Incident Dementia Cases Research Articles

Sex-specific dementia risk in known or suspected obstructive sleep apnea: a 10-year longitudinal population-based study

Abstract Study Objectives To evaluate sex-specific associations between known or suspected obstructive sleep apnea (OSA) and dementia risk over 10 years among older women and men. Methods This study included 18 815 women and men age 50+ years (dementia-free at baseline) who participated in the Health and Retirement Study (HRS), a nationally representative cohort of US adults. Presence of OSA was defined by self-reported diagnosis or key HRS items that correspond to elements of a validated OSA screening tool (STOP-Bang). Incident dementia cases were identified using a validated, HRS-based algorithm derived from objective cognitive assessments. Survey-weighted regression models based on pseudo-values were utilized to estimate sex- and age-specific differences in cumulative incidence of dementia by OSA status. Results Data from 18 815 adults were analyzed, of which 9% of women and 8% of men (weighted proportions) met criteria for incident dementia. Known/suspected OSA was more prevalent in men than in women (weighted proportions 68% vs. 31%). Unadjusted sex-stratified analyses showed that known/suspected OSA was associated with higher cumulative incidence of dementia across ages 60–84 years for women and men. By age 80, relative to adults without known/suspected OSA, the cumulative incidence of dementia was 4.7% higher (CI 2.8%, 6.7%) for women with known/suspected OSA, and 2.5% (CI 0.5%, 4.5%) for men with known/suspected OSA, respectively. Adjusted associations between age-specific OSA and cumulative incidence of dementia attenuated for both women and men but remained statistically significant. Conclusions OSA contributes to dementia risk in older adults, particularly women. This study illuminates the impact of a potentially modifiable yet frequently overlooked risk factor for dementia onset.

TRAJECTORIES OF DEPRESSIVE SYMPTOMS BEFORE THE ONSET OF DEMENTIA: EXAMINING RACIAL/ETHNIC DISPARITIES

Abstract Biological and cognitive changes can often be detected up to 16 years prior to a formal diagnosis of Alzheimer’s disease (AD). Psychological symptoms of AD (e.g., depression) may also start to develop during this prodromal phase. Depressive symptoms may be an early marker of neurodegeneration and/or a reaction to early cognitive decline. Higher levels of depressive symptoms could create additional burdens for individuals with preclinical AD and their families. Unfortunately, little is known about the trajectory of depression during the preclinical phase of AD. Using the Langa-Weir method for algorithmic classification, a sample of incident dementia cases (n=2168) was identified from longitudinal data from the Health and Retirement Study (2000-2018). Depressive symptoms were measured with eight dichotomous items from the Center for Epidemiologic Studies Depression (CES-D). Latent growth curve models estimated the trajectory of depressive symptoms over up to 10 waves prior to dementia classification, and disparities across racial/ethnic groups were examined. Results show that depressive symptoms increased slightly over time throughout the preclinical phase of AD, following a quadratic trajectory. Older Hispanic adults reported consistently higher levels of depressive symptoms across timepoints, followed by older non-Hispanic Black and older non-Hispanic White adults. These findings highlight the importance of examining the psychological changes occurring during the preclinical phase of dementia for understanding the disease progression of AD and racial/ethnic disparities in psychological burden. The implications of using algorithmic dementia classifications in studying cognitive race/ethnic disparities will also be discussed.

DOWNWARD DEMENTIA TREND GOES INTO REVERSE IN ENGLAND AND WALES? ENGLISH LONGITUDINAL STUDY OF AGING 2002–2019

Abstract Recent evidence suggests dementia incidence rates are declining in high-income countries. However, data for the trend after 2010 are scarce. We examined the temporal trend in England and Wales from 2002-2019, considering bias and non-linearity. We used population-based panel data linked to the mortality register across wave 1 (2002-2003) to wave 9 (2018-2019) of the English Longitudinal Study of Ageing. Uniform standard criteria based on cognitive and functional impairment were used to ascertain incident dementia cases. Crude incidence rates were determined in seven overlapping initially dementia-free sub-cohorts followed over four years. We estimated the age- and sex-adjusted trend of dementia incidence with Cox and multi-state models. Restricted cubic splines allowed for potential non-linearity. 19 806 people were included in the study. Crude dementia incidence declined from 2002 to 2008 (8.7 to 7.4 per 1000 person-years), and increased from 2008 to 2019 (7.4 to 10.3 per 1000 person-years). Adjusting for age and sex, and accounting for missing dementia cases due to death, estimated dementia incidence declined by 28.8% from 2002 to 2008 (incidence rate ratio 0.71, 95% CI 0.58-0.88), and increased by 25.2% from 2008 to 2016 (incidence rate ratio 1.25, 1.03-1.54). The higher education group had a sharper decline of dementia incidence from 2002 to 2008, and a smaller increase after 2008. Dementia incidence may not be declining. There was a rebound after 2008 in England and Wales. If the upward dementia incidence trend continues, along with population ageing, the burden on health and social care may be large.

The predictive validity of a Brain Care Score for dementia and stroke: data from the UK Biobank cohort.

