Role In Dementia Research Articles

Associations of combined accelerated biological aging and genetic susceptibility with incident dementia: a prospective study in the UK Biobank

BackgroundAccelerated biological aging has been verified to be a critical risk factor for a number of age-related diseases, but its role in dementia remained unclear. Whether it modified the effects of genetic factors was also unknown. This study evaluated the associations between accelerated biological aging and dementia and the moderating role of accelerated biological aging in the genetic susceptibility to the disease.MethodsWe included 200,731 participants in the UK biobank. Nine clinical blood biomarkers and chronological age were used to calculate Phenotypic age acceleration (PhenoAgeAccel), which is a novel indicator for accelerated biological aging. The associations of PhenoAgeAccel with dementia, both young-onset and late-onset dementia, were assessed by Cox proportional hazard models. Apolipoprotein E (APOE) alleles and polygenic risk scores (PRS) were used to evaluate the genetic risk of dementia. The interactions between genetic susceptibility and biological aging were tested on both multiplicative and additive scales.ResultsThese findings showed individuals who were in the highest quartile of PhenoAgeAccel had a higher risk with incidence of dementia compared to individuals in the lowest quartile of PhenoAgeAccel (HR: 1.145 (95% CI: 1.050, 1.249)). Individuals with biologically older had a higher risk of dementia than individuals with biologically younger (HR: 1.069 (95% CI: 1.004, 1.138)). Furthermore, compared to individuals with biologically younger and low APOE ε4-related genetic risk, individuals with biologically younger and high APOE ε4-related genetic risk (HR:3.048 (95% CI: 2.811, 3.305)) had a higher risk of dementia than individuals with biologically older and high APOE ε4-related genetic risk (HR: 2.765 (95% CI: 2.523, 3.029)). Meanwhile, referring to low dementia PRS and biologically younger, the risk of dementia increased by 72.7% (HR: 1.727 (95% CI: 1.538, 1.939) in the biologically younger and high PRS group and 58.7% (HR: 1.587 (95% CI: 1.404, 1.793) in the biologically older and high PRS group, respectively. The negative interactions between PhenoAgeAccel with APOE ε4 and PRS were also tested on the additive scale.ConclusionsAccelerated biological aging could bring the extra risk of dementia but attenuate the effects of genetic risk on dementia. These findings provide insights for precise prevention and intervention of dementia.

Cervical cancer and risk of dementia: real-world insights from a nationwide cohort study in Taiwan

ObjectiveCervical cancer, linked to human papillomavirus (HPV), ranks fourth among women’s cancers globally. Several studies have found an association between viral infections or cancer and dementia, which is a major...

Citicoline: A Cholinergic Precursor with a Pivotal Role in Dementia and Alzheimer's Disease.

Citicoline is a naturally occurring compound with pleiotropic effects on neuronal function and cognitive processes. Based on previous studies, which shed light on the positive effects of citicoline 1 g when combined with acetylcholinesterase inhibitors (AChEIs) and/or memantine, we further investigated the benefits of citicoline in combination therapy in Alzheimer's disease and mixed dementia. We integrated the datasets of CITIMEM and CITIDEMAGE, increasing the overall sample size to enhance statistical power. We analyzed data from these two investigator-initiated studies involving 295 patients. The primary outcome was the assessment over time of the effects of combined treatment versus memantine given alone or AChEI plus memantine on cognitive functions assessed by Mini-Mental State Examination (MMSE). The secondary outcomes were the influence of combined treatment on daily life functions, mood, and behavioral symptoms assessed by activities of daily life (ADL) and instrumental ADL, Geriatric Depression Scale, and Neuropsychiatric Inventory Scale. One-hundred-forty-three patients were treated with memantine and/or AChEI (control group), and 152 patients were treated with memantine and/or AChEI plus citicoline 1 g/day orally (Citicoline group). A significant difference in MMSE score was found in the average between the two groups of treatment at 6 and 12 months. This study confirmed the effectiveness of combined citicoline treatment in patients with mixed dementia and Alzheimer's disease, with a significant effect on the increase of MMSE score over time. The treated group also showed a significant reduction in the Geriatric Depression Scale and a significant increase in the instrumental ADL scale.

