Increased Risk Of Dementia Research Articles

RACIAL AND ETHNIC DISPARITIES IN SOCIAL ISOLATION AND 11-YEAR DEMENTIA RISK AMONG OLDER ADULTS IN THE UNITED STATES

Abstract Social isolation has been linked to cognitive impairment. Research on this relationship, however, remains limited because validated social isolation measures have been underutilized when examining dementia risk, while also considering differences among racial-ethnic groups. To address this gap, we analyzed 11 years of data (2011–2021) from the National Health and Aging Trends Study to examine the interplay between social isolation, race-ethnicity, and dementia. We constructed a longitudinal score using a validated social isolation variable for our sample of 6,155 community-dwelling U.S. adults aged 65 years and older. After applying sampling weights and imputing missing data, our analysis revealed a higher average longitudinal frequency of social isolation among Black (27.6%), Hispanic (26.6%), and Asian (21.0%) older adults compared to non-Hispanic White (19.1%) respondents during the 11-year period (t=-7.35, p<.001). Cox regression models indicated higher frequency of social isolation was significantly associated with a 45% increased dementia risk after adjusting for sociodemographic covariates (adjusted Hazard Ratio [aHR]=1.45, 95% CI=1.14-1.84, p<.01), but this association was non-significant after further adjusting for health covariates (aHR=1.16, 95% CI=0.92-1.46, p=.20). Race-ethnicity was also not a significant moderator in the association between social isolation and dementia. Our results suggest older adults of color experience higher longitudinal frequency of social isolation. Despite the elevated dementia risk we observed among older adults with higher social isolation, race-ethnicity did not moderate this relationship. Future research is needed to investigate the underlying mechanisms contributing to racial-ethnic disparities for social isolation, and develop targeted interventions to mitigate the associated risk for dementia.

INTERACTION BETWEEN NATIVITY AND NEIGHBORHOOD ON DEMENTIA RISK: FINDINGS FROM TEN YEARS OF NATIONAL US DATA

Abstract Prior research indicates neighborhood disadvantage increases dementia risk. There is, however, inconclusive evidence on the relationship between nativity and cognitive impairment. To our knowledge, our study is the first to analyze how nativity and neighborhood interact to influence dementia risk. Ten years of prospective cohort data (2011-2020) were retrieved from the National Health and Aging Trends Study, a nationally representative sample of 5,362 U.S. older adults aged 65+. Cox regression analyzed time to dementia diagnosis using nativity status (foreign or native-born) and composite scores for neighborhood physical disorder (litter, graffiti, vacancies) and social cohesion (know, help, trust each other), after applying sampling weights and imputing missing data. Average baseline neighborhood physical disorder was significantly higher among foreign-born (0.28) compared to native-born (0.18) older adults [t=-2.4, p=.02]. Average baseline neighborhood social cohesion was significantly lower for foreign-born (3.57) compared to native-born (4.33) older adults [t=5.5, p<.001]. After adjusting for sociodemographic, health, and neighborhood variables, foreign-born older adults had a 51% significantly higher dementia risk (aHR=1.51, 95% CI=1.19-1.90, p<.01). There were no statistically significant interactions for nativity with neighborhood physical disorder or social cohesion. Our findings suggest foreign-born older adults have higher neighborhood physical disorder and lower social cohesion compared to native-born older adults. Despite the higher dementia risk we observed for foreign-born older adults, this relationship was not moderated by either neighborhood physical disorder or social cohesion. Further research is needed to understand what factors are contributing to elevated dementia risk among foreign-born older adults.

INTERPERSONAL, COMMUNITY, AND SOCIETAL STRESSORS MEDIATE BLACK–WHITE MEMORY DISPARITIES

Abstract Psychosocial factors may contribute to racial disparities in cognitive aging beyond socioeconomic status. Contextual stressors at multiple ecological levels, which may be related to structural racism, disproportionately affect Black older adults in the U.S. and may explain increased dementia risk. This study examined the extent to which interpersonal, community, and societal level stressors independently explained Black-White disparities in memory at baseline and over time. The sample included 16,890 older Black and White adults (Mage=67.98, 22% Black) from the US Health and Retirement Study who completed psychosocial questionnaires and a word list memory task. Interpersonal, community, and societal stressors were operationalized as self-reported everyday discrimination, neighborhood physical disorder, and subjective societal status, respectively. Latent growth curves modeled memory performance over six years. Stressors were modeled simultaneously and allowed to correlate. Covariates included age, sex, education, wealth, and questionnaire year. Compared to White older adults, Black older adults experienced higher discrimination (b = -.004, SE=.001, p<.001), greater neighborhood physical disorder (b = -.012, SE=.002, p<.001), and lower perceived societal status (b = -.003, SE=.001, p=.001), each of which independently mediated the association between Black race and worse initial memory. Together, these stressors explained 11% of the racial disparity in initial memory. There was no racial disparity in memory decline. Individual experiences of stressors across multiple contextual levels contribute to racial disparities in memory, providing evidence that structural racism negatively influences dementia risk among Black older adults. Future research should consider protective factors that buffer against negative impacts of structural racism on health.

