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Observational studies have shown consistently that modifiable risk factors during life are associated with increased dementia risk in old age but randomized controlled trials (RCTs) on dementia prevention evaluating the treatment of these risk factors did not find consistent effects on cognitive outcomes. The discrepancy in findings is potentially attributable to inherent differences between the two study designs. Although RCTs are the gold standard for establishing causality, designing and conducting an RCT for dementia prevention is complex. Quasi‐experimental studies (QESs) may contribute to investigating causality without randomization. QESs use variation in exposure to a risk factor or intervention in an observational setting to deduct causal effects. Design‐specific approaches are used to control for confounding, the main caveat of QESs. In this article we address the challenges, opportunities, and limitations of QESs for research into dementia prevention. Highlights: Despite consistent associations between modifiable risk factors and dementia, the mostly neutral effects of randomized controlled trials (RCTs) challenge the causality of these associations.RCTs in the field of dementia prevention are often problematic due to ethical, practical, or financial constraints, and their results may have limited generalizability.Four quasi‐experimental study (QES) designs may be suitable to study causality between risk factors and dementia; we critically appraise these study designs for dementia‐prevention studies.We describe how specific QES designs can be used to study the effects of risk‐factor modification for 12 known risk factors for dementia. [ABSTRACT FROM AUTHOR]

Dementia is a leading global public health challenge. Prevention approaches have traditionally focused on individual‐level strategies. However, such approaches have limited potential, particularly for resource‐constrained populations in which exposure to risk factors is greatest, and exposure to protective factors is lowest. A population‐level approach to dementia risk reduction is therefore essential to meet the scale of the challenge and to tackle global inequalities in risk and incidence of disease. Such approaches can be highly cost effective. In this viewpoint article, we describe what such an approach should look like, barriers and facilitators to success, and how we should go about achieving it. We include 10 strategic goals to achieve population‐level dementia risk reduction and protection enhancement, targeted at researchers, professionals, funders, science communicators, governments, businesses, and policy makers. If we are to significantly reduce the prevalence of dementia there must be increased emphasis on population‐level approaches. Highlights: Dementia risk reduction is a global public health priorityPopulation‐level approaches change societal conditions to make them less conducive to dementia's modifiable risk factors, and increase exposure to protective factors.Urgent development of population‐level approaches is required to reduce the prevalence of, and inequalities in, dementiaAction is required from researchers, governments and business, funders, public health professionals, and science communicators. [ABSTRACT FROM AUTHOR]

Hypertension is an important risk factor for Alzheimer's disease (AD) and all‐cause dementia. The mechanisms underlying this association are unclear. Hypertension may be associated with AD neuropathological changes (ADNC), but reports are sparse and inconsistent. This systematic review included 15 autopsy studies (n = 5879) from observational cohorts. Studies were highly heterogeneous regarding populations, follow‐up duration, hypertension operationalization, neuropathological methods, and statistical analyses. Hypertension seems associated with higher plaque and tangle burden, but results are inconsistent. Four studies (n = 3993/5879; 68%), reported clear associations between hypertension and ADNC. Another four suggested that antihypertensive medication may protect against ADNC. Larger studies with longer follow‐up reported the strongest relationships. Our findings suggest a positive association between hypertension and ADNC, but effects may be modest, and possibly attenuate with higher hypertension age and antihypertensive medication use. Investigating interactions among plaques, tangles, cerebrovascular pathology, and dementia may be key in better understanding hypertension's role in dementia development. [ABSTRACT FROM AUTHOR]

More and more frequently, clinical trials for Alzheimer disease (AD) are targeting cognitively unimpaired individuals who are at increased risk of developing the disease. It is not always clear whether AD biomarker information should be disclosed to research participants: on the one hand, research participants may be interested in learning this information because of its perceived utility, but on the other hand, learning this information may be harmful, as there are very few effective preventive or therapeutic options available for AD. In this article, we bring together three separate sets of ethical guidance literature: on the return of individual research results, on an individual's right to access personal data, and on transparent enrollment into clinical trials. Based on these literatures, we suggest policies for the disclosure of AD biomarker test results in longitudinal observational cohort studies, clinical trials, and hybrid research projects, such as the European Prevention of Alzheimer's Dementia (EPAD) project, in which we served as an ethics team. We also present and critically discuss recommendations for disclosure of AD biomarkers in practice. We underscore that, as long as the clinical validity of AD biomarkers remains limited, there are good reasons to avoid actively disclosing them to cognitively unimpaired research participants. [ABSTRACT FROM AUTHOR]