Memory enhancing and neuroprotective effects of apomorphine in a rat model of dementia.

Oxidative stress from generation of increased reactive oxygen species or has been reported to play an important role in dementia. Oxidative stress due to free radicals of oxygen or reactive oxygen species could be precipitating factors in the etiology of dementia. Apomorphine has been reported to have neuroprotective effects. To monitor memory enhancing and neuroprotective effects of apomorphine, we determined the antioxidant enzymes activities, lipid peroxidation, acetylcholine esterase (AChE) activity in brain and plasma, following repetitive administration of apomorphine in rat model of dementia. Biogenic amine levels were also monitored in hippocampus. Repeated administration of scopolamine was taken as an animal model of dementia. Decreased glutathione peroxidase, superoxide dismutase and catalase activities were observed in these animal models of dementia. While increased lipid peroxidation was also observed in the brain and plasma samples. The results showed significant effects of apomorphine. The activities of antioxidant enzymes displayed increased activities in both brain and plasma. Glutathione peroxidase and catalase activities were found to be significantly higher in brain and plasma of apomorphine treated rats. Superoxide dismutase (SOD) was significantly decreased in plasma of scopolamine injected rats; and a decreased tendency (non-significant) of SOD in brain was also observed. AChE activity in brain and plasma was significantly decreased in scopolamine treated rats. Learning and memory of rats in the present study was assessed by Morris Water Maze (MWM). Short-term memory and long-term memory was impaired significantly in scopolamine treated rats, which was prevented by apomorphine. Moreover, a marked decrease in biogenic amines was also found in the brain of scopolamine treated rats and was reverted in apomorphine treated rats. Results showed that scopolamine-treatment induced memory impairment and induced oxidative stress in rats as compared to saline-treated controls. These impairments were significantly restored by apomorphine administration. In conclusion, our data suggests that apomorphine at the dose of 1mg/kg could be a potential therapeutic agent to treat dementia and related disorders.

The role of dementia in the association between APOE4 and all-cause mortality: pooled analyses of two population-based cohort studies

The ε4 allele of the apolipoprotein E gene (APOE4) plays a role in neurodegeneration and in cardiovascular disease, but findings on its association with mortality are inconsistent. We aimed to examine the association between APOE4 and mortality, and the role of dementia in this association. In this pooled analysis, data on White participants aged 45-90 years who underwent APOE genotyping were drawn from two population-based cohorts: the Whitehall II study (UK), which began in 1985 and is ongoing, and the Three-City study (France), initiated in 1999 and ended in 2012. In the Three-City study, vital status was ascertained through linkage to the national registry of death Institut National de la Statistique des Études économiques, and dementia was ascertained via a neuropsychological evaluation and validation of diagnoses by an independent committee of neurologists and geriatricians. In the Whitehall II study, vital status was ascertained through linkage to the UK national mortality register, and dementia cases were ascertained by linkage to three national registers. Participants with prevalent dementia at baseline and participants missing an APOE genotype were excluded from analyses. Cox regression proportional hazard models were used to examine the association of APOE4 with all-cause, cardiovascular, and cancer mortality. The role of dementia in the association between APOE4 status and mortality was examined by excluding participants who developed dementia during follow-up from the analyses. An illness-death model was then used to examine the role of incident dementia in these associations. 14 091 participants (8492 from the Three-City study and 5599 from the Whitehall II study; 6668 [47%] of participants were women and 7423 [53%] were men), with a median follow-up of 15·4 years (IQR 10·6-21·2), were included in the analyses. Of these participants, APOE4 carriers (3264 [23%] of the cohort carried at least one ε4 allele) had a higher risk of all-cause mortality compared with non-carriers, with hazard ratios (HR) of 1·16 (95% CI 1·07-1·26) for heterozygotes and 1·59 (1·24-2·06) for homozygotes. Compared with APOE3 homozygotes, higher cardiovascular mortality was observed in APOE4 carriers, with a HR of 1·23 (1·01-1·50) for heterozygotes, and no association was found between APOE4 and cancer mortality. Excluding cases of incident dementia over the follow-up resulted in attenuated associations with mortality in homozygotes but not in heterozygotes. The illness-death model indicated that the higher mortality risk in APOE4 carriers was not solely attributable to dementia. We found a robust association between APOE4 and all-cause and cardiovascular mortality but not cancer mortality. Dementia explained a significant proportion of the association with all-cause mortality for APOE4 homozygotes, while non-dementia factors, such as cardiovascular disease mortality, are likely to play a role in shaping mortality outcomes in APOE4 heterozygotes. National Institutes of Health. For the French translation of the abstract see Supplementary Materials section.