Sarcopenia and diabetes-induced dementia risk.

This study aimed to investigate whether sarcopenia independently increases the risk of diabetes-induced dementia in elderly individuals diagnosed with type 2 diabetes mellitus. The study cohort consisted of a large sample of elderly individuals aged 60 years and above, who were diagnosed with type 2 diabetes mellitus between 2008 and 2018. To minimize potential bias and achieve covariate balance between the sarcopenia and non-sarcopenia groups, we employed propensity score matching. Various statistical analyses, including Cox regression models to assess dementia risk and associations, competing risk analysis to account for mortality and Poisson regression analysis for incidence rates, were used. Before propensity score matching, the study included 406 573 elderly type 2 diabetes mellitus patients, with 20 674 in the sarcopenia group. Following propensity score matching, the analysis included a total of 41 294 individuals, with 20 647 in the sarcopenia group and 20 647 in the non-sarcopenia group. Prior to propensity score matching, elderly type 2 diabetes mellitus patients with sarcopenia exhibited a significantly higher risk of dementia (adjusted hazard ratio: 1.12, 95% confidence interval: 1.07-1.17). After propensity score matching, the risk remained significant (adjusted hazard ratio: 1.14, 95% confidence interval: 1.07-1.21). Incidence rates of dementia were notably higher in the sarcopenia group both before and after propensity score matching, underscoring the importance of sarcopenia as an independent risk factor. Our study highlights sarcopenia as an independent risk factor for diabetes-induced dementia in elderly type 2 diabetes mellitus patients. Advanced age, female gender, lower income levels, rural residency, higher adapted diabetes complication severity index and Charlson Comorbidity Index scores and various comorbidities were associated with increased dementia risk. Notably, the use of statins was linked to a reduced risk of dementia. This research underscores the need to identify and address modifiable risk factors for dementia in elderly type 2 diabetes mellitus patients, offering valuable insights for targeted interventions and healthcare policies.

Hearing loss and dementia in older adults: A narrative review.

The prevalence of hearing loss is high among older adults; globally, 65% of adults over 60 years have hearing loss. Over the past decade, evidence from epidemiologic studies has linked hearing loss to nearly two times greater risk of dementia. The hypothesized mechanistic pathways through which hearing loss could contribute to increased dementia risk include the effects of hearing on greater cognitive load, changes in brain structure and function, and decreased social engagement. These mechanistic pathways may be modified by management of hearing loss using existing intervention (eg, hearing aids). Hearing treatment may be an effective intervention for slowing cognitive decline in some older adults. In this review, we update existing reviews of the current epidemiologic research on the association between hearing loss and dementia risk and discuss hypothesized mechanisms of this association. We also discuss management of hearing loss as a potential intervention for slowing cognitive decline and reducing dementia risk.

Association between first-line antidepressant use and risk of dementia in older adults: a retrospective cohort study

BackgroundPrior studies suggested that antidepressant use is associated with an increased risk of dementia compared to no use, which is subject to confounding by indication. We aimed to compare the dementia risk among older adults with depression receiving first-line antidepressants (i.e., SSRI/SNRI) versus psychotherapy, which is also considered the first-line therapy for depression.MethodsThis retrospective cohort study was conducted using the US Medical Expenditure Panel Survey from 2010 to 2019. We included adults aged ≥ 50 years diagnosed with depression who initiated SSRI/SNRI or psychotherapy. We excluded patients with a dementia diagnosis before the first record of SSRI/SNRI use or psychotherapy. The exposure was the patient’s receipt of SSRI/SNRI (identified from self-report questionnaires) or psychotherapy (identified from the Outpatient Visits or Office-Based Medical Provider Visits files). The outcome was a new diagnosis of dementia within 2 years (i.e., survey panel period) identified using ICD-9/ICD-10 codes from the Medical Conditions file. Using a multivariable logistic regression model, we reported adjusted odds ratios (aORs) with 95% confidence intervals (CIs). We also conducted subgroup analyses by patient sex, age group, race/ethnicity, severity of depression, combined use of other non-SSRI/SNRI antidepressants, and presence of underlying cognitive impairment.ResultsAmong 2,710 eligible patients (mean age = 61 ± 8, female = 69%, White = 84%), 89% used SSRIs/SNRIs, and 11% received psychotherapy. The SSRI/SNRI users had a higher crude incidence of dementia than the psychotherapy group (16.4% vs. 11.8%), with an aOR of 1.36 (95% CI = 1.06–1.74). Subgroup analyses yielded similar findings as the main analyses, except no significant association for patients who were aged < 65 years (1.23, 95% CI = 0.93–1.62), male (1.34, 95% CI = 0.95–1.90), Black (0.76, 95% CI = 0.48–1.19), had a higher PHQ-2 (1.39, 95% CI = 0.90–2.15), and had underlying cognitive impairment (1.06, 95% CI = 0.80–1.42).ConclusionsOur findings suggested that older adults with depression receiving SSRIs/SNRIs were associated with an increased dementia risk compared to those receiving psychotherapy.

