Short- and long-term impact of aspirin cessation in older adults: a target trial emulation.

BACKGROUND: The net benefit of aspirin cessation in older adults remains uncertain. This study aimed to use observational data to emulate a randomized trial of aspirin cessation versus continuation in older adults without cardiovascular disease (CVD). METHODS: Post hoc analysis using a target trial emulation framework applied to the immediate post-trial period (2017-2021) of a study of low-dose aspirin initiation in adults aged ≥ 70 years (ASPREE; NCT01038583). Participants from Australia and the USA were included if they were free of CVD at the start of the post-trial intervention period (time zero, T0) and had been taking open-label or randomized aspirin immediately before T0. The two groups in the target trial were as follows: aspirin cessation (participants who were taking randomized aspirin immediately before T0; assumed to have stopped at T0 as instructed) versus aspirin continuation (participants on open-label aspirin at T0 regardless of their randomized treatment; assumed to have continued at T0). The outcomes after T0 were incident CVD, major adverse cardiovascular events (MACE), all-cause mortality, and major bleeding during 3, 6, and 12 months (short-term) and 48 months (long-term) follow-up. Hazard ratios (HRs) comparing aspirin cessation to continuation were estimated from propensity-score (PS) adjusted Cox proportional-hazards regression models. RESULTS: We included 6103 CVD-free participants (cessation: 5427, continuation: 676). Over both short- and long-term follow-up, aspirin cessation versus continuation was not associated with elevated risk of CVD, MACE, and all-cause mortality (HRs, at 3 and 48 months respectively, were 1.23 and 0.73 for CVD, 1.11 and 0.84 for MACE, and 0.23 and 0.79 for all-cause mortality, p > 0.05), but cessation had a reduced risk of incident major bleeding events (HRs at 3 and 48 months, 0.16 and 0.63, p < 0.05). Similar findings were seen for all outcomes at 6 and 12 months, except for a lowered risk of all-cause mortality in the cessation group at 12 months. CONCLUSIONS: Our findings suggest that deprescribing prophylactic aspirin might be safe in healthy older adults with no known CVD.

Gender-specific analysis of social connection patterns and risk of dementia in community-dwelling older people.

INTRODUCTION: Poor social connection is considered a risk factor for dementia. Since socializing behaviors may cluster together or act compensatorily, we aimed to investigate social connection patterns and their association with dementia, for men and women separately. METHODS: A total of 12,896 community-dwelling older adults (mean ± SD age: 75.2 ± 4.3 years, 54% women) without major cognitive impairment were included. Latent class analysis was conducted using 24 baseline social connection indicators. Cox proportional hazards regression was used to estimate the association between latent classes and incident dementia over 12 (median: 8.4) years follow-up. RESULTS: Three distinct classes were identified in both genders: strong social connections with an intermediate friend-relative network (Class 1: men, 43.8%; women, 37.9%), weak social connections (Class 2: men, 29.6%; women, 27.4%), and strong social connections with a larger friend-relative network (Class 3: men, 26.6%; women, 34.7%). Compared to Class 1, men in Class 2 (HR: 1.38, 95% CI: 1.08-1.77) and women in Class 3 (HR: 1.27, 95% CI: 1.01-1.60) had an increased risk of dementia. DISCUSSION: Dementia risk varies with different social connection patterns among older men and women. HIGHLIGHTS: Three distinct social connection patterns were identified based on 24 indicators. These patterns were related to dementia risk differently in men and women. In men, a weak social connection pattern was associated with a higher dementia risk. In women, a strong social connection with a relatively larger friend-relative network was associated with a greater dementia risk.

The impact of incident stroke on cognitive trajectories in later life.

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

Effect of Low-Dose Aspirin on the Course of Age-Related Macular Degeneration: A Secondary Analysis of the ASPREE Randomized Clinical Trial.