Expressed Emotion in Families of People With Dementia: A Review of Scale-Based Measures.

Research on the concept of expressed emotion (EE) has expanded in recent years but its role in dementia still requires elucidation. Understanding the role of EE in the dementia context could help in the development of appropriate interventions. The current review synthesized relevant literature to investigate the prevalence and correlates of EE status in families of people with dementia. A comprehensive search of four databases from inception to 2022 produced 2,683 papers; 18 studies met inclusion criteria. The use of EE criteria differed not only across cultural contexts, but even within the same cultural context. Overall, the prevalence of EE in families with dementia compared with other psychiatric conditions was not high. Specific changes in EE over time remain to be explored, and findings emphasize the need to carefully discriminate High EE status based on the cultural background of family members with dementia. [Journal of Gerontological Nursing, 50(2), 17-25.].

Online Psychoeducational Programmes and Multicomponent Exercise for the Patients with Mild Dementia and their Caregivers: A Systematic Review

Background: Dementia is a chronic disorder which, mainly, affects people over 65 years old. It is estimated that it affects over 50.000.000 people around the world. Non- pharmacological strategies can play a vital role in dementia, considering that most of them are low-cost, safe and have no side effects.Psychoeducational programmes aim to inform the informal caregivers about dementia and its progress, and exercise has been showing positive effects in dementia. Their combination has been examined lately in a few studies in terms of enhancing the cognitive functions and quality of life for both patients and caregivers and decrease the unwanted behaviours.

OBJECTIVE SLEEP AND CIRCADIAN REST–ACTIVITY RHYTHMS AND MULTIPLE DOMAINS OF COGNITIVE FUNCTION IN OLDER ADULTS

Abstract Evidence suggests that sleep and circadian rest-activity rhythms (RAR) play a key role in dementia and Alzheimer Disease (AD) pathology. Studies with objective measures of sleep and RAR and multiple domains of cognition remain limited. We studied 820 older adults enrolled in the Study of Muscle, Mobility and Aging (SOMMA). Actigraphs were worn for one week, and processed for sleep-wake measures including total sleep time (TST) and sleep efficiency (SE); and parametric (acrophase, pseudo-F) and non-parametric (interdaily stability [IS], intradaily variability [IV], and relative amplitude [RA]) 24-hour RAR variables. Cognitive assessments included global cognition (the Montreal Cognitive Assessment), executive function (Trails B test), memory (California Verbal Learning Test-short form; and psychomotor performance (Digit-Symbol Coding Test). Adjusting for age, sex, clinic site and education, we examined adjusted mean cognitive test scores by categories of sleep and RAR exposures. Mean age was 76 years, 58% were female, and 15% were non-white. Higher RA, reflecting a more robust 24-hour RAR, was associated with better cognition on all tests (p for trend <0.05). Reduced SE was related to lower cognitive function (psychomotor performance, global cognition, memory; p<.05). There were no associations with TST and any cognitive measures examined. SE and RAR were variably associated with both global and specific domains of cognition in older men and women. The RA in particular was strongly related to multiple domains of cognition related to AD, and may be useful in identifying individuals at risk. Additional analyses will explore sex differences and longitudinal associations.

Objective Sleep and Circadian Rest‐Activity Rhythms and Multiple Domains of Cognitive Function in Older Men and Women