Benzodiazepine use in relation to long‐term dementia risk and imaging markers of neurodegeneration: a population‐based cohort study.

AbstractBackgroundBenzodiazepine use is common, particularly in older adults. Benzodiazepines have well‐established acute adverse effects on cognition. However, long‐term effects on dementia risk remain uncertain, and on subclinical imaging markers of neurodegeneration largely undetermined.MethodWe included 5443 cognitively healthy participants (MMSE≥26) from the population‐based Rotterdam Study (57.4% women, mean age 70.6 years). Benzodiazepine use from 1991 until baseline (2005‐2008) was derived from ATC‐coded pharmacy records, from which we determined drug type (anxiolytics vs. sedative‐hypnotics vs. both) and cumulative dose. We determined the association of benzodiazepine use with dementia risk until 2020 using Cox regression, and with change in neuroimaging markers during 5‐yearly repeated brain MRI using linear mixed models. Models were adjusted for demographics, lifestyle factors and comorbidity, including presence of anxiety, depression and sleeping problems.ResultDuring a mean follow‐up of 11.2 years, 726 participants (13.3%) developed dementia. Benzodiazepine use occurred in 1675 (30.8%) participants, of whom 845 (50.4%) had used anxiolytics, 390 (23.3%) had used sedative‐hypnotics, and 440 (26.3%) had used both. Current use of any type of benzodiazepine at baseline, but not former use, was associated with an increased dementia risk during follow‐up (HR[95%CI] for current users: 1.56[1.17‐2.09]; and past users: 1.07[0.87‐1.31]). Excess risk in current users persisted after excluding a 2‐year lag‐time of benzodiazepine use prior to baseline. Dementia risk was dependent on cumulative dose (&gt;median: HR[95%CI] 1.31[1.05‐1.63] vs. &lt; = median: HR[95%CI] 1.01[0.78‐1.31]). Use was not associated with volume of grey matter, white matter, hippocampus, amygdala or thalamus at baseline. During follow up, high cumulative dose was associated with accelerated decrease in hippocampal volume (p = 0.021). Regarding drug type, dementia risk was increased with anxiolytics (overall HR[95%CI]: 1.37[1.10‐1.71]), which was paralleled by accelerated atrophy of grey matter (p = 0.036), albeit no dose‐response relationship was observed. Sedative‐hypnotics were not associated with dementia risk or brain atrophy. Combined use of anxiolytics and sedative‐hypnotics at baseline was associated with increased dementia risk (HR[95%CI]: 1.70[1.05‐2.76]), but this attenuated after excluding use during a 2‐year lag time before baseline (HR[95%CI]: 1.08[0.71‐1.64]), and was not associated with brain atrophy.ConclusionChronic use of benzodiazepines in a population of cognitively healthy older adults is associated with increased dementia risk.

Glycemic variability and dementia risk in a diverse cohort of older adults with type 2 diabetes

AbstractBackgroundType 2 diabetes is associated with a two‐fold increase in dementia risk. Although glycemic variability is becoming increasingly recognised as contributing to end‐organ damage, less is known about its contribution to dementia risk. We aimed to study the association between HbA1c variability and dementia risk in a large, diverse sample of people in Northern California.MethodOver 209,000 members of a fully integrated health care delivery system with type 2 diabetes aged ≥ 50 years were followed from 1996 to 2018 to obtain repeated measures of HbA1c, dementia diagnoses, and comorbidities. Variability was measured using standard deviation (SD), coefficient of variation, and average real variability. Cox proportional hazards models estimated the association between HbA1c variability in the first 3 years of cohort entry and incident dementia at least 2 years after the end of the exposure period adjusting for age (as timescale) and baseline health conditions.ResultThere were a total of 209,703 people in the cohort (mean baseline age 61.0 years (SD = 9.2), 47.5% women) (Table1). Approximately 49.6% of the sample were non‐Latino White. The mean number of HbA1c values available for each participant was 5.8 (SD = 2.3). The mean HbA1c for each participant in the first 3 years was 7.4% (SD = 1.33). Greater HbA1c variability was associated with greater hazard of dementia when measured using SD (aHR = 1.12 [95%CI: 1.10, 1.14]), coefficient of variation (aHR = 2.17 [95%CI: 1.85, 2.55]) (Figure1), or average real variability (aHR = 1.06 [95%CI: 1.06, 1.07]). When stratified by mean HbA1c, we found that ‐ relative to the lowest quintile of variation ‐ increasing variability of SD of HbA1c was associated with greater hazard of dementia in HbA1c categories of &lt;6% (p = 0.0004) and 6 ‐8% (p&lt;0.0001) but not in those with a mean HbA1c ≥8% (p = 0.42).ConclusionGreater HbA1c variability is associated with greater dementia hazard in those with good glycemic control. The absence of association in less well controlled (HbA1c ≥8%) patients may stem from greater variability including lower risk periods of optimal glycemic control. These results support current clinical recommendations to minimize glycemic variability and extend known benefits to include lowering of dementia risk.