The 21-point Brain Care Score (BCS) was developed through a modified Delphi process in partnership with practitioners and patients to promote behavior changes and lifestyle choices in order to sustainably reduce the risk of dementia and stroke. We aimed to assess the associations of the BCS with risk of incident dementia and stroke. The BCS was derived from the United Kingdom Biobank (UKB) baseline evaluation for participants aged 40-69 years, recruited between 2006-2010. Associations of BCS and risk of subsequent incident dementia and stroke were estimated using Cox proportional hazard regressions, adjusted for sex assigned at birth and stratified by age groups at baseline. The BCS (median: 12; IQR:11-14) was derived for 398,990 UKB participants (mean age: 57; females: 54%). There were 5,354 incident cases of dementia and 7,259 incident cases of stroke recorded during a median follow-up of 12.5 years. A five-point higher BCS at baseline was associated with a 59% (95%CI: 40-72%) lower risk of dementia among participants aged <50. Among those aged 50-59, the figure was 32% (95%CI: 20-42%) and 8% (95%CI: 2-14%) for those aged >59 years. A five-point higher BCS was associated with a 48% (95%CI: 39-56%) lower risk of stroke among participants aged <50, 52% (95%CI, 47-56%) among those aged 50-59, and 33% (95%CI, 29-37%) among those aged >59. The BCS has clinically relevant and statistically significant associations with risk of dementia and stroke in approximately 0.4 million UK people. Future research includes investigating the feasibility, adaptability and implementation of the BCS for patients and providers worldwide.

Associations between balance, strength and incident dementia in older men: the Health in Men Study

AbstractBackgroundIncreased amount of physical activity has been associated with reduced incidence of dementia. It is less clear whether the discrete physical performance measures of balance and strength are associated with dementia incidence. We investigated whether baseline measures of balance and strength were associated with incident dementia.MethodA cohort of 1,314 men with no recorded history of dementia, aged 79‐97 underwent physical performance assessments between 2011 and 2013. These assessments were performed during wave 4 of the Health in Men Study, initially recruiting participants 1996‐9 in Perth, Australia. Balance was assessed with a modified Balance Outcome Measure for Elder Rehabilitation (mBOOMER) score: a combination of three tests, the Timed Up and Go, Step and Functional Reach Tests. Strength was tested using knee extension with a spring dynamometer, measured in kilograms. Incident dementia was identified up to December 2017 from the Western Australian Data Linkage System and the national Aged Care Assessment Program. Data were analysed using Cox proportional hazards models. Balance and strength measures were entered as restricted cubic splines to allow for non‐linear relationships. Models were adjusted for sociodemographic, lifestyle and health variables, including hours of physical activity.ResultA total of 187 (14.2%) incident cases of dementia were identified. Higher (better) mBOOMER scores were associated with decreased risk of incident dementia, with greater changes in risk occurring at higher scores (1 vs 0: HR 0.91, 95% CI 0.81‐1.01, 6 vs 5: HR 0.91, 95% CI 0.81‐1.01, 9 vs 8: HR 0.77, 95% CI 0.70‐0.84, 12 vs 11: HR 0.51, 95% CI 0.37‐0.69). Higher knee extension strength was associated with a decreased risk of incident dementia, with greater changes occurring at lower levels then plateauing at around 25 kilograms (5kg vs 4kg: HR 0.93, 95% CI 0.89‐0.97, 15kg vs 14kg: HR 0.93, 95% CI 0.89‐0.97, 25kg vs 24kg: HR 0.99, 95% CI 0.95‐1.02, 35kg to 34kg: HR 1.00, 95% CI 0.95‐1.06). Relationships remained after excluding those with a dementia diagnosis within two years of baseline physical performance assessment.ConclusionBetter balance and strength are both associated with decreased risk of developing dementia, thus representing potentially modifiable risk factors.

Social engagement, amyloid burden, and dementia: the Atherosclerosis Risk in Communities (ARIC)‐PET study

AbstractBackgroundAlthough amyloid deposition in the brain is often associated with subsequent dementia risk, not everyone with brain amyloid will develop dementia. This discrepancy illustrates the potential importance that risk factors and lived experiences may have in modifying this association. Compared to participants with low social engagement (SE) in mid‐life, we hypothesized that participants with high mid‐life SE will show a weaker association between amyloid burden and incident dementia.MethodWe included data from 310 non‐demented participants of the Atherosclerosis Risk in Communities (ARIC)‐PET study. Social support and isolation were assessed via interviewer‐administered questionnaires (Visit 2; 1990 – 1992). Based upon categorization of both factors, participants were classified as having high, intermediate, or low mid‐life SE (Table 1). Brain amyloid was evaluated with florbetapir PET (Visit 5; 2011‐2014). Elevated amyloid burden was defined as standardized uptake value ratio (SUVR) &gt;1.2 in the global cortex. Incident dementia cases were identified from visit 5 through 2019 through ongoing surveillance utilizing in‐person neurocognitive testing, informant interviews, and hospitalization codes. Relative contributions of mid‐life SE and elevated florbetapir SUVR to incident dementia, independently and with multiplicative interaction terms, were evaluated with Cox regression models, adjusted for demographics, APOEe4 and vascular risk factorsResultAmong 310 participants, 48 developed dementia (median follow‐up: 4.7 years). Mid‐life SE and elevated SUVR each independently predicted dementia risk but did not interact on a multiplicative scale. Participants with high or intermediate mid‐life SE, relative to low mid‐life SE, were less likely to develop dementia (Table 2). Although the interaction between mid‐life SE and elevated SUVR was not significant, stratified models suggested a stronger association between amyloid burden and dementia in participants with high mid‐life SE (Table 3).ConclusionGreater mid‐life SE was associated with lower odds of developing dementia, independent of elevated SUVR. Although protective, there was no strong evidence for effect modification of mid‐life SE on the association between amyloid and dementia risk. Future longitudinal studies evaluating the potential influence of social factors measured throughout the life course are needed to inform our understanding as to what factors may preserve cognition in the presence of elevated brain pathology.

