decline or dementia. METHODS: Time to walk 3 meters and grip strength were measured in a randomized placebo-controlled clinical trial involving community-dwelling, initially cognitively healthy older adults (N = 19,114). RESULTS: Over a median 4.7 years follow-up, slow gait and weak grip strength at baseline were independently associated with risk of incident dementia (hazard ratio [HR] = 1.44, 95% confidence interval [CI]: 1.19-1.73; and 1.24, 95% CI: 1.04-1.50, respectively) and cognitive decline (HR = 1.38, 95% CI: 1.26-1.51; and 1.04, 95% CI: 0.95-1.14, respectively) and when combined, were associated with 79% and 43% increase in risk of dementia and cognitive decline, respectively. Annual declines in gait and in grip over time showed similar results. DISCUSSION: Gait speed and grip strength are low-cost markers that may be useful in the clinical setting to help identify and manage individuals at greater risk, or with early signs, of dementia, particularly when measured together. HIGHLIGHTS: Grip strength and gait speed are effective predictors and markers of dementia.Dementia risk is greater than cognitive decline risk with declines in gait or grip.Decline in gait speed, more so than in grip strength, predicts greater dementia risk.Greater risk prediction results from combining grip strength and gait speed.

INTRODUCTION: Neuroimaging-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. METHODS: Brain-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. RESULTS: Subgroups 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. CONCLUSION: These re

Background: This study examined the risk of mortality in older adults with newly detected cognitive impairment or dementia. Methods: Data from the Australian cohort of the ASPirin in Reducing Events in the Elderly (ASPREE) trial were examined. The ASPREE clinical trial compared daily low-dose aspirin to a placebo and involved 16,703 individuals aged 70 years and over, who were without major cognitive impairment, physical disability, or cardiovascular disease at recruitment. During the trial, evidence of cognitive impairment, based on cognitive testing and medical record information, triggered dementia adjudication of participants using DSM-IV criteria. Cox proportional hazard models were used to compare mortality rates across the dementia, trigger-only, and no-trigger groups. Results: Over a median 4.7-year follow-up period, 806 participants triggered dementia adjudication, with 485 (60.2%) judged to have dementia. Following recruitment, mortality risks were 32.9, 33.6, and 10.8 events per 1000 person-years in the dementia, trigger-no-dementia, and no-trigger groups, respectively. In the fully adjusted model, mortality risks remained higher in the dementia and trigger-no-dementia groups, with hazard ratios of 1.7 (95% CI: 1.3–2.1) and 1.9 (95% CI: 1.5–2.6), respectively. There was no discernible difference between the dementia and trigger-no-dementia groups in mortality rates following recruitment, or following a dementia trigger. These two groups were more likely to die from sepsis, respiratory disease, and dementia, but less likely to die from cancer than the no-trigger group, χ2 = 161.5, p < 0.001. Conclusion: ASPREE participants who triggered for a dementia evaluation experienced a substantially higher mortality rate than those who remained cognitively intact. The increase was indistinguishable among persons who met DSM-IV criteria for dementia vs. those who triggered for a dementia evaluation but failed to meet DSM-IV criteria. Future work should investigate wh

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 < .001). The highest proportions of dementia cases were in trajectories with major decline in global cognition (56.9%) and memory (33.2%). DISCUSSION: Inter-individual variability in cognitive trajectories was observed across all domains. Some individuals appear resilient to cognitive decline even with advancing age. Further research into factors promoting cognitive resilience is needed.