Importance: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in old age. There is no proven intervention to prevent AMD and, apart from lifestyle, nutritional, and supplement advice, there is no intervention to delay its progression. Objective: To determine the impact of long-term low-dose aspirin on the incidence and progression of AMD. Design, Setting and Participants: The Aspirin in Reducing Events in the Elderly-AMD (ASPREE-AMD) study was an Australian-based substudy of the ASPREE trial, a multicenter, international, randomized, double-masked, placebo-clinical trial investigating the efficacy of low-dose aspirin in prolonging disability-free survival among older individuals. Retinal photography was conducted at baseline from March 2010 to January 2015, then 3 and 5 years after randomization. AMD status was determined using color retinal images and treatment records. Australian participants in ASPREE aged 70 years and older without dementia, independence-limiting physical disability, cardiovascular disease, or chronic illness limiting 5-year survival and with gradable retinal images at baseline were included. Data were analyzed from December 2022 to December 2023. Interventions: Aspirin (100 mg daily, enteric coated) or placebo. Main Outcomes and Measures: Incidence of AMD and progression from early/intermediate to late AMD. Outcomes were analyzed by modified intention-to-treat analysis. Results: A total of 4993 participants were enrolled in this substudy. Baseline characteristics were similar between groups. At the time of sponsor-determined trial termination, retinal follow-up data were available for 3208 participants, 3171 of whom were analyzed for AMD incidence and progression, with a median (IQR) age of 73.5 (71.5-76.4) years and even sex distribution (1619 [51%] female). Median (IQR) follow-up time was 3.1 (3.0-3.5) years. Cumulative AMD incidence was 195 of 1004 (19.4%) in the aspirin group and 187 of 979 (19.1%) in the placebo group (relative risk [RR], 1.02; 95% CI, 0.85-1.22; P = .86). Cumulative progression from early/intermediate AMD to late AMD was observed in 14 of 615 (2.3%) participants in the aspirin group and 18 of 573 (3.1%) in the placebo group (RR, 0.72; 95% CI, 0.36-1.44; P = .36). Conclusions and Relevance: In this trial, low-dose aspirin administered for 3 years did not affect the incidence of AMD. The evidence was weaker for progression of AMD due to low number of progressed cases. Overall, these results do not support suggestion that low-dose daily aspirin prevents the development or progression of AMD. Trial Registration: anzctr.org Identifier: ACTRN12613000755730.

Social Activities and Risk of Dementia in Community-Dwelling Older People: Gender-Specific Findings From a Prospective Cohort Study.

OBJECTIVES: This study examines the gender-specific associations between a wide range of social activities and dementia risk. METHODS: A prospective cohort study was conducted involving community-dwelling older Australians (≥70 years) without significant cognitive impairment at enrolment. During the first year of enrolment, we assessed 25 self-reported social activities covering various aspects, including support from relatives and friends, community participation, social interactions with surroundings, and loneliness. Dementia diagnosis followed DSM-IV criteria, adjudicated by an international expert panel. To estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between social activities and dementia, we performed Cox proportional hazards models, adjusting for age, educational attainment, baseline global cognition, and depressive symptoms. RESULTS: Among 9,936 participants who completed all social activity questionnaires (median [IQR] age: 73.4 [71.6-77.1] years; 47.4% men), dementia was diagnosed in 3.8% of men (n = 181/4,705) and 2.6% of women (n = 138/5,231) over a median 6.4 years (IQR: 5.3-7.6, range: 0.2-10.1) follow-up. Gender-specific relationships emerged: caregiving for a person with illness/disability in women (HR: 0.65, 95% CI: 0.42-0.99), and having ≥9 relatives feeling close to call for help in men (HR: 0.56, 95% CI: 0.33-0.96; reference <9 relatives) were associated with reduced dementia risk. Unexpectedly, in women, having ≥5 friends with whom they felt comfortable discussing private matters were associated with a greater dementia risk (HR: 1.69, 95% CI: 1.10-2.59; reference ≤2 friends). Imputed models further identified that babysitting/childminding was associated with lower dementia risk in men (HR: 0.75, 95% CI: 0.56-0.99). No other social activities showed significant associations with dementia. DISCUSSION: This study provides evidence of social activities influencing dementia risk. Further investigations are required to uncover the mechanisms driving these observed relationships.

The ASPREE Healthy Ageing Biobank: Methodology and participant characteristics.