Pregnancy‐Related Cardiometabolic Disease and Dementia Risk: A Twin Study

AbstractBackgroundPregnancy related complications such as gestational diabetes mellitus (GDM) and pregnancy‐induced hypertension (PIH) have been shown to increase risk of cardiometabolic disease and may subsequently contribute to all cause dementia. While GDM and PIH have been genetically associated with their later life, non‐pregnancy related counterparts, it remains to be seen if these conditions independently contribute to dementia risk. This study investigated the degree to which GDM and PIH are genetically associated with dementia.MethodData were analyzed from 5,930 females in the Swedish Twin Registry who reported at least one pregnancy. Traditional twin analyses were conducted to determine the degree to which GDM and PIH are genetically influenced, as well as the degree of genetic and environmental overlap with the non‐pregnancy related variant of these conditions. Survival analyses examined relationships between 1) GDM and dementia and 2) PIH and dementia. Hypertension and diabetes outside of pregnancy were included in their respective models as covariates.ResultFor individuals who reported having been pregnant, risk of later life cardiometabolic risk factors were significantly increased if the similar conditions were experienced during pregnancy (P&lt;.001). Both GDM and PIH showed evidence of significant familial associations, with a higher OR in MZ twins for both conditions (GDM OR = 6.74; 95% CI, 1.06 to 2.76; PIH OR = 8.27; 95% CI, 1.89 to 2.38). The survival models indicated that while neither pregnancy‐related condition was independently associated with dementia risk, diabetes outside of pregnancy was associated with a more than three‐fold increase in dementia risk (HR = 3.77, 95% CI = 1.17 – 1.63).ConclusionIn this large, population‐based cohort we found significant associations between pregnancy conditions and their respective cardiometabolic conditions. Cross‐twin associations further indicated that the association between pregnancy and non‐pregnancy cardiometabolic risk factors was driven by genetic influences. However, GDM and PIH did not appear to convey risk for dementia. These findings suggest that mechanisms driving diabetes and hypertension during pregnancy, while related to their later‐life counterparts, do not increase risk of neurocognitive decline.

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.

COVID‐19 Infection and Dementia: Analyses of time‐varying risk, subtypes, and subpopulations from the UK Biobank

AbstractBackgroundAlthough COVID‐19 patients were suggested to experience worse cognitive outcomes, there is a paucity of evidence on time‐varying risk of dementia, especially the subtypes, as well as among critical subpopulations.MethodOut of over 50,000 individuals from a general population in the UK Biobank, SARS‐COV‐2 infected patients between March 1, 2020, and July 31, 2021 and maximally 5:1 propensity score matched contemporary non‐infected individuals were selected, with baseline dementia cases excluded. Matching was done on demographic characteristics, lifestyle, and comorbidities. Dementia was captured according to primary care, inpatient records, and death registry, with the follow‐up ending at the earliest of outcome occurrence, death, or August 31, 2021. Associations were evaluated using time‐varying hazard ratios (HRs) and odds ratios (ORs).ResultWith a mean age of 65.0 years for 18,032 COVID‐19 patients and 83,008 controls, participants were followed for a median of 247 (IQR: 204‐305) days and 255 dementia cases occurred, including 90 Alzheimer’s disease (AD) cases and 42 vascular dementia cases. Compared with matched controls, COVID‐19 infection was associated with increased risks of dementia during the acute phase (first 30 days), with HRs (95% CIs) being 12.77 (6.77, 24.08) for all‐cause dementia, 9.21 (2.77, 30.59) for AD, 5.53 (1.69, 18.11) for vascular dementia, and 25.35 (8.74, 73.56) for other dementia. Dementia risk declined drastically after COVID‐19 infection and sustained for all‐cause dementia, vascular dementia, and other dementia, while became non‐significant for AD. Among those not hospitalized during the acute phase, elevated dementia risk in the follow‐up remained for all‐cause dementia, vascular dementia, and other dementia, with ORs being 1.82, 4.55, and 1.64, respectively. Among most of the subpopulations classified by demographic characteristics, APOE genotype, and comorbidities (except for those with baseline chronic obstructive pulmonary diseases), COVID‐19 infection was associated with an elevated all‐cause dementia risk and no modification effect was detected.ConclusionDeclined yet sustained elevated dementia risk since COVID‐19 infection was found, with differential trends for dementia subtypes. Increased dementia risk from COVID‐19 infection also applied for the non‐hospitalized during the acute phase and most subpopulations. The potential dementia risk associated with Omicron variants warrants further evaluation.