BACKGROUND: Health-related quality of life (HRQoL) has been shown to predict adverse health outcome in the general population. OBJECTIVE: We examined the cross-sectional association between HRQoL and cognitive performance at baseline. Next, we explored whether baseline HRQoL predicted 5-year incident cognitive decline and dementia and whether there were gender differences. METHODS: 19,106 community-dwelling participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, aged 65-98 years, free of major cognitive impairments, and completed the HRQoL 12-item short-form (SF-12) at baseline (2010-2014), were followed until June 2017. The physical (PCS) and mental component scores (MCS) of SF-12 were calculated. The cognitive tests were assessed at baseline, year 1, 3, 5, and 7 or close-out visit. Cognitive decline was defined as > 1.5 SD drop from baseline on any of the cognitive tests. Dementia was adjudicated according to DSM-IV criteria. Linear and Cox proportional-hazards regressions were used to examine the cross-sectional and longitudinal associations respectively. RESULTS: At baseline, higher PCS and MCS were associated with better cognition. Over a median 4.7-year follow-up, higher MCS was associated with a reduced risk of cognitive decline and dementia (12% and 15% respectively, per 10-unit increase) and a 10-unit higher PCS was associated with a 6% decreased risk of cognitive decline. PCS did not predict dementia incidence. Findings were not different by gender. CONCLUSION: Our study found that higher HRQoL, in particular MCS, predicted a reduced risk of cognitive decline and dementia over time in community-dwelling older people.

BACKGROUND: ASPirin in Reducing Events in the Elderly, a randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast, prior randomized controlled trials, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality. METHODS: 19 114 Australian and US community-dwelling participants aged 70 years and older (US minorities 65 years and older) without cardiovascular disease, dementia, or physical disability were randomly assigned and followed for a median of 4.7 years. Fatal and nonfatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records. RESULTS: 981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64). CONCLUSIONS: In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and, thus, suggest caution with its use in this age group.

The role of aspirin for primary prevention in older adults with chronic kidney disease (CKD) is unclear. Therefore, post hoc analysis of the randomized controlled trial ASPirin in Reducing Events in the Elderly (ASPREE) was undertaken comparing 100 mg of enteric-coated aspirin daily against matching placebo. Participants were community dwelling adults aged 70 years and older in Australia, 65 years and older in the United States, all free of a history of dementia or cardiovascular disease and of any disease expected to lead to death within five years. CKD was defined as present at baseline if either eGFR under 60mL/min/1.73m2 or urine albumin to creatinine ratio 3 mg/mmol or more. In 4758 participants with and 13004 without CKD, the rates of a composite endpoint (dementia, persistent physical disability or death), major adverse cardiovascular events and clinically significant bleeding in the CKD participants were almost double those without CKD. Aspirin's effects as estimated by hazard ratios were generally similar between CKD and non-CKD groups for dementia, persistent physical disability or death, major adverse cardiovascular events and clinically significant bleeding. Thus, in our analysis aspirin did not improve outcomes in older people while increasing the risk of bleeding, with mostly consistent effects in participants with and without CKD.

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.

Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing.

BACKGROUND: Processing speed, which can be assessed using the Symbol Digit Modalities Test (SDMT), is central to many brain functions. Processing speed declines with advanced age but substantial impairments are indicative of brain injury or disease. OBJECTIVE: The purpose of this study was to provide SDMT normative data for older community-dwelling individuals in the U.S. and Australia. METHODS: The ASPREE trial recruited 19,114 relatively healthy older men and women in Australia and the U.S. from the general community. All participants were without a diagnosis of dementia and with a Modified Mini-Mental State examination score of 78 or more at enrolment. The SDMT was administered at baseline as part of a neuropsychological test battery. RESULTS: The median age of participants was 74 years (range 65-99), and 56% were women. The median years of education was 12. Ethno-racial differences in SDMT performance were observed and normative data were thus presented separately for 16,289 white Australians, 1,082 white Americans, 891 African-Americans, and 316 Hispanic/Latinos. There were consistent positive associations found between SDMT and education level, and negative associations between SDMT and age. Mean scores for women were consistently higher than men with the exception of Hispanic/Latinos aged ≥70 years. CONCLUSION: This study provides comprehensive SDMT normative data for whites (Australian and U.S.), Hispanic/Latinos, and African-Americans, according to gender, age, and education level. These norms can be used clinically as reference standards to screen for cognitive impairments in older individuals.