AbstractBackgroundEmerging evidence from experimental and epidemiologic studies suggests that sleep and circadian rest‐activity rhythms (RAR) play a key role in dementia and Alzheimer Disease (AD) pathology. Studies with objective measures of sleep and RAR and multiple domains of cognition in older adults remain limited.MethodWe studied 820 older men and women enrolled in the Study of Muscle, Mobility, and Aging (SOMMA), a unique cohort designed to study the cellular biology of aging and related loss of mobility. In this initial cross‐sectional analysis, participants wore wrist actigraphs for a mean of 8.0 consecutive days; recordings were processed for traditional sleep‐wake measures including total sleep time (TST) and sleep efficiency (SE); as well as parametric (acrophase, pseudo‐F) and non‐parametric (interdaily stability [IS], intradaily variability [IV], and relative amplitude [RA]) 24‐hour RAR variables. Measures of cognitive function included global cognition (the Montreal Cognitive Assessment), executive function (Trails B test), memory (California Verbal Learning Test‐short form; and psychomotor performance (Digit‐Symbol Coding Test). In models adjusted for age, sex, clinic site and education, we examined adjusted mean cognitive test scores by quartiles or categories of sleep and RAR exposures.ResultMean age of the cohort was 76 years, 58% were female, and 15% were non‐white. Mean TST and SE were 6.9 hours and 85%, respectively. Higher RA, reflecting a more robust 24‐hour RAR, was associated with better cognition on all tests (p for trend <0.05). The association of higher pseudo‐F, a parametric measure or robustness of RAR, to cognition was limited to psychomotor performance (p<0.03). Better psychomotor performance was also related to higher IS (consistency of RAR across days); whereas those with delayed timing (acrophase) had worse psychomotor performance (p<.0006). Lower SE was related to worse cognitive function (psychomotor performance, global cognition, memory; p<.05). There were no associations between TST and any cognitive measures.ConclusionSE and RAR were variably associated with both global and specific domains of cognition in older men and women. The RA in particular was strongly related to multiple domains of cognition related to AD, and may be useful in identifying individuals at risk. Additional analyses will explore gender differences and longitudinal associations.

Genetic Insights into the Risk of Metabolic Syndrome and Its Components on Dementia: A Mendelian Randomization.

The role of metabolic syndrome (MetS) on dementia is disputed. We conducted a Mendelian randomization to clarify whether the genetically predicted MetS and its components are casually associated with the risk of different dementia types. The genetic predictors of MetS and its five components (waist circumference, hypertension, fasting blood glucose, triglycerides, and high-density lipoprotein cholesterol [HDL-C]) come from comprehensive public genome-wide association studies (GWAS). Different dementia types are collected from the GWAS in the European population. Inverse variance weighting is utilized as the main method, complemented by several sensitivity approaches to verify the robustness of the results. Genetically predicted MetS and its five components are not causally associated with the increasing risk of dementia (all p > 0.05). In addition, no significant association between MetS and its components and Alzheimer's disease, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and dementia due to Parkinson's disease (all p > 0.05), except the association between HDL-C and dementia with Lewy bodies. HDL-C may play a protective role in dementia with Lewy bodies (OR: 0.81, 95% CI: 0.72-0.92, p = 0.0010). From the perspective of genetic variants, our study provides novel evidence that MetS and its components are not associated with different dementia types.

T Lymphocytes and Their Potential Role in Dementia with Lewy Bodies.

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia. People with DLB have an inferior prognosis compared to Alzheimer's disease (AD), but the diseases overlap in their neuropathology and clinical syndrome. It is imperative that we enhance our understanding of the aetiology and pathogenesis of DLB. The impact of peripheral inflammation on the brain in dementia has been increasingly explored in recent years, with T lymphocyte recruitment into brain parenchyma identified in AD and Parkinson's disease. There is now a growing range of literature emerging on the potential role of innate and adaptive immune cells in DLB, including T lymphocytes. In this review, we examine the profile of T lymphocytes in DLB, focusing on studies of post-mortem brain tissue, cerebrospinal fluid, and the blood compartment. We present an integrated viewpoint on the results of these studies by proposing how changes to the T lymphocyte profile in the brain and periphery may relate to each other. Improving our understanding of T lymphocytes in DLB has the potential to guide the development of disease-modifying treatments.