ASPirin in Reducing Events in the Elderly (ASPREE), a placebo-controlled prevention trial of low dose aspirin, provided the opportunity to establish a biospecimen biobank from initially healthy persons aged 70+ years for future research. The ASPREE Healthy Ageing Biobank (ASPREE Biobank) collected, processed and stored blood and urine samples at -80degC or under nitrogen vapour at two timepoints, three years apart, from a willing subset of Australian ASPREE participants. Written informed consent included separate opt-in questions for biomarker and genetic testing. Fractionated blood and urine were aliquoted into multiple low-volume, barcoded cryotubes for frozen storage within 4 hours of collection. Specially designed and outfitted mobile laboratories provided opportunities for participation by people in regional and rural areas. Detailed, high quality demographic, physiological and clinical data were collected annually through the ASPREE trial. 12,219 participants contributed blood/urine at the first timepoint, 10,617 of these older adults provided 3-year follow-up samples, and an additional 1,712 provided saliva for DNA. The mean participant age was 74 years, 54% were female and 46% lived outside major cities. Despite geographical and logistical challenges, nearly 100% of blood/urine specimens were processed and frozen within 4 hours of collection into >1.4 million aliquots. After a median of 4.7 years, major clinical events among ASPREE Biobank participants included 332 with dementia, 613 with cardiovascular disease events, 1259 with cancer, 357 with major bleeds and 615 had died. The ASPREE Biobank houses and curates a large number of biospecimens collected prior to the clinical manifestations of major disease, and 3-year follow-up samples, all linked to high quality, extensive phenotypic information. This provides the opportunity to identify or validate diagnostic, prognostic and predictive biomarkers, and potentially study biological effectors, of ageing-related diseases or maintenance of older-age good health.

Associations of body habitus and its changes with incident dementia in older adults.

BACKGROUND: This study examined the associations of body mass index (BMI) and waist circumference (WC), as well as their short- and long-term changes over time, with incident dementia in older individuals. METHODS: Data came from 18,837 community-dwelling individuals aged 65+ years from Australia and the United States, who were relatively healthy without major cognitive impairment at enrolment. Anthropometric measures were prospectively assessed at baseline, as well as change and variability from baseline to year two (three time-points). In a subgroup (n = 11,176), self-reported weight at age 18 and 70+ years was investigated. Dementia cases satisfied DSM-IV criteria. Cox regression was used to examine the associations between anthropometric measures and incident risk of dementia. RESULTS: Compared to normal weight, an overweight (HR: 0.67, 95%CI: 0.57-0.79, p < 0.001) or obese BMI (HR: 0.73, 95%CI: 0.60-0.89, p = 0.002), or a larger WC (elevated, HR: 0.71, 95%CI: 0.58-0.86, p < 0.001; highly elevated, HR: 0.65, 95%CI: 0.55-0.78, p < 0.001; relative to low) at baseline was associated with lower dementia risk. In contrast, substantial increases in BMI (>5%) over 2 years after baseline were associated with higher dementia risk (HR: 1.49, 95% CI: 1.17-1.91, p = 0.001). Increased dementia risk was also seen with an underweight BMI at baseline and a 2-year BMI decrease (>5%), but these associations appeared only in the first 4 years of follow-up. Compared to normal weight at both age 18 and 70+ years, being obese at both times was associated with increased dementia risk (HR: 2.27, 95%CI: 1.22-4.24, p = 0.01), while obesity only at age 70+ years was associated with decreased risk (HR: 0.70, 95%CI: 0.51-0.95, p = 0.02). CONCLUSIONS: Our findings suggest that long-term obesity and weight gain in later life may be risk factors for dementia. Being underweight or having substantial weight loss in old age may be early markers of pre-clinical dementia.

Angiotensin Receptor Blockers and Cognition: a Scoping Review.

PURPOSE OF REVIEW: To provide an overview of the association between angiotensin II receptor blocker (ARB) use and cognitive outcomes. RECENT FINDINGS: ARBs have previously shown greater neuroprotection compared to other anti-hypertensive classes. The benefits are primarily attributed to the ARB's effect on modulating the renin-angiotensin system via inhibiting the Ang II/AT1R pathway and activating the Ang II/AT2R, Ang IV/AT4R, and Ang-(1-7)/MasR pathways. These interactions are associated with pleiotropic neurocognitive benefits, including reduced ß-amyloid accumulation and abnormal hyperphosphorylation of tau, ameliorated brain hypo-fusion, reduced neuroinflammation and synaptic dysfunction, better neurotoxin clearing, and blood-brain barrier function restoration. While ACEis also inhibit AT1R, they simultaneously lower Ang II and block the Ang II/AT2R and Ang IV/AT4R pathways that counterbalance the potential benefits. ARBs may be considered an adjunctive approach for neuroprotection. This preliminary evidence, coupled with their underlying mechanistic pathways, emphasizes the need for future long-term randomized trials to yield more definitive results.