Glomerular filtration rate proteinuria and risk of dementia: a cohort study from the national health insurance database

AbstractBackgroundThe previous studies had shown conflicting results about the association between kidney dysfunction and dementia. One of the causes may be the use of different indicators to define kidney dysfunction. Although estimated glomerular filtration rate (eGFR) and proteinuria reflect the kidney’s different aspects, few studies used both indicators to examine the association between kidney dysfunction and dementia. In addition, even in the same study, the correlation between kidney dysfunction and dementia was different depending on the indicator. We aimed to demonstrate the association between kidney dysfunction and dementia using renal indicators‐ eGFR and proteinuria independently or together.MethodWe used the National Health Insurance database covering the entire population in South Korea to identify and follow up with the population who checked up in the National Health Screening Program (NHSP) from January 2009 to December 2010. Dementia was defined as a newly diagnosed dementia among the population without a history of dementia before enrollment. We used Cox proportional hazard model to examine between eGFR or proteinuria and the risk of dementia.ResultThere were 283,747 incident dementia cases during 132,811,487 person‐years of follow‐up. The risk of dementia was progressively higher with lower eGFR; compared to eGFR≥100 mL/min, hazard ratio (HR) 1.09, confidence interval [CI], 1.07‐1.12 in eGFR 90‐100 mL/min, HR 1.08, 95% CI, 1.06‐1.10 in eGFR 60‐90 mL/min, HR 1.22, 95% CI, 1.19‐1.24, in eGFR 30‐60 mL/min, HR 1.99, 95% CI, 1.86‐2.12 in eGFR 15‐30 mL/min, and HR 3.05, 95% CI, 2.96‐3.14 in eGFR &lt;15 mL/min or dialysis. The proteinuria was also correlated with dementia (HR 1.25, 95% CI, 1.23‐1.27) after adjusting eGFR. Proteinuria contributed to the stratification of the high‐risk patients for dementia in each eGFR stratum; HR 1.39[95% CI, 1.26‐1.53]in eGFR ≥100 mL/min, HR 1.28[95% CI, 1.21‐1.35]in eGFR 90‐100 mL/min, HR 1.23[95% CI, 1.20‐1.27] in eGFR 60‐90 mL/min, HR 1.24[95% CI, 1.20‐1.28] in eGFR 30‐60 mL/min, HR 1.06[95% CI, 0.89‐1.26] in eGFR 15‐30 mL/min, and HR 1.16[95% CI, 1.10‐1.22] in eGFR &lt;15 mL/min or dialysis.ConclusioneGFR and proteinuria were associated with dementia independently. The use of both eGFR and proteinuria was useful for the stratification of dementia risk.

Social engagement, amyloid burden, and dementia: the Atherosclerosis Risk in Communities (ARIC)‐PET study

AbstractBackgroundAlthough amyloid deposition in the brain is often associated with subsequent dementia risk, not everyone with brain amyloid will develop dementia. This discrepancy illustrates the potential importance that risk factors and lived experiences may have in modifying this association. Compared to participants with low social engagement (SE) in mid‐life, we hypothesized that participants with high mid‐life SE will show a weaker association between amyloid burden and incident dementia.MethodWe included data from 310 non‐demented participants of the Atherosclerosis Risk in Communities (ARIC)‐PET study. Social support and isolation were assessed via interviewer‐administered questionnaires (Visit 2; 1990 – 1992). Based upon categorization of both factors, participants were classified as having high, intermediate, or low mid‐life SE (Table 1). Brain amyloid was evaluated with florbetapir PET (Visit 5; 2011‐2014). Elevated amyloid burden was defined as standardized uptake value ratio (SUVR) &gt;1.2 in the global cortex. Incident dementia cases were identified from visit 5 through 2019 through ongoing surveillance utilizing in‐person neurocognitive testing, informant interviews, and hospitalization codes. Relative contributions of mid‐life SE and elevated florbetapir SUVR to incident dementia, independently and with multiplicative interaction terms, were evaluated with Cox regression models, adjusted for demographics, APOEε4 and vascular risk factorsResultAmong 310 participants, 48 developed dementia (median follow‐up: 4.7 years). Mid‐life SE and elevated SUVR each independently predicted dementia risk but did not interact on a multiplicative scale. Participants with high or intermediate mid‐life SE, relative to low mid‐life SE, were less likely to develop dementia (Table 2). Although the interaction between mid‐life SE and elevated SUVR was not significant, stratified models suggested a stronger association between amyloid burden and dementia in participants with high mid‐life SE (Table 3).ConclusionGreater mid‐life SE was associated with lower odds of developing dementia, independent of elevated SUVR. Although protective, there was no strong evidence for effect modification of mid‐life SE on the association between amyloid and dementia risk. Future longitudinal studies evaluating the potential influence of social factors measured throughout the life course are needed to inform our understanding as to what factors may preserve cognition in the presence of elevated brain pathology.