BACKGROUND: Despite readily available treatments, control of blood pressure (BP) with population aging remains suboptimal. Further, there are gaps in the understanding of the management of high BP in the aged. We explored antihypertensive treatment and control among elderly hypertensive participants free from overt cardiovascular disease (CVD), and identified factors related to both "untreated" and "treated but uncontrolled" high BP. METHODS: We analyzed baseline data from 19,114 individuals aged ≥65 years enrolled from Australia and United States (US) in the ASPirin in Reducing Events in the Elderly study. Hypertension was defined as an average systolic/diastolic BP ≥140/90 mm Hg and/or the use of any BP lowering medication. "Controlled hypertension" was defined if participants were receiving antihypertensive medication and BP <140 and 90 mm Hg. Descriptive analyses were used to summarize hypertension control rates; logistic regression was used to investigate relationships with treatment and BP control. RESULTS: Overall, 74% (14,213/19,114) of participants were hypertensive; and of these 29% (4,151/14,213) were untreated. Among those treated participants, 53% (5,330/10,062) had BP ≥140/90 mm Hg. Participants who were untreated were more likely to be men, have higher educational status, and be in good physical health, and less likely to have significant comorbidities. The factors related to "treated but uncontrolled" BP included older age, male, Black race (vs. White), using antihypertensive monotherapy (vs. multiple) and residing in Australia (vs. US). CONCLUSIONS: High levels of "untreated" and "treated but uncontrolled" BP occur in healthy elderly people without CVD, suggesting there are opportunities for better BP control in the primary prevention of CVD in this population. CLINICAL TRIALS REGISTRATION: NCT01038583.

OBJECTIVES: To investigate the association between depressive symptoms and several medical morbidities, and their combination, in a large older population. DESIGN: Cross-sectional study of baseline data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. SETTING: Multicentric study conducted in Australia and the United States. PARTICIPANTS: A total of 19,110 older adults (mean age = 75 years [standard deviation = ±4.5]). MEASUREMENTS: Depressive symptoms were measured using the Center for Epidemiological Studies Depression (CES-D 10) scale. Medical morbidities were defined according to condition-specific methods. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) to test associations before and after accounting for possible confounders. RESULTS: Depressive symptoms were significantly associated with obesity (OR = 1.19; 95% CI = 1.07-1.32), diabetes (OR = 1.22; 95% CI = 1.05-1.42), gastroesophageal reflux disease (GERD) (OR = 1.41; 95% CI = 1.28-1.57), metabolic syndrome (OR = 1.16; 95% CI = 1.03-1.29), osteoarthritis (OR = 1.41; 95% CI = 1.27-1.57), respiratory conditions (OR = 1.25; 95% CI = 1.10-1.42), history of cancer (OR = 1.19; 95% CI = 1.05-1.34), Parkinson's disease (OR = 2.56; 95% CI = 1.83-3.56), polypharmacy (OR = 1.60; 95% CI = 1.44-1.79), and multimorbidity (OR = 1.29; 95% CI = 1.12-1.49). No significant association was observed between depressive symptoms and hypertension, chronic kidney disease, dyslipidemia, and gout (P > .05). A significant dose-response relationship was evident between the number of medical comorbidities and the prevalence of depression (OR = 1.18; 95% CI = 1.13-1.22). CONCLUSION: Late-life depressive symptoms are significantly associated with several medical morbidities, and there appears to be a cumulative effect of the number of somatic diseases on the prevalence of depression. These findings augment the evidence for a complex relationship between mental and physical he

Cardiovascular drugs impact many pathways involved in depression pathophysiology and treatment. However, their distinct impact on mood is underrecognized and the literature is conflicting. Therefore, using a very large and well-characterised sample of older adults with hypertension, we aimed to investigate the prevalence of depressive symptoms in users of different antihypertensive classes. We analysed baseline data from 14,195 older individuals with hypertension enroled in a large clinical trial. Median age was 75 years. The association of antihypertensive use by class and depression prevalence, as measured by a validated depression scale, was determined using logistic regression models. Multivariable logistic models were implemented to account for important confounding factors. Our analyses showed a positive association between depressive symptoms and the use of beta blockers (BB) (OR: 1.37; 95% CI: 1.17-1.60, p < 0.01), compared with users of other antihypertensive classes. All other classes of antihypertensives (including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and calcium channel blockers) were not significantly associated with depressive symptoms. In secondary analysis, this relationship was stronger for lipophilic (39%) and nonselective BB (52%) compared with hydrophilic (26%) and selective medications (31%), respectively. This study adds further evidence for a probable association between BB and depression in a large sample of older adults with hypertension and no history of cardiovascular disease or heart failure. These findings should regenerate interest and increase awareness of clinicians about the possible adverse effects of these medications in an otherwise healthy older population.