Low-Density-Lipoprotein Cholesterol and Mortality Outcomes Among Healthy Older Adults: A Post Hoc Analysis of ASPREE Trial.

BACKGROUND: The prognostic implication of cholesterol levels in older adults remains uncertain. This study aimed to examine the relationship between low-density-lipoprotein cholesterol (LDL-c) and mortality outcomes in older individuals. METHODS: This post hoc analysis examined the associations of LDL-c levels with mortality risks from all-cause, cardiovascular disease (CVD), cancer, and combined non-CVD/noncancer conditions in a cohort of individuals aged ≥65 years from the ASPirin in Reducing Events in the Elderly trial (NCT01038583). At baseline, participants had no diagnosed dementia, physical disability, or CVD, and were not taking lipid-lowering agents. Outcome analyses were performed using multivariable Cox models. RESULTS: We analyzed 12 334 participants (mean age: 75.2 years). Over a median 7-year follow-up, 1 250 died. Restricted cubic splines found a U-shaped relation for LDL-c and all-cause mortality, cancer mortality, and noncancer/non-CVE mortality (nadir: 3.3-3.4 mmol/L); the risk of CVD mortality was similar at LDL-c below 3.3 mmol/L and increased above 3.3 mmol/L. Similar trends were observed in analyses modeling LDL-c by quartiles. When modeling LDL-c as a continuous variable, the risk of all-cause mortality, cancer mortality, and noncancer/non-CVD mortality was decreased by 9%, 16%, and 18%, respectively, per 1-mmol/L higher LDL-c, and the risk of CVD mortality was increased by 19% per 1-mmol/L higher LDL-c. Reduced all-cause and non-CVD/noncancer mortality risks were only significant in males but not females (pinteraction < .05). CONCLUSIONS: There were U-shaped relationships between LDL-c and all-cause mortality, cancer mortality, and noncancer/non-CVD mortality in healthy older adults. Higher LDL-c levels were associated with an increased risk of CVD mortality. Future studies are warranted to confirm our results.

Long-term blood pressure variability and frailty risk in older adults.

INTRODUCTION: In healthy older adults, the relationship between long-term, visit-to-visit variability in blood pressure (BP) and frailty is uncertain. METHODS: Secondary analysis of blood pressure variability (BPV) and incident frailty in >13 000 participants ≥65-70 years enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial and its observational follow-up (ASPREE-XT). Participants were without dementia, physical disability, or cardiovascular disease at baseline. BPV was estimated using standard deviation of mean BP from three annual visits (baseline through the second annual follow-up). Frailty was defined using Fried phenotype and a frailty deficit accumulation index (FDAI). Participants with frailty during the BPV estimation period were excluded from the main analysis. Adjusted Cox proportional hazards regression evaluated the association between BPV and incident frailty, and linear mixed models for change in frailty scores, through a maximum of 9 years of follow-up. RESULTS: Participants in the highest systolic BPV tertile were at higher risk of frailty compared to those in the lowest (referent) tertile of systolic BPV [Fried hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.04-1.31; FDAI HR 1.18, 95% CI 1.07-1.30]. Findings were consistent when adjusted for multiple covariates and when stratified by antihypertensive use. Linear mixed models showed that higher systolic BPV was associated with increasing frailty score over time. Diastolic BPV was not consistently associated. CONCLUSIONS: High systolic BPV, independent of mean BP, is associated with increased risk of frailty in healthy older adults. Variability of BP across visits, even in healthy older adults, can convey important risk information beyond mean BP. TRIAL REGISTRATION: ClinicalTrials.gov NCT01038583 and ISRCTN83772183.

Cardiovascular Disease Risk Scores and Incident Dementia and Cognitive Decline in Older Men and Women.