The impact of modifiable risk factor reduction on future dementia burden: a microsimulation modeling study

AbstractBackgroundForty percent of dementia cases could potentially be prevented through modifiable risk factors. However, the effect of risk factor reductions might be partially offset by individuals living longer and developing dementia later. Using a microsimulation model, we determined the effect of reductions in smoking and hypertension prevalence on the future dementia burden.MethodThe microsimulation model ‘MISCAN‐Dementia’ was used to simulate life histories and dementia development of 10 million individuals. We modelled mid‐life (40‐59 years) hypertension and late‐life (65+ years) smoking as risk factors (Figure 1), simulating four risk groups: (1) neither risk factor, (2) smoking only, (3) hypertension only, and (4) both risk factors. Sex‐specific population data were used to determine risk factor prevalence. Based on prior literature, smoking and hypertension were each set to a 1.6‐fold increase in dementia risk, and a loss of life expectancy of 4 and 2 years, respectively. Reductions in risk factor prevalence of 100% (i.e. elimination), 50%, 25% and 10% were modeled and evaluated in terms of life years (LYs) without dementia gained, LYs with dementia averted and incident dementia cases averted.ResultCompared to no reduction, for the lifetime of 1000 individuals, elimination of hypertension results in 360 LYs without dementia gained, 40 LYs with dementia averted and 4 incident cases averted. Although smoking elimination results in 600 LYs without dementia gained, it also causes 75 more dementia LYs and 10 more incident cases. These additional LYs with dementia occur primarily at older ages, due to relatively high life expectancy gains compared to moderate reductions in dementia risk (Figure 2). Reductions of 50%, 25% and 10% result in similar findings at lower magnitudes.ConclusionReductions in prevalence of hypertension and smoking result in a gain in life years free of dementia. However, for smoking this coincides with a (smaller) increase in life years with dementia at older ages. These findings suggest that treatment or prevention of dementia risk factors will generally result in a larger number of cognitively healthy life years, but potentially at the cost of minor increases in years with dementia for risk factors with large effects on survival.

What do we still need to know about antihypertensives and dementia prevention?

AbstractThere is a substantial evidence base linking higher blood pressures to an increased risk of cognitive decline and dementia and an increasingly strong evidence base showing reduced dementia risk with blood pressure lowering. Several clinical trials including SPRINT‐MIND have strongly suggested that antihypertensive treatment to lower blood pressure reduces dementia risk. Furthermore, a recent individual participant data meta‐analysis combining data from 5 large double‐blind placebo‐controlled trials of antihypertensives in a late‐mid to early‐late life population (N = 28008) found a 13% reduction in incident dementia cases (OR0.87 (95%CI: 0.75,0.99))(1). The blood pressure difference between the two combined trial arms was ∼10mmHg in systolic blood pressure and there was no clear U shape indicating no increase in risk at lower pressures. This is supported by numerous earlier meta‐analyses of published trial and epidemiological data. Blood pressure lowering is acknowledged as one of the most promising ways in which we might reduce the risk of dementia and cognitive decline.Despite this substantial progress and although we are arguably closer than ever before to answering the question of whether blood pressure lowering reduces dementia risk, there have been no double‐blind placebo‐controlled trials that have definitively shown dementia risk reduction with antihypertensive use. In the absence of strong results, recommendations for antihypertensive use inevitably remain cautious. Furthermore, not only do we still lack a definitive blood pressure dementia risk reduction trial, such a trial would need to be large and complex. Uncertainties also exist about how to deliver treatment against the backdrop of widespread antihypertensive use to reduce cardiovascular risks such as stroke or heart attack. Research is also still progressing on key practical questions. For example, whether we should have a goal blood pressure for brain health, how far we should lower blood pressure to reduce dementia risk, what is the ideal treatment package and how much do factors such as age and frailty matter? We present the key evidence so far and an ongoing pilot trial designed to answer the leading questions in the field.(1)Peters et al Eur Heart J 2022

Social engagement and the risk of incident dementia: the Atherosclerosis Risk in Communities study

AbstractBackgroundStrong psychosocial health has been linked to preserved cognition and functional independence in older adults. Associations between late‐life psychosocial health and dementia risk have been established in older adults, but it remains less clear how one’s social interactions in mid‐life may relate to dementia risk in late life. We hypothesized that social engagement in mid‐life will be negatively associated with the risk of dementia in late‐life.MethodWe included data from 13,216 dementia‐free participants at midlife (mean age: 57.0 years, SD: 5.7 years, 54.9% female, 23.8% Black) from the Atherosclerosis Risk in Communities (ARIC) cohort study. Social support and isolation were assessed via interviewer‐administered questionnaires (visit 2: 1990‐1992). Based upon categorization of both factors, participants were classified as having high, intermediate, or low mid‐life social engagement. Incident dementia cases were identified from visit 2 through December 31, 2019 with ongoing surveillance (e.g., in‐person neurocognitive testing, informant interviews, and hospitalization codes). Primary analyses used Cox proportional hazards regression models and were adjusted for demographics, APOE ε4, occupational/marital status, depressive symptoms, and vascular risk factors measured at visit 2. Secondary analyses examined whether sex and/or race modified the association between mid‐life social engagement and dementia risk with formal tests for interaction.ResultAmong 13,261 participants, 2,555 developed dementia (median follow‐up: 23.7 years). Participants with high (hazard ratio (HR): 0.77, 95% CI: 0.68 ‐ 0.86) or intermediate social engagement (HR: 0.84, 95% CI: 0.74 – 0.95) in mid‐life had a lower risk for developing dementia, compared to participants with low social engagement in mid‐life (Figure 1, Table 1). Sex modified this effect (p‐value for interaction = 0.042) whereas race did not. In males, only those with high social engagement in mid‐life had a lower risk of dementia; the association between males with intermediate social engagement in mid‐life and dementia risk was not significant (Table 2).ConclusionGreater social engagement in mid‐life is associated with a lower risk of dementia. This finding provides further evidence that mid‐life may be a critical time window for dementia prevention. Longitudinal studies evaluating the mechanisms by which psychosocial factors modify the likelihood of incident dementia are needed.