The association between change and stability in subjective health ratings and dementia risk: a multi‐cohort study in Swedish and Danish twins

AbstractBackgroundPoorer self‐rated health (SRH) is associated with increased dementia risk (Stephan et al., 2021). However, it is unclear whether genetic and/or environmental variance accounts for this risk. Although SRH declines with age (Finkel et al. 2020), it is unknown whether rates of change in SRH are independently associated with dementia outcomes. Using a validated latent dementia index (LDI) (Beam et al., 2022), we tested whether stability and change components of SRH predicted LDI via genetic and environmental pathways in two international cohorts of twins.MethodOur data consisted of two samples of monozygotic (MZ) and dizygotic (DZ) twins. We used data from the Swedish Adoption Twin Study of Aging (SATSA; Ntwins = 548, Npairs = 339) and the Longitudinal Study of Aging Danish Twins (LSADT; Ntwins = 3238, Npairs = 2561). Bivariate Cholesky decompositions and three‐level growth‐curve models with predictive intercepts and slopes were used for our cross‐sectional and longitudinal analyses respectively. All models were estimated in Mplus (Muthen &amp; Muthen, 2017) using maximum likelihood with robust standard errors.ResultsCross‐sectional model results indicate that those with poorer SRH have lower LDI scores (b = ‐0.01, p = .008), even after adjusting for shared genetic covariance, age, sex, education, and depressive symptoms. Predictive growth models indicate that rates of change in SRH are negatively associated with LDI after adjusting for age, sex, education, and depressive symptoms (b = ‐0.17, p = .032). The degree of genetic confounding in the association between rates of change and LDI was inconclusive.ConclusionOur study provides novel insights into the relationship between individual ratings of health and dementia risk. SRH predicted dementia likelihood after controlling for genetic confounding, opening up the possibility that subjective ratings of health account for unique variance in dementia risk. Additionally, changes in SRH also predicted dementia likelihood beyond their mean score. Taken together these results highlight the importance of subjective health measures in understanding dementia risk.

Association of Cardiometabolic Multimorbidity with Dementia and Alzheimer’s Plasma Biomarkers in Older Adults: a population‐based study

AbstractBackgroundIndividual cardiometabolic disorders are associated with an increased dementia risk. However, the relationship of cardiometabolic multimorbidity (CMM) with dementia has not been studied in Chinese older adults and the underlying mechanisms are poorly understood.MethodThis population‐based study included 5665 rural‐dwelling adults (age ≥60 years, 57.3% women) in the baseline examination (March‐September 2018) of the Multimodal Interventions to Delay Dementia and Disability in Rural China study. Cardiometabolic diseases (CMDs), which included heart disease, stroke, type 2 diabetes, and obesity, were assessed through clinical and neurological examinations. CMM was defined as the concurrent presence of two or more CMDs. Amyloid‐β(Aβ), total tau, and neurofilament light chain (NfL) were measured using Simoa platform in a subsample (n = 1434). Dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) were clinically diagnosed following international criteria. Data were analyzed using the general linear and logistic regression and mediation models.ResultOf the 5665 participants, 1091 (19.26%) were detected with CMM, and 302 (5.33%) were diagnosed with dementia (193 with AD and 98 with VaD). The multivariable‐adjusted odds ratios of CMM (vs. no CMD) were 3.00 (95% confidence interval [CI] 2.19‐4.11) for all‐cause dementia, 1.66 (1.11‐2.47) for AD, and 12.5 (6.47‐24.18) for VaD. There was a significant interaction between CMM and sex on the likelihood of dementia and subtypes (P for interaction&lt;0.05), such that the associations of CMM with dementia and subtypes were stronger in men than in women. In the biomarker subsample, CMM was significantly associated with higher plasma NfL (demographic‐adjusted β coefficient = 0.059; 95% CI 0.028‐0.091), Aβ40 (0.034; 0.018‐0.049), and Aβ42 (1.068; 0.636‐1.501); the observed association remained significant even in the multivariable‐adjusted model (P&lt;0.001). The mediation analysis showed that plasma NfL could mediate 19.46% of the association between CMM and AD (P&lt;0.05), whereas plasma Aβ and total tau showed no significant mediation (P&gt;0.05).ConclusionCMM is associated with increased likelihoods of dementia, AD, and VaD in older adults, especially in men. Neurodegenerative pathway might play a part in the association of CMM with AD.