INTRODUCTION: Risk factors for cardiovascular disease (CVD) also increase the risk of dementia. However, whether commonly used CVD risk scores are associated with dementia risk in older adults who do not have a history of CVD, and potential gender differences in this association, remains unclear. The aim of this study was to determine whether CVD risk scores are prospectively associated with cognitive decline and dementia in initially healthy older men and women. METHODS: A total of19,114 participants from a prospective cohort of individuals aged 65+ years without known CVD or dementia were recruited. The atherosclerotic cardiovascular disease risk score (ASCVDRS), Systematic Coronary Risk Evaluation 2-Older Persons (SCORE2-OP), and the Framingham risk score (FRS) were calculated at baseline. Risk of dementia (according to DSM-IV criteria) and cognitive decline (defined as a >1.5 standard deviation decline in global cognition, episodic memory, psychomotor speed, or verbal fluency from the previous year) were assessed using hazard ratio. RESULTS: Over a median follow-up of 6.4 years, 850 individuals developed dementia and 4,352 cognitive decline. Men and women in the highest ASCVDRS tertile had a 41% (95% CI 1.08, 1.85) and 45% (1.11, 1.89) increased risk of dementia compared to the lowest tertile, respectively. Likewise, men and women in the highest SCORE2-OP tertile had a 64% (1.24, 2.16) and 60% (1.22, 2.11) increased risk of dementia compared to the lowest tertile, respectively. Findings were similar, but the risk was slightly lesser when examining risk of cognitive decline for both ASCVDRS and SCORE2-OP. However, FRS was only associated with the risk of cognitive decline among women (highest vs. lowest tertiles: 1.13 [1.01-1.26]). CONCLUSION: These findings suggest the utility of the ASCVDRS and SCORE2-OP in clinical practice, to not only assess future risk of CVD, but also as potential early indicators of cognitive impairment, even in relatively healthy older men and women.

Daily low-dose aspirin and incident type 2 diabetes in community-dwelling healthy older adults: a post-hoc analysis of efficacy and safety in the ASPREE randomised placebo-controlled trial.

BACKGROUND: Inflammation has been implicated in the pathogenesis of diabetes. This study investigated the randomised treatment effect of low-dose aspirin on incident type 2 diabetes and fasting plasma glucose (FPG) concentrations among older adults. METHODS: ASPREE was a double-blind, placebo-controlled trial of daily oral low-dose aspirin. The study population included community-dwelling individuals aged 70 years or older (≥65 years for US minority ethnic groups) in the USA and Australia who were free of cardiovascular disease, independence-limiting physical disability, or dementia. For the post-hoc analysis, we excluded participants with diabetes at baseline or with incomplete or missing incident diabetes data during follow-up. Participants were randomly assigned 1:1 to oral 100 mg daily enteric-coated aspirin or placebo. Incident diabetes was defined as self-reported diabetes, commencement of glucose-lowering medication, or a FPG concentration of 7·0 mmol/L or more assessed at annual follow-up visits among participants with no diabetes at baseline. We used Cox proportional hazards models and mixed-model repeated measures to assess the effect of aspirin on incident diabetes and FPG concentrations in the intention-to-treat population. We assessed major bleeding in participants who had taken at least one dose of study medication. FINDINGS: Between March 10, 2010, and Dec 24, 2014, a total of 16 209 participants were included (8086 [49·9%] randomly assigned to aspirin and 8123 [50·1%] randomly assigned to placebo). During a median follow-up of 4·7 years (IQR 3·6-5·7), 995 (in 6·1% individuals) incident cases of type 2 diabetes were recorded (459 in the aspirin group and 536 in the placebo group). Compared with placebo, the aspirin group had a 15% reduction in risk of incident diabetes (hazard ratio 0·85 [95% CI 0·75 to 0·97]; p=0·013) and a slower rate of increase in FPG concentration at year 5 (between-group difference estimate -0·048 mmol/L [95% CI -0·079 to -0·018]; p=0·0017). Major bleeding (major gastrointestinal bleeding, intracranial bleeding, and clinically significant bleeding at other sites) occurred in 510 (3·2%) of 16 104 participants (300 [3·7%] in the aspirin group and 210 [2·6%] in the placebo group). Compared with placebo, the aspirin group had a 44% increase in risk of major bleeding (hazard ratio 1·44 [95% CI 1·21 to 1·72]; p<0·0001). INTERPRETATION: Aspirin treatment reduced the incidence of type 2 diabetes and slowed the increase in FPG concentration but increased major bleeding among community-dwelling older adults. Given the increasing prevalence of type 2 diabetes among older adults, the potential for anti-inflammatory agents such as aspirin to prevent type 2 diabetes or improve glucose levels warrants further study with a comprehensive assessment of all potential safety events of interest. FUNDING: US National Institute on Aging, US National Cancer Institute, National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency.