Hospital-Diagnosed Infections, Autoimmune Diseases, and Subsequent Dementia Incidence

Systemic inflammation has been suggested to explain reported associations between infections and dementia. Associations between autoimmune diseases and dementia also suggest a role for peripheral systemic inflammation. To investigate the associations of infections and autoimmune diseases with subsequent dementia incidence and to explore potential shared signals presented by the immune system in the 2 conditions. This nationwide, population-based, registry-based cohort study was conducted between 1978 and 2018 (40-year study period). All Danish residents born 1928 to 1953, alive and in Denmark on January 1, 1978, and at age 65 years were included. Persons with prior registered dementia and those with HIV infections were excluded. Data were analyzed between May 2022 and January 2023. Hospital-diagnosed infections and autoimmune diseases. All-cause dementia, defined as the date of a first registered dementia diagnosis after age 65 years in the registries. Poisson regression with person-years at risk as an offset variable was used to analyze time to first dementia diagnosis. A total of 1 493 896 individuals (763 987 women [51%]) were followed for 14 093 303 person-years (677 147 [45%] with infections, 127 721 [9%] with autoimmune diseases, and 75 543 [5%] with dementia). Among individuals with infections, 343 504 (51%) were men, whereas among those with autoimmune diseases, 77 466 (61%) were women. The dementia incidence rate ratio (IRR) following any infection was 1.49 (95% CI, 1.47-1.52) and increased along with increasing numbers of infections in a dose-dependent manner. Dementia rates were increased for all infection sites in the short term, but not always in the long term. The dementia IRR following any autoimmune disease was 1.04 (95% CI, 1.01-1.06), but no dose-dependent increase was observed, and only a few autoimmune conditions showed increased IRRs for dementia. These findings may point toward a role for infection-specific processes in the development of dementia, rather than general systemic inflammation, as previously hypothesized. Assessing these 2 conditions in a single setting may allow for additional insights into their roles in dementia and for hypotheses on possible underlying mechanisms.

Autonomic nervous system flexibility for understanding brain aging.

A recent call was made for autonomic nervous system (ANS) measures as digital health markers for early detection of Alzheimer's disease and related dementia (AD/ADRD). Nevertheless, contradictory or inconclusive findings exist. To help advance understanding of ANS' role in dementia, we draw upon aging and dementia-related literature, and propose a framework that centers on the role of ANS flexibility to guide future work on application of ANS function to differentiating the degree and type of dementia-related brain pathologies. We first provide a brief review of literature within the past 10 years on ANS and dementia-related brain pathologies. Next, we present an ANS flexibility model, describing how the model can be applied to understand these brain pathologies, as well as differentiate or even be leveraged to modify typical brain aging and dementia. Lastly, we briefly discuss the implication of the model for understanding resilience and vulnerability to dementia-related outcomes.

Repositioning of Anti-Diabetic Drugs against Dementia: Insight from Molecular Perspectives to Clinical Trials.

Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aβ production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood-brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer's disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway.

Polypyrimidine tract binding protein knockdown reverses depression-like behaviors and cognition impairment in mice with lesioned cholinergic neurons.

Depression is a common comorbidity of dementia and may be a risk factor for dementia. Accumulating evidence has suggested that the cholinergic system plays a central role in dementia and depression, and the loss of cholinergic neurons is associated with memory decline in aging and Alzheimer's patients. A specific loss of cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) is correlated with depression and dysfunction of cognition in mice. In this study, we examined the potential regenerative mechanisms of knockdown the RNA-binding protein polypyrimidine tract binding protein (PTB) in reversing depression-like behaviors and cognition impairment in mice with lesioned cholinergic neurons. We lesioned cholinergic neurons in mice induced by injection of 192 IgG-saporin into HDB; then, we injected either antisense oligonucleotides or adeno-associated virus-shRNA (GFAP promoter) into the injured area of HDB to deplete PTB followed by a broad range of methodologies including behavioral examinations, Western blot, RT-qPCR and immunofluorescence. We found that the conversion of astrocytes to newborn neurons by using antisense oligonucleotides on PTB in vitro, and depletion of PTB using either antisense oligonucleotides or adeno-associated virus-shRNA into the injured area of HDB could specifically transform astrocytes into cholinergic neurons. Meanwhile, knockdown of PTB by both approaches could relieve the depression-like behaviors shown by sucrose preference, forced swimming or tail-suspension tests, and alleviate cognitive impairment such as fear conditioning and novel object recognition in mice with lesioned cholinergic neurons. These findings suggest that supplementing cholinergic neurons after PTB knockdown may be a promising therapeutic strategy to revert depression-like behaviors and cognitive impairment.