Background and purpose: The optimal management of post‐stroke cognitive impairment (PSCI) remains controversial. These joint European Stroke Organisation (ESO) and European Academy of Neurology (EAN) guidelines provide evidence‐based recommendations to assist clinicians in decision making regarding prevention, diagnosis, treatment and prognosis. Methods: Guidelines were developed according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available to provide recommendations. Results: There was limited randomized controlled trial (RCT) evidence regarding single or multicomponent interventions to prevent post‐stroke cognitive decline. Lifestyle interventions and treating vascular risk factors have many health benefits, but a cognitive effect is not proven. We found no evidence regarding routine cognitive screening following stroke, but recognize the importance of targeted cognitive assessment. We describe the accuracy of various cognitive screening tests, but found no clearly superior approach to testing. There was insufficient evidence to make a recommendation for use of cholinesterase inhibitors, memantine nootropics or cognitive rehabilitation. There was limited evidence on the use of prediction tools for post‐stroke cognition. The association between PSCI and acute structural brain imaging features was unclear, although the presence of substantial white matter hyperintensities of presumed vascular origin on brain magnetic resonance imaging may help predict cognitive outcomes. Conclusions: These guidelines highlight fundamental areas where robust evidence is lacking. Further definitive RCTs are needed, and we suggest priority areas for future research. [ABSTRACT FROM AUTHOR]

Numerous clinical trials of anti‐amyloid beta (Aβ) immunotherapy in Alzheimer's disease have been performed. None of these have provided convincing evidence for beneficial effects. Using traditional frequentist meta‐analysis, the conclusion is that there is absence of evidence for a therapeutic effect, with a point estimate effect size of 0.05 (95% confidence interval −0.00 to 0.10, P =.055). In addition, this non‐significant effect equates to 0.4 points per year on the cognitive subscale of the Alzheimer's Disease Assessment Scale. This is well below the minimally clinically important difference. Bayesian meta‐analysis of these trial data provides strong evidence of absence of a therapeutic effect, with a Bayes factor of 11.27 in favor of the null hypothesis, opposed to a Bayes factor of 0.09 in favor of a treatment effect. Bayesian analysis is particularly valuable in this context of repeatedly reported small, non‐significant effect sizes in individual trials. Mechanisms other than removal of Aβ from the brain may be probed to slow progression of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Introduction: Although not designed as such, dementia risk scores might be useful surrogate outcomes for dementia prevention trials. Their suitability may be improved by using continuous scoring systems, taking into account all changes in risk factors, not only those crossing cut‐off values. Methods: In three large multidomain dementia prevention trials with 1.5 to 2 years of follow‐up (Multidomain Alzheimer Preventive Trial, Prevention of Dementia by Intensive Vascular Care and Healthy Ageing Through Internet Counselling in the Elderly) we assessed (1) responsiveness (sensitivity to change) and (2) actual and simulated intervention effects of the original and crude/weighted z‐score versions of the cardiovascular risk factors, aging and incidence of dementia, and Lifestyle for Brain Health scores. Results: All versions of the risk scores were generally responsive, and able to detect small though statistically significant between‐group differences after multidomain interventions. Simulated intervention effects were well detected in z‐score versions as well as in the original scores. Discussion: Dementia risk scores and their z‐score versions show potential as surrogate outcomes. How changes in risk scores affect dementia remains to be determined. [ABSTRACT FROM AUTHOR]