Peripheral insulin resistance and creatinine levels are associated with plasma phosphorylated tau

AbstractBackgroundType 2 diabetes (T2D) and insulin resistance (IR) are associated with increased dementia risk, but their association with plasma AD biomarkers e.g., plasma phosphorylated tau (pTau) is unknown. Here, we tested the relationship between diabetes, IR, and pTau, as well as considering the influence of comorbid conditions (obesity and kidney disease) on plasma biomarker measurements.Method425 participants from the Wisconsin Registry for Alzheimer’s Prevention were included based on availability of plasma assays. Plasma pTau181 and pTau231 were measured using a single molecule array (Simoa) assay on Quanterix. Diabetes status at baseline visit was determined using fasting blood glucose and medication usage. IR was measured using the homeostatic model assessment of IR (HOMA2‐IR) and z‐scored. Obesity was indicated through body mass index (BMI) and kidney function was determined by blood creatinine levels. We used Welch’s t‐test to examine differences in pTau levels based on diabetes status. Pearson correlations tested the linear relationships between longitudinal pTau181 and pTau231 with baseline HOMA2‐IR, BMI, and creatinine. Two linear mixed effects models were fitted; one for each of the pTau markers. Each model included random intercepts and age‐related slopes with fixed effects of baseline z‐scored HOMA2‐IR, BMI, and creatinine. Results were considered significant at p&lt;.05unadjusted.ResultSample characteristics are in the Table. Baseline HOMA2‐IR correlated with pTau181 (r = 0.066, p = 0.021), but not pTau 231. Baseline creatinine associated with both pTau181 and pTau231 (Figure 1). Creatinine was also longitudinally associated with pTau231 (β = 4.82, p = 0.004; Figure 2). When accounting for BMI and creatinine, HOMA2‐IR was no longer associated with longitudinal pTau181 or pTau231. Age was robustly associated with pTau181 (β = 0.04, p = 6.06×10−7) and pTau231 (β = 0.15, p = 5.21×10−7) change. Plasma pTau did not differ based on diabetes status.ConclusionIR associated with pTau181 but this relationship did not hold when adjusting for obesity and kidney function. Creatinine levels were associated with longitudinal changes in pTau231 levels. Age was strongly associated with pTau181 and pTau231 change, such that older age was associated with increasing pTau181 and pTau231 levels. Though this study was completed in a largely healthy cohort, the results suggest comorbid conditions are important considerations when utilizing plasma pTau biomarkers as primary outcomes.

Loneliness and daily subjective cognitive concerns among cognitively normal older adults and individuals with MCI

AbstractBackgroundLoneliness is associated with increased dementia risk and is bidirectionally associated with cognitive decline across several years. Less is known about how loneliness and cognitive function are bidirectionally related on shorter timescales. This study examined daily associations between loneliness and self‐reported cognitive concerns in cognitively normal older adults and those with mild cognitive impairment (MCI).MethodCommunity‐dwelling older adults from the Einstein Aging Study (n = 311, age 70‐90 years, 65.9% female, 41.8% Black/African American, 12.5% Hispanic, 30.9% met Jak/Bondi criteria for MCI) completed a two week ecological momentary assessment (EMA) protocol via smartphone. Participants rated their current feelings of loneliness up to 5 times per day (4 via notifications, and 1 at end of day). These ratings were averaged to obtain a loneliness severity score for each day. Subjective cognitive concerns (prospective and retrospective memory lapses, attention/executive function difficulties) were assessed at the end of each day. Participants also reported how much each concern bothered them and/or disrupted their daily activities. Multilevel models were used to assess same‐day and next‐day associations between loneliness and each of the subjective cognitive concern outcomes bidirectionally.ResultsThere were bidirectional same‐day associations observed between loneliness severity and greater number and more bother of attention/executive concerns, as well as greater disruption of all cognitive concerns. When considering associations of present day loneliness with next day cognitive concerns, greater severity of loneliness predicted more bother of attention/executive concerns on the following day. Additionally, present day number of attention/executive concerns and disruption of all cognitive concerns predicted next day loneliness severity. All effects remained significant after adjusting for age, sex, years of education, and MCI status.ConclusionThese findings demonstrate that loneliness is dynamically associated with attention and executive function, but not memory lapses, on a day‐to‐day basis. Associations between loneliness and experience of bother and disruption due to cognitive concerns, suggest that loneliness may signal greater severity of, or less ability to cope with, cognitive difficulties.