The Correlation between Metformin Use and Incident Dementia in Patients with New-Onset Diabetes Mellitus: A Population-Based Study.

The evidence of metformin's effect on dementia is conflicting. This study investigates the association between metformin use and the risk of dementia among patients with diabetes mellitus (DM). This study included patients with new-onset DM between 2002 and 2013. We divided the patients into patients who used metformin and patients who did not. Two models were used to assess metformin use: the cumulative defined daily dose (cDDD) of metformin use and the intensity of metformin use. This study with 3-year and 5-year follow-ups investigated the risk of dementia among patients with DM who used metformin. At the 3-year follow-up, patients who received cDDD < 300 had an odds ratio (OR) of developing dementia of 0.92 (95% confidence interval [CI] = 0.89-0.96); patients who used metformin at intensities <10 and 10-25 DDD/month had ORs of 0.92 (95% CI: 0.87-0.97) and 0.92 (95% CI: 0.85-1.00), respectively. Metformin use at cDDD 300-500 (OR = 0.80, 95% CI = 0.56-1.15) or >500 (OR = 1.48, 95% CI = 0.48-4.60) or at an intensity >25 DDD/month (OR = 0.84, 95% CI = 0.60-1.18) were not associated with an incident of dementia. There were similar results at the 5-year follow-up. Patients with a low intensity of metformin use had a lower risk of dementia. However, higher doses of metformin with higher intensity exhibited no protective role in dementia. Prospective clinical trials are warranted to evaluate the actual underlying mechanisms between metformin dosage and the risk of dementia.

Comparative Effectiveness and Safety of Oral Anticoagulants by Dementia Status in Older Patients With Atrial Fibrillation

The development of an optimal stroke prevention strategy, including the use of oral anticoagulant (OAC) therapy, is particularly important for patients with atrial fibrillation (AF) who are living with dementia, a condition that increases the risk of adverse outcomes. However, data on the role of dementia in the safety and effectiveness of OACs are limited. To assess the comparative safety and effectiveness of specific OACs by dementia status among older patients with AF. This retrospective comparative effectiveness study used 1:1 propensity score matching among 1 160 462 patients 65 years or older with AF. Data were obtained from the Optum Clinformatics Data Mart (January 1, 2013, to June 30, 2021), IBM MarketScan Research Database (January 1, 2013, to December 31, 2020), and Medicare claims databases maintained by the Centers for Medicare & Medicaid Services (inpatient, outpatient, and pharmacy; January 1, 2013, to December 31, 2017). Data analysis was performed from September 1, 2021, to May 24, 2022. Apixaban, dabigatran, rivaroxaban, or warfarin. Composite end point of ischemic stroke or major bleeding events over the 6-month period after OAC initiation, pooled across databases using random-effects meta-analyses. Among 1 160 462 patients with AF, the mean (SD) age was 77.4 (7.2) years; 50.2% were male, 80.5% were White, and 7.9% had dementia. Three comparative new-user cohorts were established: warfarin vs apixaban (501 990 patients; mean [SD] age, 78.1 [7.4] years; 50.2% female), dabigatran vs apixaban (126 718 patients; mean [SD] age, 76.5 [7.1] years; 52.0% male), and rivaroxaban vs apixaban (531 754 patients; mean [SD] age, 76.9 [7.2] years; 50.2% male). Among patients with dementia, compared with apixaban users, a higher rate of the composite end point was observed in warfarin users (95.7 events per 1000 person-years [PYs] vs 64.2 events per 1000 PYs; adjusted hazard ratio [aHR], 1.5; 95% CI, 1.3-1.7), dabigatran users (84.5 events per 1000 PYs vs 54.9 events per 1000 PYs; aHR, 1.5; 95% CI, 1.2-2.0), and rivaroxaban users (87.4 events per 1000 PYs vs 68.5 events per 1000 PYs; aHR, 1.3; 95% CI, 1.1-1.5). In all 3 comparisons, the magnitude of the benefits associated with apixaban was similar regardless of dementia diagnosis on the HR scale but differed substantially on the rate difference (RD) scale. The adjusted RD of the composite outcome per 1000 PYs for warfarin vs apixaban users was 29.8 (95% CI, 18.4-41.1) events in patients with dementia vs 16.0 (95% CI, 13.6-18.4) events in patients without dementia. The corresponding adjusted RD estimates of the composite outcome were 29.6 (95% CI, 11.6-47.6) events per 1000 PYs in patients with dementia vs 5.8 (95% CI, 1.1-10.4) events per 1000 PYs in patients without dementia for dabigatran vs apixaban users and 20.5 (95% CI, 9.9-31.1) events per 1000 PYs in patients with dementia vs 15.9 (95% CI, 11.4-20.3) events per 1000 PYs in patients without dementia for rivaroxaban vs apixaban users. The pattern was more distinct for major bleeding than for ischemic stroke. In this comparative effectiveness study, apixaban was associated with lower rates of major bleeding and ischemic stroke compared with other OACs. The increased absolute risks associated with other OACs compared with apixaban were greater among patients with dementia than those without dementia, particularly for major bleeding. These findings support the use of apixaban for anticoagulation therapy in patients living with dementia who have AF.