Normative Data for Single-Letter Controlled Oral Word Association Test in Older White Australians and Americans, African-Americans, and Hispanic/Latinos.

Background: The Controlled Oral Word Association Test (COWAT) is a commonly used measure of verbal fluency. While a normal decline in verbal fluency occurs in late adulthood, significant impairments may indicate brain injury or diseases such as Alzheimer's disease. Normative data is essential to identify when test performance falls below expected levels based on age, gender, and education level. Objective: This study aimed to establish normative performance data on single-letter COWAT for older community-dwelling adults. Methods: Over 19,000 healthy men and women, without a diagnosis of dementia or a Modified Mini-Mental State Examination score below 77/100, were recruited for the ASPREE trial. Neuropsychological assessments, including the COWAT with letter F, were administered at study entry. Results: Median participant age was 75 years (range 65-98), with 56.5% being women. The majority of participants had 9-11 years of education in Australia and over 12 years in the U.S. The COWAT performance varied across ethno-racial groups and normative data were thus presented separately for 16,335 white Australians, 1,084 white Americans, 896 African-Americans, and 316 Hispanic/Latinos. Women generally outperformed men in the COWAT, except for Hispanic/Latinos. Higher education levels consistently correlated with better COWAT performance across all groups, while the negative association with age was weaker. Conclusions: This study provides comprehensive normative data for the COWAT stratified by ethno-racial groups in Australia and the U.S., considering age, gender, and education level. These norms can serve as reference standards for screening cognitive impairments in older adults in both clinical and research settings.

Association Between Triglycerides and Risk of Dementia in Community-Dwelling Older Adults: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: It has been suggested that higher triglyceride levels were associated with a lower risk of Alzheimer disease. This study aimed to examine the association of triglycerides with dementia and cognition change in community-dwelling older adults. METHODS: This prospective longitudinal study used data from the Aspirin in Reducing Events in the Elderly (ASPREE) randomized trial of adults aged 65 years or older without dementia or previous cardiovascular events at enrollment. The main outcome was incident dementia. Other outcomes included changes in composite cognition and domain-specific cognition (global cognition, memory, language and executive function, and psychomotor speed). The association between baseline triglycerides and dementia risk was estimated using Cox proportional hazard models adjusting for relevant risk factors. Linear mixed models were used to investigate cognitive change. The analysis was repeated in a subcohort of participants with available APOE-ε4 genetic data with additional adjustment for APOE-ε4 carrier status and an external cohort (UK Biobank) with similar selection criteria applied. RESULTS: This study included 18,294 ASPREE participants and 68,200 UK Biobank participants (mean age: 75.1 and 66.9 years; female: 56.3% and 52.7%; median [interquartile range] triglyceride: 106 [80-142] mg/dL and 139 [101-193] mg/dL), with dementia recorded in 823 and 2,778 individuals over a median follow-up of 6.4 and 12.5 years, respectively. Higher triglyceride levels were associated with lower dementia risk in the entire ASPREE cohort (hazard ratio [HR] with doubling of triglyceride: 0.82, 95% CI 0.72-0.94). Findings were similar in the subcohort of participants with APOE-ε4 genetic data (n = 13,976) and in the UK Biobank cohort (HR was 0.82 and 0.83, respectively, all p ≤ 0.01). Higher triglycerides were also associated with slower decline in composite cognition and memory over time (p ≤ 0.05). DISCUSSION: Older adults with higher triglyceride levels within the normal to high-normal range had a lower dementia risk and slower cognitive decline over time compared with individuals with lower triglyceride levels. Higher triglyceride levels may be reflective of better overall health and/or lifestyle behaviors that would protect against dementia development. Future studies are warranted to investigate whether specific components within the total circulating pool of plasma triglycerides may promote better cognitive function, with the hope of informing the development of new preventive strategies.