APOE4 Carriers with Perivascular Spaces Exhibit Altered Cerebral Blood Flow

AbstractBackgroundPerivascular spaces (PVS) are fluid‐filled spaces surrounding arterioles, capillaries and venules in the brain, which support metabolic waste clearance. Enlarged PVS are associated with increased dementia risk. Changes in arterial pulsatility are hypothesized to be associated with accumulation of toxic solutes and PVS widening. However, few prior studies have examined whether cerebral blood flow (CBF) is linked to PVS.MethodIndependently living older adults (N = 60, mean age = 68.1 years; SD = 7.5; age range 55‐88 years; 30.0% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. Pseudo‐continuous arterial spin labeling was utilized to determine CBF in gray matter CBF (mL/100g tissue/min). Regional mean values were determined for regions of interest. PVS were qualitatively scored in the basal ganglia (BG), and centrum semiovale (CS). APOE genotyping was conducted on the blood cell pellet fraction.ResultAfter accounting for age and sex, multiple linear regression analysis revealed a significant negative association between BG‐PVS and CBF in the left inferior occipital gyrus (B = ‐.07, 95% CI (‐.13, ‐.01), p = .022), right inferior occipital gyrus (B = ‐.06, 95% CI (‐.12, ‐.001), p = .048), left middle occipital gyrus (B = ‐.05, 95% CI (‐.10, ‐.001), p = .047), right middle occipital gyrus (B = ‐.08, 95% CI (‐.13, ‐.02), p = .007), and right inferior temporal gyrus (B = ‐.05, 95% CI (‐.09, ‐.01), p = .025) as well as a positive association in the left precuneus (B = .05, 95% CI (.01, .08), p = .022). When stratified by APOE4 status, all associations were significant only in APOE4 carriers. CS‐PVS were not associated with CBF.ConclusionThese findings indicate altered CBF in older adults with BG‐PVS but not CS‐PVS. Resting CBF was altered in specific brain regions, predominantly in APOE4 carriers. APOE4 is known to convey both vascular risk and risk for Alzheimer’s disease (AD). Additional longitudinal studies are warranted to explore the association between PVS and CBF in individuals at risk for dementia to further understand vascular contributions to the development of AD and other dementias.

Physically demanding work and cognitive impairment in late life

AbstractBackgroundCognitive decline is increasing in prevalence worldwide and poses a heavy burden on society. Sociodemographic factors and health behaviors associated with cognitive decline have been described. While physical exercise has been reported as a protective factor, less education acts as a risk factor. Conversely, work activities associated with lower educational levels are frequently more physically demanding. Few studies have analyzed the impact of work activities on cognition.MethodWe used data from the Brazilian Longitudinal Study of Aging, with a sample of 8,336 complete cases. Linear regression was performed to assess the impact of physical demand at work on cognitive performance, as measured by a global cognitive score composed of temporal orientation, verbal fluency, and memory tests. Work activities were classified by the question “How would you describe physical demand of the job you had most of your life?”, with the following possible answers: “mostly sitting”, “mostly standing or walking”, “some physical effort” and “intense physical effort”. Age, sex, marital status, educational level, household income per capita, number of comorbidities, smoking and alcohol consumption, and level of physical activity were used as covariates.ResultWhen compared to a “mostly sitting” type of work (e.g., office job), a “mostly standing or walking” (e.g., security worker) job did not show any difference in cognitive performance (β = ‐0.03, p = 0.089). On the other hand, a “some physical effort” job (carrying weights or using tools, such as nurse or carpenter) and an “intense physical effort” job (carrying heavy weights, such as miner or construction worker) showed an increasingly worse cognitive performance (respectively, β = ‐0.09, p = 0.000 and β = ‐0.11, p = 0.000).ConclusionAlthough sedentarism has been shown to be associated with a worse cognitive performance and increased dementia risk, physically demanding jobs do not appear to be beneficial. Meanwhile, work stress associated with these activities might exert a negative effect on cognition independent of educational level and physical exercise unrelated to work. Some data suggest mentally demanding jobs, on the contrary, can be beneficial. With development of new technologies, moving from physical work into mental work can potentially reduce dementia risk.

Attention‐deficit/hyperactivity disorder in old age and the risk of dementia: A national cohort study in Israel

AbstractBackgroundEvidence of the association between Attention‐Deficit/Hyperactivity Disorder (ADHD) and the risk of dementia is scarce, inconsistent, and subject to potential sources of bias that are as yet unconsidered. Our objective was to examine the association between ADHD and dementia risk.MethodA prospective national cohort study born 1933‐1952, without a dementia diagnosis for two years, were followed up for incident dementia from 2002‐2020. Information was from electronic health records in a healthcare maintenance organization in Israel. ADHD diagnosis was classified as present from the age of the first diagnosis, otherwise absent. Competing risk Cox regression models were fit to quantify the risk of incident dementia with the Hazard Ratio (HR) and their associated 95% Confidence Intervals (CI) with inverse probability weights, age as the underlying time‐scale, unadjusted and, in the primary analysis, adjusted by 18 covariates.ResultOf 110,196 participants aged 50‐70 years in 2002, 56,914 (51.6%) were female. During follow‐up there were a total of 746 (0.7%) cases of ADHD, and 8,339 (7.6%) of incident dementia. The percentage of incident dementia was 13.1% (N = 98) among those with ADHD present and 7.5% (N = 8,241) among those with ADHD absent. In the primary analysis, the group with ADHD was statistically significantly (P&lt;.05) associated with a higher risk of dementia (unadjusted: HR = 3.57, CI = 2.89, 4.42; adjusted HR = 2.73, CI = 2.04, 3.65) compared to the group with ADHD absent. Eight of ten sensitivity analyses replicated the statistically significant association observed in the primary analysis. Psychostimulant medication offset the association between ADHD and dementia risk to null, and evidence of reverse causation was mild.ConclusionADHD is associated with increased dementia risk. Policymakers, caregivers, patients, and clinicians may wish to monitor ADHD in old age reliably.