The role of dementia and Alzheimer's disease in older adults' representations of aging and anxieties regarding one's own future

Dementia and Alzheimer's disease crucially influence the images of advanced age and represent a significant framework for the construction of anxieties regarding aging. By drawing on twenty-five in-depth interviews with older adults (age 65+ years) living in the Czech Republic, in this study, the influences of dementia and Alzheimer's disease on older adults' narratives of expectations and worries pertaining to their aging and future are analyzed. Three distinct ways in which participants narrate personal concerns related to Alzheimer's disease and integrate the risk of developing such a condition into their representations of fears associated with old age were identified: 1) Dementia as a perceived immediate risk, 2) dementia as the metonym of the fourth age, and 3) dementia as a distant tragedy but not a personal worry. These approaches differ in terms of the perception of the risk of developing dementia, anxiety-related responses related to future expectations, and the role of dementia in their representation of ‘bad’ old age. The different positions of dementia (specific health condition vs. signifier of dependency in old age) affected the participants' strategies related to medical screening and information seeking.

A pancreatic player in dementia: pathological role for islet amyloid polypeptide accumulation in the brain.

Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia. While multiple factors contribute to this predisposition, one of these involves the increased secretion of amylin, or islet amyloid polypeptide, that accompanies the pathophysiology of type 2 diabetes mellitus. Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia, including Alzheimer's disease and vascular dementia, but the exact mechanisms underlying islet amyloid polypeptide's causative role in dementia are unclear. In this review, we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage, ultimately leading to the clinical symptoms of dementia. We discuss the evidence for islet amyloid polypeptide deposition in the brain, islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration, neuroinflammation caused by islet amyloid polypeptide deposition, vascular damage induced by islet amyloid polypeptide accumulation, and islet amyloid polypeptide-induced cytotoxicity. There are very few therapies approved for the treatment of dementia, and of these, clinical responses have been controversial at best. Therefore, investigating new, targetable pathways is vital for identifying novel therapeutic strategies for treating dementia. As such, we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.

Impact of impaired cerebral blood flow autoregulation on cognitive impairment.

Although the causes of cognitive impairment are multifactorial, emerging evidence indicates that cerebrovascular dysfunction plays an essential role in dementia. One of the most critical aspects of cerebrovascular dysfunction is autoregulation of cerebral blood flow (CBF), mainly mediated by the myogenic response, which is often impaired in dementia individuals with comorbidities, such as diabetes and hypertension. However, many unsolved questions remain. How do cerebrovascular networks coordinately modulate CBF autoregulation in health and disease? Does poor CBF autoregulation have an impact on cognitive impairment, and what are the underlying mechanisms? This review summarizes the cerebral vascular structure and myogenic (a three-phase model), metabolic (O2, CO2, adenosine, and H+), and endothelial (shear stress) factors in the regulation of CBF; and the consequences of CBF dysautoregulation. Other factors contributing to cerebrovascular dysfunction, such as impaired functional hyperemia and capillary abnormalities, are included as well. Moreover, this review highlights recent studies from our lab in terms of novel mechanisms involved in CBF autoregulation and addresses a hypothesis that there is a three-line of defense for CBF autoregulation in the cerebral vasculature.