Ethnic Variation in Modifiable Risk Factors for Dementia

AbstractBackgroundWe aimed to estimate the population attributable fraction (PAF) of 12 modifiable risk factors (defined by the Lancet Commission 2020), for incident dementia cases in the UK Biobank (UKB), stratified by ethnicity. We considered if ethnic differences in dementia risk, were accounted for by modifiable risk factors. To identify appropriate priorities in dementia prevention, tailored to ethnicity.MethodThe UKB is a cohort study with 502,656 volunteer participants registered between 2006‐2010, aged 40‐60 years at baseline, and followed for up to 16.8 years. To estimate the PAF of 12 modifiable risk factors (diabetes, hypertension, depression, hearing loss, obesity, traumatic brain injury (TBI), less education, social isolation, physical inactivity, air pollution, and smoking), we first estimated hazard ratios (HRs)(adjusted for age, gender, and Townsend quintiles), or when ethnicity interacted with risk factors, then we estimated HRs stratified by ethnicity. HRs were then converted to relative risk for PAF calculation.Results6,624 incident cases of dementia developed in 1.3%(95%CI = 1.3‐1.3)(n = 6316/471297){of Whites}, in 1.3%(95%CI = 1.1‐1.5)(n = 104/8031){of Blacks}, and in 1.0%(95%CI = 0.8‐1.2)(n = 79/8001){of South Asians (S.Asian)}. The mean age at dementia diagnosis was 71.6 years(SD,6.1){in S.Asians}; 71.8 years(SD,6.8){in Blacks}; and 73.6 years(SD,5.5){in Whites}. The combined PAF(95%CI) for dementia were: 35.6%(35.5‐35.8){in Whites}, 33.9%(32.8‐34.9){in Blacks}, and 41.0%(39.9‐42.0){in S.Asians}. The highest individual PAFs in each ethnic group, compared to the rest, were as follow. Blacks and S.Asians, respectively, for midlife hypertension: 9.6%(9.0‐10.3) and 10.1%(9.5‐10.8) vs 6.5%(6.4‐6.5){in Whites}. S.Asians for (1)Depression: 8.5%(7.9‐9.1) vs 4.0%(3.6‐4.4){in Blacks}, and 5.8%(5.7‐5.9){in Whites}; (2)Diabetes: 6.0%(5.4‐6.5) vs 5.1%(4.6‐5.6){in Blacks}, and 3.5%(3.4‐3.5){in Whites}; (3)Excessive alcohol: 1.4%(1.2‐1.7) vs 0.0%{in Blacks and Whites}. Whites for (1)Hearing loss: 3.6%(3.6‐3.7) vs 2.4%(2.1‐1.8){in Blacks}, and 3.0%(2.6‐3.4){in S.Asians}; (2)TBI: 2.5%(2.4‐2.5) vs 1.3%(1.1‐1.6){in Blacks}, and 1.7%(1.4‐2.0){in S.Asians}; (3)Less education: 5.0%(4.9‐5.1) vs 3.3%(2.9‐3.7){in Blacks}, and 3.2%(2.9‐3.6){in S.Asians}; (4)Physical inactivity: 2.6%(2.6‐2.7), vs 2.1%(1.8‐2.5){in Blacks}, and 2.2%(1.8‐2.5){in S.Asian; (5)Social isolation: 2.3%(2.2‐2.3) vs 1.9%(1.6‐2.1){in Blacks}, and 1.9%(1.6‐2.2){in S.Asians. The remaining risk factor PAFs did not differ between all ethnic groups.ConclusionIn this relatively wealthy, and healthy population, there remain ethnic disparities in the effect of modifiable risk factors on dementia. Interventions for midlife hypertension are a priority in South Asians and Blacks, particularly depression and alcohol consumption in South Asians.

Impact of Multivitamin‐Mineral and Cocoa Extract on Incidence of Mild Cognitive Impairment and Dementia: Results from the Cocoa Supplement and Multivitamin Outcomes Study for the Mind COSMOS‐Mind

AbstractBackgroundCOSMOS‐Mind, a large, randomized placebo‐controlled pragmatic trial in older adults, recently reported that daily supplementation with multivitamin‐mineral, but not cocoa extract, benefited global cognition. We assessed effects of these supplements on prespecified secondary outcomes of mild cognitive impairment (MCI) and all‐cause dementia (DM). We also assessed treatment‐related cognitive trajectories leading to conversion to MCI or dementia.MethodCOSMOS‐Mind (N = 2262) administered a telephone‐based cognitive battery at baseline and annually for 3 years. Proxies of participants meeting criteria for suspected cognitive impairment based on a cognitive screener (TICSm) were interviewed. An expert panel adjudicated cognitive status. Incidence rates of MCI, and separately DM, were compared among arms with proportional hazards regression. Changes in cognitive trajectories leading to MCI and DM were assessed with linear models.ResultAt baseline, adjudication for suspected cognitive impairment was triggered for 419 (20%) participants, yielding adjudications of 217 (10%) MCI and 4 (0.2%) DM cases. During follow‐up, triggers were less frequent in the MVM than placebo arms: hazard ratio = 0.73 (p = 0.04). Across 3 years, 110 incident MCI and 14 incident DM cases were adjudicated. Incidence rates of these outcomes did not vary by assignment to multivitamin‐mineral or cocoa extract (all p≥0.05), however statistical power was low. Incident MCI was associated with a marked decline in cognitive function from the previous year (p&lt;0.001). When participants assigned to multivitamin‐mineral versus placebo converted to MCI, their scores for global cognition (p = 0.03) and executive function (p&lt;0.001) were higher and had declined less relative to the previous year (p = 0.03 for global cognition; p = 0.004 for executive function). Daily cocoa extract use did not attenuate cognitive decline leading up to MCI.ConclusionCOSMOS‐Mind does not provide evidence that cocoa extract or multivitamin‐mineral therapy lowers risk of incident MCI or DM. Multivitamin‐mineral therapy, but not cocoa extract, may provide cognitive resilience countering conversion to MCI.