Association of a healthy lifestyle with mortality in older people.

BACKGROUND: Unhealthy lifestyle behaviours such as smoking, high alcohol consumption, poor diet or low physical activity are associated with morbidity and mortality. Public health guidelines provide recommendations for adherence to these four factors, however, their relationship to the health of older people is less certain. METHODS: The study involved 11,340 Australian participants (median age 7.39 [Interquartile Range (IQR) 71.7, 77.3]) from the ASPirin in Reducing Events in the Elderly study, followed for a median of 6.8 years (IQR: 5.7, 7.9). We investigated whether a point-based lifestyle score based on adherence to guidelines for a healthy diet, physical activity, non-smoking and moderate alcohol consumption was associated with subsequent all-cause and cause-specific mortality. RESULTS: In multivariable adjusted models, compared to those in the unfavourable lifestyle group, individuals in the moderate lifestyle group (Hazard Ratio (HR) 0.73 [95% CI 0.61, 0.88]) and favourable lifestyle group (HR 0.68 [95% CI 0.56, 0.83]) had lower risk of all-cause mortality. A similar pattern was observed for cardiovascular related mortality and non-cancer/non-cardiovascular related mortality. There was no association of lifestyle with cancer-related mortality. CONCLUSIONS: In a large cohort of initially healthy older people, reported adherence to a healthy lifestyle is associated with reduced risk of all-cause and cause-specific mortality. Adherence to all four lifestyle factors resulted in the strongest protection.

Adverse events in older adults and the risk of dementia and cognitive decline.

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

Lifestyle Enrichment in Later Life and Its Association With Dementia Risk.

Importance: Lifestyles enriched with socially and mentally stimulating activities in older age may help build cognitive reserve and reduce dementia risk. Objective: To investigate the association of leisure activities and social networks with dementia risk among older individuals. Design, Setting, and Participants: This longitudinal prospective cohort study used population-based data from the ASPREE Longitudinal Study of Older Persons (ALSOP) for March 1, 2010, to November 30, 2020. Community-dwelling individuals in Australia aged 70 years or older who were generally healthy and without major cognitive impairment at enrollment were recruited to the ALSOP study between March 1, 2010, and December 31, 2014. Data were analyzed from December 1, 2022, to March 31, 2023. Exposures: A total of 19 measures of leisure activities and social networks assessed at baseline were classified using exploratory factor analysis. Main Outcomes and Measures: Dementia was adjudicated by an international expert panel according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria. Cox proportional hazards regression examined dementia risk over 10 years, adjusting for education, socioeconomic status, and a range of health-related factors. Results: This study included 10 318 participants. Their median age was 73.8 (IQR, 71.6-77.2) years at baseline, more than half (52.6%) were women, and most self-identified as White (98.0%). In adusted analyses, more frequent engagement in adult literacy activities (eg, writing letters or journaling, using a computer, and taking education classes) and in active mental activities (eg, playing games, cards, or chess and doing crosswords or puzzles) was associated with an 11.0% (adjusted hazard ratio [AHR], 0.89 [95% CI, 0.85-0.93]) and a 9.0% (AHR, 0.91 [95% CI, 0.87-0.95]) lower risk of dementia, respectively. To a lesser extent, engagement in creative artistic activities (craftwork, woodwork, or metalwork and painting or drawing) (AHR, 0.93 [95% CI, 0.88-0.99]) and in passive mental activities (reading books, newspapers, or magazines; watching television; and listening to music or the radio) (AHR, 0.93 [95% CI, 0.86-0.99]) was also associated with reduced dementia risk. In contrast, interpersonal networks, social activities, and external outings were not associated with dementia risk in this sample. Conclusions and Relevance: These results suggest that engagement in adult literacy, creative art, and active and passive mental activities may help reduce dementia risk in late life. In addition, these findings may guide policies for geriatric care and interventions targeting dementia prevention for older adults.

Association of Proton Pump Inhibitor Use With Incident Dementia and Cognitive Decline in Older Adults: A Prospective Cohort Study.