How to perform a general population‐based recruitment strategy for a multidomain intervention trial for dementia prevention—the CITA GO‐ON trial experience

AbstractBackgroundFINGER trial has demonstrated the potential for dementia prevention by targeting different lifestyle domains in older adults. It highlighted the importance of selecting the correct window of opportunity for preventive actions by including participants at high risk of dementia. This approach is being tested worldwide to support future public health interventions, where the selection of the appropriate target population is crucial. Here we share our approach and results in recruiting older adults with increased dementia risk and cognitive frailty from the general population for the CITA Go‐On trial.MethodCITA GO‐ON is a single‐center randomized controlled trial in which non‐demented‐adults between 60‐80y will be allocated to receive standard care or a risk factor control and lifestyle‐based multidomain intervention. It replicates FINGER trial inclusion criteria, but the recruitment strategy is based on the community level in Gipuzkoa (Spain) instead of a previous health registry. Together with press and social media releases, mailing, and small group talks, the main recruitment strategy has been coordinated with local governments. Interested people fulfill an online form that allows identifying those who meet the pre‐established requirements (CAIDE dementia risk score ≥6) prior to attending an individualized face‐to‐face cognitive screening visit (evaluation of exclusion criteria and brief cognitive testing).ResultBy December 2022, we have reached and informed about the trial more 24000 people including all citizens older than 60 in three small municipalities in collaboration with the local town halls. Of these, 1919 completed the pre‐screening questionnaire using REDCap, 868 were screened and 450 recruited (mean age: 68,57 (6,58), 50,87% female, and mean CAIDE: 7,49 (1,39)). In person calculated (mean (sd): 6,98 (1,70)) and self‐reported (mean (sd): 7,23 (1,77)) CAIDE score is similar (p = 0,062) in our experience. Table 1 resumes age, sex, CAIDE and MMSE of the interested sample. Recruitment period is still opened.ConclusionCITA GO‐ON recruitment is a multi‐disciplinary population oriented efficient strategy to identify adults at high risk of dementia understanding and willing to participate in a multi‐modal intervention prevention trial. It allows to select candidates from the whole population, and not only those linked to specialized health care systems or registries.

Increased worry associated with self‐reported, but not informant‐reported, subjective cognitive decline predicts risk of incident dementia

AbstractBackgroundSubjective cognitive decline (SCD), in the absence of impaired testing, may be an indicator of early Alzheimer’s disease (AD) and other dementias. However, not all individuals with SCD have cognitive decline. ‘SCD plus’ criteria were proposed in an effort to increase the likelihood of identifying preclinical dementia in individuals with SCD. Two of these criteria include the expression of concern (worry) about the SCD and confirmation of the SCD by an observer (informant). This study investigates whether longitudinal changes in self‐ and informant‐reported SCD‐worry are associated with increased risk of incident dementia over time.MethodParticipants were 873 older adults (M = 78.65‐years; 55% female) and 849 informants from the Sydney Memory and Ageing Study. SCD‐worry was defined as responding “Yes” to the following: “Have you noticed growing difficulties with your/their memory?” and “Have you been concerned about your/their memory getting worse?”. Changes in SCD‐worry over time were modelled using latent growth curve analyses with logit transformation. Participants’ and informants’ propensity to report SCD‐worry at baseline and change over time were analysed using Cox regressions to determine associations with incident dementia risk over 10‐years.Results32% of participants who reported noticing memory difficulties at baseline also reported worry associated with this, where only 19% of informants reported worry associated with SCD at baseline. Controlling for demographics, APOE4, mood and personality, participants’ initial level (p &lt; .001) and change in SCD‐worry over time (p = .002), were associated with dementia risk. Controlling for the same covariates, informants’ initial SCD‐worry (p &lt; .001) was associated with dementia risk, though SCD‐worry change was not (p = .862). When modelled together, participants’ initial level of, and longitudinal change in, SCD‐worry were still independently associated with increased dementia risk (p’s &lt; .001); informants’ initial SCD‐worry remained significant (see Table 1).ConclusionOur findings highlight the need to factor in concerns held by individuals that go beyond just recognising cognitive changes have occurred, as the latter is a common phenomenon in older adults. Our results suggest that worries about perceived cognitive changes may characterise individuals at greater dementia risk.