Is metabolic-healthy obesity associated with risk of dementia? An age-stratified analysis of the Whitehall II cohort study.

Metabolically healthy obesity is hypothesized to be a benign condition but whether this is the case for dementia remains debated. We examined the role of age at assessment of metabolic-obesity phenotypes in associations with incident dementia. Obesity (body mass index ≥ 30kg/m2) and poor metabolic health (≥ 2 of elevated serum triglycerides, low HDL-C, elevated blood pressure, and elevated serum fasting glucose) were used to define four metabolic-obesity phenotypes (metabolically healthy (MHNO) and unhealthy non-obesity (MUNO), metabolically healthy (MHO) and unhealthy obesity (MUO)) at < 60, 60 to < 70, and ≥ 70years using 6 waves of data from the Whitehall II study and their associations with incident dementia was examined using Cox regression. Analyses with exposures measured < 60, 60 to < 70, and ≥ 70years involved 410 (5.8%), 379 (5.6%), and 262 (7.4%) incident dementia cases over a median follow-up of 20.8, 10.3, and 4.2years respectively. In analyses of individual components, obesity before 60years (HR 1.41, 95% CI: [1.08, 1.85]) but not at older ages was associated with dementia; unhealthy metabolic status when present < 60years (HR 1.33, 95% CI: [1.08, 1.62]) and 60 to < 70years (HR 1.32, 95% CI: [1.07, 1.62]) was associated with dementia. Compared to the metabolically healthy non-obesity group, the risk of dementia was higher in those with metabolically healthy obesity before 60years (1.69; 95% CI: [1.16, 2.45]); this was not the case when metabolic-obesity phenotype was present at 60 to < 70years or ≥ 70years. Analyses at older ages were on smaller numbers due to death and drop-out but inverse probability weighting to account for missing data yielded similar results. Individuals with metabolically healthy obesity before age 60 had a higher risk of incident dementia over a 27-year follow-up; the excess risk dissipates when metabolic health and obesity are measured after 70years.

Different types of screen time, physical activity, and incident dementia, Parkinson’s disease, depression and multimorbidity status

BackgroundSeveral previous studies have shown that excessive screen time is associated with an increased prevalence of dementia, Parkinson’s disease (PD), and depression. However, the results have been inconsistent. This study aimed to prospectively investigate the association between different types of screen time and brain structure, as well as the incidence of dementia, Parkinson’s disease, depression, and their multimorbidity status.MethodsWe included 473,184 participants initially free of dementia, PD, and depression from UK Biobank, as well as 39,652 participants who had magnetic resonance imaging (MRI) data. Screen time exposure variables including TV viewing and computer using were self-reported by participants. Cox proportional hazards regression models were used to estimate the association between different types of screen time and the incidence of dementia, Parkinson’s disease, depression, and their multimorbidity status. Multiple linear regression models were used to assess the linear relationship between different types of screen time and MRI biomarkers in a subgroup of participants.ResultsDuring the follow up, 6,096, 3,061, and 23,700 participants first incident cases of dementia, PD, and depression respectively. For moderate versus the lowest computer uses, the adjusted HRs (95% CIs) were 0.68 (0.64, 0.72) for dementia, 0.86 (0.79, 0.93) for PD, 0.85 (0.83, 0.88) for depression, 0.64 (0.55, 0.74) for dementia and depression multimorbidity, and 0.59 (0.47, 0.74) for PD and depression multimorbidity. The multivariable HRs (95% CIs) for the highest versus the lowest group of TV viewing time were 1.28 (1.17, 1.39) for dementia, 1.16 (1.03, 1.29) for PD, 1.35 (1.29, 1.40) for depression, 1.49 (1.21, 1.84) for dementia and depression multimorbidity, and 1.44 (1.05, 1.97) for PD and depression multimorbidity. Moderate computer using time was negatively associated with white matter hyperintensity volume (β = -0.042; 95% CI -0.067, -0.017), and positively associated with hippocampal volume (β = 0.059; 95% CI 0.034, 0.084). Participants with the highest TV viewing time were negatively associated with hippocampal volume (β = -0.067; 95% CI -0.094, -0.041). In isotemporal substitution analyses, substitution of TV viewing or computer using by equal time of different types of PA was associated with a lower risk of all three diseases, with strenuous sports showing the strongest benefit.ConclusionWe found that moderate computer use was associated with a reduced risk of dementia, PD, depression and their multimorbidity status, while increased TV watching was associated with a higher risk of these disease. Notably, different screen time may affect the risk of developing diseases by influencing brain structures. Replacing different types of screen time with daily-life PA or structured exercise is associated with lower dementia, PD, and depression risk.