BACKGROUND & AIMS: Prior studies have suggested that proton pump inhibitor (PPI) use is associated with increased risk of dementia; however, these have been limited by incomplete assessment of medication use and failure to account for confounders. Furthermore, prior studies have relied on claims-based diagnoses for dementia, which can lead to misclassification. We investigated the associations of PPI and histamine-2 receptor antagonist (H2RA) use with dementia and cognitive decline. METHODS: We conducted a post hoc analysis of ASPirin in Reducing Events in the Elderly (ASPREE), a randomized trial of aspirin in the United States and Australia, including 18,934 community-based adults ≥65 years of all races/ethnicities. Baseline and recent PPI and H2RA use were determined according to review of medications during annual in-person study visits. Incident dementia was defined according to Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, criteria. Secondary endpoints include cognitive impairment, no dementia (CIND) and changes in cognition. Associations of medication use with dementia and CIND outcomes were examined using Cox proportional hazards models. Changes in cognitive test scores were examined using linear mixed-effects models. RESULTS: Baseline PPI use vs nonuse was not associated with incident dementia (multivariable hazard ratio, 0.88; 95% confidence interval, 0.72-1.08), CIND (multivariable hazard ratio, 1.00; 95% confidence interval, 0.92-1.09), or with changes in overall cognitive test scores over time (multivariable B, -0.002; standard error, 0.01; P = .85). Similarly, no associations were observed between H2RA use and all cognitive endpoints. CONCLUSIONS: In adults ≥65 years of age, PPI and H2RA use were not associated with incident dementia, CIND, or decline in cognition over time. These data provide reassurance about the safety of long-term use of PPIs among older adults.

Longitudinal association between handgrip strength, gait speed and risk of serious falls in a community-dwelling older population.

OBJECTIVE: Both grip strength and gait speed can be used as markers of muscle function, however, no previous study has examined them in the same population with respect to risk of falls. METHODS: In this prospective cohort study, utilising data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and ASPREE-Fracture substudy, we analysed the association of grip strength and gait speed and serious falls in healthy older adults. Grip strength was measured using a handheld dynamometer and gait speed from 3-metre timed walks. Serious falls were confined to those involving hospital presentation. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for associations with falls. RESULTS: Over an average of 4.0±1.3 years, amongst 16,445 participants, 1,533 had at least one serious fall. After adjustment for age, sex, physical activity, body mass index, Short Form 12 (state of health), chronic kidney disease, polypharmacy and aspirin, each standard deviation (SD) lower grip strength was associated with 27% (HR 1.27, 95% CI 1.17-1.38) higher risk of falls. The results remained the same for males and females. There was a dose-response relationship in the association between grip strength and falls risk. The higher risk of falls was observed in males in all body mass index (BMI) categories, but only in obese females. The association between gait speed and falls risk was weaker than the association between grip strength and falls risk. CONCLUSIONS: All males and only obese females with low grip strength appear to be at the greatest risk of serious falls. These findings may assist in early identification of falls.

Validation of newly derived polygenic risk scores for dementia in a prospective study of older individuals.

INTRODUCTION: Recent genome-wide association studies identified new dementia-associated variants. We assessed the performance of updated polygenic risk scores (PRSs) using these variants in an independent cohort. METHODS: We used Cox models and area under the curve (AUC) to validate new PRSs (PRS-83SNP, PRS-SBayesR, and PRS-CS) compared with an older PRS-23SNP in 12,031 initially-healthy participants ≥70 years of age. Dementia was rigorously adjudicated according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. RESULTS: PRS-83SNP, PRS-SBayesR, and PRS-CS were associated with incident dementia, with fully adjusted (including apolipoprotein E [APOE] ε4) hazard ratios per standard deviation (SD) of 1.35 (1.23-1.47), 1.37 (1.25-1.50), and 1.42 (1.30-1.56), respectively. The AUC of a model containing conventional/non-genetic factors and APOE was 74.7%. This was improved to 75.7% (p = 0.007), 76% (p = 0.004), and 76.1% (p = 0.003) with addition of PRS-83SNP, PRS-SBayesR, and PRS-CS, respectively. The PRS-23SNP did not improve AUC (74.7%, p = 0.95). CONCLUSION: New PRSs for dementia significantly improve risk-prediction performance, but still account for less risk than APOE genotype overall.