OBJECTIVE: This study was conducted to estimate prevalence rates and factors associated with depressive symptoms indexed by the Centre for Epidemiological Studies-Depression (CES-D-10) score in a large sample of community-dwelling healthy older adults from Australia and the United States. Convergent and divergent validity of the CES-D-10 were also examined. METHODS: A total of 19 114 individuals aged greater than or equal to 65 years old were enrolled from a primary prevention clinical trial. Depressive symptoms were classified using the CES-D-10 score greater than or equal to 8 and greater than or equal to 10. Gender-specific prevalence for subgroups according to sociodemographic characteristics were reported, and factors associated with depressive symptoms were estimated. RESULTS: The overall prevalence rates of depressive symptoms were 9.8%, 95% CI, 8.5-11.2 and 5.0%, 95% CI, 4.0-6.0, according to the CES-D-10 score greater than or equal to 8 and greater than or equal to 10, respectively. Depressive symptoms were more common in women, individuals with less than 12 years of education, those living alone or in a residential care, ethnic minorities, current smokers, and former alcohol users. Convergent and divergent validities of the CES-D-10 were confirmed by observing strong negative association with the SF-12 mental health component and a modest negative association with SF-12 physical component, respectively. CONCLUSIONS: This study reports the prevalence of depressive symptoms in Australian and US community-dwelling healthy older populations. These findings emphasize the high burden of the condition and factors associated with depressive symptoms, to better inform clinicians and help with early detection and treatment of depression in this age group.

The failure of current strategies to provide an explanation for controversial findings on the pattern of pathophysiological changes in Alzheimer's Disease (AD) motivates the necessity to develop new integrative approaches based on multi-modal neuroimaging data that captures various aspects of disease pathology. Previous studies using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (sMRI) report controversial results about time-line, spatial extent and magnitude of glucose hypometabolism and atrophy in AD that depend on clinical and demographic characteristics of the studied populations. Here, we provide and validate at a group level a generative anatomical model of glucose hypo-metabolism and atrophy progression in AD based on FDG-PET and sMRI data of 80 patients and 79 healthy controls to describe expected age and symptom severity related changes in AD relative to a baseline provided by healthy aging. We demonstrate a high level of anatomical accuracy for both modalities yielding strongly age- and symptom-severity- dependant glucose hypometabolism in temporal, parietal and precuneal regions and a more extensive network of atrophy in hippocampal, temporal, parietal, occipital and posterior caudate regions. The model suggests greater and more consistent changes in FDG-PET compared to sMRI at earlier and the inversion of this pattern at more advanced AD stages. Our model describes, integrates and predicts characteristic patterns of AD related pathology, uncontaminated by normal age effects, derived from multi-modal data. It further provides an integrative explanation for findings suggesting a dissociation between early- and late-onset AD. The generative model offers a basis for further development of individualized biomarkers allowing accurate early diagnosis and treatment evaluation.

In the present study, changes in the parahippocampal white matter (PWM), in the region that includes the perforant path, were investigated, in vivo, in 14 individuals with amnestic mild cognitive impairment (aMCI) compared to 14 elderly controls with no cognitive impairment (NCI). For this purpose, (1) volumetry; (2) diffusion tensor imaging (DTI) derived measures of mean diffusivity (MD) and fractional anisotropy (FA); and (3) tractography were used. In addition, regression models were utilized to examine the association of PWM measurements with memory decline. The results from this study confirm previous findings in our laboratory and others, showing that compared to controls, individuals with aMCI have PWM volume loss. In addition to volume reduction, participants with aMCI demonstrated a significant increase in MD, but no difference in FA, both in the PWM region and in fibers modeled to pass through the PWM region. Further, the DTI metric of MD was associated with declarative memory performance, suggesting it may be a sensitive marker for memory dysfunction. These results indicate that there is general tissue loss and degradation (decreased volume; increased MD) in individuals with aMCI compared to older people with normal cognitive function. However, the microstructural organization of remaining fibers, as determined by measures of anisotropic diffusion, is not significantly different from that of controls.