Association of plasma high-density lipoprotein cholesterol level with risk of incident dementia: a cohort study of healthy older adults

Recent studies have reported associations between high plasma high-density lipoprotein cholesterol (HDL-C) levels and risk of all-cause mortality, age-related macular degeneration, sepsis and fractures, but associations with dementia risk remain unclear. To determine whether high plasma HDL-C levels are associated with increased incident dementia risk in initially-healthy older people. We conducted a post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial; a double-blind, randomized, placebo-controlled trial of daily low-dose aspirin in healthy older people. ASPREE recruited 16,703 participants aged ≥70 years (from Australia) and 2411 participants aged ≥65 years (from the US) between 2010 and 2014. Participants had no diagnosed cardiovascular disease, dementia, physical disability, or life-threatening illness at enrolment and were cognitively healthy (3MS score ≥78). All-cause dementia was a primary trial endpoint, and determined by DSM-IV criteria. Cox regression was used to examine hazard ratios between HDL-C categories <40mg/dL, 40-60mg/dL (reference category), 60-80mg/dL, and >80mg/dL and dementia. Restricted cubic spline curves were used to determine nonlinear associations. Data analysis was performed from October 2022 to January 2023. Of the 18,668 participants, 850 (4.6%) cases of incident dementia were recorded over 6.3 (SD 1.8) years. Participants with high HDL-C (>80mg/dL) had a 27% higher risk of dementia (HR 1.27, 95% CI 1.03, 1.58). Age stratified analyses demonstrated that the risk of incident dementia was higher in participants ≥75 years compared to participants <75 years (HR 1.42, 95% CI 1.10, 1.83 vs HR 1.02, 95% CI 0.68, 1.51). Associations remained significant after adjusting for covariates including age, sex, country of enrolment, daily exercise, education, alcohol consumption, weight change over time, non-HDL-C, HDL-C-PRS, and APOE genotype. In a population of initially-healthy older adults aged ≥75 years, high HDL-C levels were associated with increased risk of all-cause dementia. National Institutes of Health, USA; National Health and Medical Research Council Australia; Monash University (Melbourne, VIC, Australia); and the Victorian Cancer Agency (Australia).

6 Depressive Symptoms are Associated With Decline Over Time in Verbal Fluency Performance in Female but not Male Community-Dwelling Older Adults

Objective:Late-life depression is prevalent among older adults and the presence of depressive symptoms has been shown to be associated cross-sectionally with worse verbal fluency performance. There is limited and mixed evidence as to whether depressive symptoms impact change in verbal fluency performance over time, and whether gender impacts this relationship.Participants and Methods:Participants were community-dwelling older adults who were dementia-free at baseline (N = 522; M age = 75.96, SD + 6.46 years). Baseline depressive symptoms were measured using the Geriatric Depression Scale. Category fluency and letter fluency performance, using the Controlled Oral Word Association Test (COWAT), were examined annually. Linear mixed effects models stratified by gender examined whether associations between baseline depressive symptoms and changes in fluency performance over five years were different in female (n = 289) as compared to male (n = 233) participants. Sensitivity analyses excluding participants with prevalent or incident mild cognitive impairment (MCI) (n = 141), excluding participants with incident dementia (n = 28), and excluding participants with prevalent or incident MCI or incident dementia (n = 169) were run. All analyses were adjusted for age, years of education, estimated premorbid functioning, and health comorbidities.Results:Depression was minimal across participants (m = 4.72, SD + 3.96). A subset of participants (n = 44) reported “possible depression,” namely levels suggestive of subclinical depression, according to clinical cutoffs. The “possible depression” group included 31 females (10.73% of females) and 13 males (5.58% of males), and the “no depression” group included 258 females (89.27% of females) and 220 males (94.42% of males). Baseline levels of depressive symptoms suggestive of subclinical depression were associated with worse decline in category fluency performance during longitudinal follow-up in females (estimate = -0.16, p = .002) but not males (estimate = -0.03, p = .658). Results remained the same when excluding prevalent and incident MCI cases (estimate = -0.19, p = .005), excluding incident dementia cases (estimate = -0.12, p = .017), and excluding prevalent and incident MCI and incident dementia cases (estimate = -0.20, p = .004). Letter fluency performance did not decline over time and was not influenced by levels of depressive symptoms in females (estimate = -0.03, p = .502) or males (estimate = 0.05, p = .452).Conclusions:Baseline presence of depressive symptoms suggestive of subclinical depression was associated with worse decline in category fluency performance during longitudinal follow-up in female but not male participants. Letter fluency performance did not decline and was not impacted by levels of depressive symptoms. Results remained significant when accounting for covariates and potential confounders. The present study elucidated the combined influence of gender and depressive symptoms on change in fluency performance in older adults and can aid in identifying individuals who may be at a greater risk of cognitive decline.

Circulating metabolites and risk of incident dementia: Aprospective cohort study.

Identifying circulating metabolites associated with dementia, cognition, and brain volume may improve the understanding of dementia pathogenesis and provide novel insights for preventive and therapeutic interventions. This cohort study included a total of 87 885 participants (median follow-up of 9.1 years, 54% female) without dementia at baseline from the UK Biobank. A total of 249 plasma metabolites were measured using nuclear magnetic resonance spectroscopy at baseline. Cox proportional regression was used to examine the associations of each metabolite with incident dementia (cases = 1134), Alzheimer's disease (AD; cases = 488), and vascular dementia (VD; cases = 257) during follow-up. Dementia-associated metabolites were further analyzed for association with cognitive deficits (N = 87 885) and brain volume (N = 7756) using logistic regression and linear regression. We identified 26 metabolites associated with incident dementia, of which 6 were associated with incident AD and 5 were associated with incident VD. These 26 dementia-related metabolites were subfractions of intermediate-density lipoprotein, large low-density lipoprotein (L-LDL), small high-density lipoprotein (S-HDL), very-low-density lipoprotein, fatty acids, ketone bodies, citrate, glucose, and valine. Among them, the cholesterol percentage in L-LDL (L-LDL-C%) was associated with lower risk of AD (HR [95% CI] = 0.92 [0.87-0.97], p = 0.002), higher brain cortical (β = 0.047, p = 3.91 × 10-6 ), and hippocampal (β = 0.043, p = 1.93 × 10-4 ) volume. Cholesteryl ester-to-total lipid ratio in L-LDL (L-LDL-CE%) was associated with lower risk of AD (HR [95% CI] = 0.93 [0.90-0.96], p = 1.48 × 10-4 ), cognitive deficits (odds ratio = 0.98, p = 0.009), and higher hippocampal volume (β = 0.027, p = 0.009). Cholesteryl esters in S-HDL (S-HDL-CE) were associated with lower risk of VD (HR [95% CI] = 0.81 [0.71-0.93], p = 0.002), but not AD. Taken together, circulating levels of L-LDL-CE% and L-LDL-C% were robustly associated with risk of AD and AD phenotypes, but not with VD. S-HDL-CE was associated with lower risk of VD, but not with AD or AD phenotypes. These metabolites may play a role in the advancement of future intervention trials. Additional research is necessary to gain a complete comprehension of the molecular mechanisms behind these associations.

Digestive System Diseases, Genetic Risk, and Incident Dementia: A Prospective Cohort Study

Introduction: Although digestive system disease affects gut microbiota and their metabolites associated with dementia risk, the association between digestive system diseases and incident dementia has not yet been established. Methods: This cohort analysis included 458,181 participants free of baseline dementia in the UK Biobank (2006-2021). The associations of fourteen digestive system diseases with dementia incidence were examined in 2022 using Cox proportional hazards regression models. Analyses were performed to differentiate the associations for early- (< 65 years) and late-onset (≥ 65 years) dementia. Interaction and stratification analyses were performed for polygenic risk score (RPS), and apolipoprotein E (APOE). Results: During a median follow-up of 12.4 years, 6415 incident dementia cases were diagnosed. Eleven digestive system diseases showed significant associations with an increased risk of dementia after controlling for covariates and multiple testing. Compared to individuals without digestive system diseases, the hazard ratios of dementia increased from 1.15 (95% confidence interval 1.09-1.23) for patients with intestinal diverticular disease to 2.31 (95% confidence interval 1.98-2.70) for patients with cirrhosis. The associations were different between certain digestive system diseases and dementia by onset age. The associations appeared to be stronger for cirrhosis (Q = 0.001), irritable bowel syndrome (Q < 0.001), gastritis and duodenitis (Q =0.002), gastroesophageal reflux disease (Q < 0.001), ulcerative colitis (Q=0.047), gallbladder disease (Q=0.012) and peptic ulcer (Q = 0.030) with early-onset dementia. There were no interactions for PRS or APOE (P >0.05). Conclusions: These findings suggest an increased need for dementia prevention among patients with digestive system diseases.

Association Between Slow-Wave Sleep Loss and Incident Dementia

Slow-wave sleep (SWS) supports the aging brain in many ways, including facilitating the glymphatic clearance of proteins that aggregate in Alzheimer disease. However, the role of SWS in the development of dementia remains equivocal. To determine whether SWS loss with aging is associated with the risk of incident dementia and examine whether Alzheimer disease genetic risk or hippocampal volumes suggestive of early neurodegeneration were associated with SWS loss. This prospective cohort study included participants in the Framingham Heart Study who completed 2 overnight polysomnography (PSG) studies in the time periods 1995 to 1998 and 2001 to 2003. Additional criteria for individuals in this study sample were an age of 60 years or older and no dementia at the time of the second overnight PSG. Data analysis was performed from January 2020 to August 2023. Changes in SWS percentage measured across repeated overnight sleep studies over a mean of 5.2 years apart (range, 4.8-7.1 years). Risk of incident all-cause dementia adjudicated over 17 years of follow-up from the second PSG. From the 868 Framingham Heart Study participants who returned for a second PSG, this cohort included 346 participants with a mean age of 69 years (range, 60-87 years); 179 (52%) were female. Aging was associated with SWS loss across repeated overnight sleep studies (mean [SD] change, -0.6 [1.5%] per year; P < .001). Over the next 17 years of follow-up, there were 52 cases of incident dementia. In Cox regression models adjusted for age, sex, cohort, positivity for at least 1 APOE ε4 allele, smoking status, sleeping medication use, antidepressant use, and anxiolytic use, each percentage decrease in SWS per year was associated with a 27% increase in the risk of dementia (hazard ratio, 1.27; 95% CI, 1.06-1.54; P = .01). SWS loss with aging was accelerated in the presence of Alzheimer disease genetic risk (ie, APOE ε4 allele) but not hippocampal volumes measured proximal to the first PSG. This cohort study found that slow-wave sleep percentage declined with aging and Alzheimer disease genetic risk, with greater reductions associated with the risk of incident dementia. These findings suggest that SWS loss may be a modifiable dementia risk factor.