Cardiovascular risk prediction is mainly based on traditional risk factors that have been validated in middle-aged populations. However, associations between these risk factors and cardiovascular disease (CVD) attenuate with increasing age. Therefore, for older people the authors developed and internally validated risk prediction models for fatal and non-fatal CVD, (re)evaluated the predictive value of traditional and new factors, and assessed the impact of competing risks of non-cardiovascular death. Post hoc analyses of 1811 persons aged 70-78 year and free from CVD at baseline from the preDIVA study (Prevention of Dementia by Intensive Vascular care, 2006-2015), a primary care-based trial that included persons free from dementia and conditions likely to hinder successful long-term follow-up, were performed. In 2017-2018, Cox-regression analyses were performed for a model including seven traditional risk factors only, and a model to assess incremental predictive ability of the traditional and eleven new factors. Analyses were repeated accounting for competing risk of death, using Fine-Gray models. During an average of 6.2 years of follow-up, 277 CVD events occurred. Age, sex, smoking, and type 2 diabetes mellitus were traditional predictors for CVD, whereas total cholesterol, HDL-cholesterol, and systolic blood pressure (SBP) were not. Of the eleven new factors, polypharmacy and apathy symptoms were predictors. Discrimination was moderate (concordance statistic 0.65). Accounting for competing risks resulted in slightly smaller predicted absolute risks. In conclusion, we found, SBP, HDL, and total cholesterol no longer predict CVD in older adults, whereas polypharmacy and apathy symptoms are two new relevant predictors. Building on the selected risk factors in this study may improve CVD prediction in older adults and facilitate targeting preventive interventions to those at high risk. [ABSTRACT FROM AUTHOR]

Introduction: Multidomain interventions, targeting multiple risk factors simultaneously, could be effective dementia prevention strategies, but may be burdensome and not universally acceptable. Methods: We studied adherence rates and predictors in the Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability and Multidomain Alzheimer Preventive Trial prevention trials, for all intervention components (separately and simultaneously). Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability participants received a 2‐year multidomain lifestyle intervention (physical training, cognitive training, nutritional counseling, and cardiovascular monitoring). Multidomain Alzheimer Preventive Trial participants received a 3‐year multidomain lifestyle intervention (cognitive training, physical activity counseling, and nutritional counseling) with either an omega‐3 supplement or placebo. Results: Adherence decreased with increasing intervention complexity and intensity: it was highest for cardiovascular monitoring, nutritional counseling, and the omega‐3 supplement, and lowest for unsupervised computer‐based cognitive training. The most consistent baseline predictors of adherence were smoking and depressive symptoms. Discussion: Reducing participant burden, while ensuring that technological tools are suitable for older individuals, maintaining face‐to‐face contacts, and taking into account participant characteristics may increase adherence in future trials. [ABSTRACT FROM AUTHOR]

In the hope of future treatments to prevent or slow down the disease, there is a strong movement towards an ever‐earlier detection of Alzheimer's disease (AD). In conjunction with scientific developments, this has prompted a reconceptualization of AD, as a slowly progressive pathological process with a long asymptomatic phase. New concepts such as 'preclinical' and 'prodromal' AD have been introduced, raising a number of conceptual and ethical questions. We evaluate whether these new concepts are theoretically defensible, in light of theories of health and disease, and whether they should be understood as disease or as an at‐risk state. We introduce a pragmatic view on disease concepts and argue that an evaluation of the reconceptualization of AD should also take its aims and effects into account, and assess their ethical acceptability. The reconceptualization of AD is useful to coordinate research into preventive strategies, and may potentially benefit future patients. However, in the short term, early detection and labelling of 'preclinical AD' can potentially harm people. Since there is no treatment available and the predictive value is unclear, it may only create a group of 'patients‐in‐waiting' who may suffer from anxiety, uncertainty and stigmatization, but will never actually develop dementia. We conclude that only if the promise of preventive medication materializes, will the reconceptualization of AD turn out unequivocally to be for the better. Otherwise, the reconceptualization may do more harm than good. [ABSTRACT FROM AUTHOR]

Objectives To explore and compare sociodemographic, clinical, and neuropsychiatric determinants of dropout and nonadherence in older people participating in an open-label cluster-randomized controlled trial-the Prevention of Dementia by Intensive Vascular care (pre DIVA) trial-over 6 years. Design Secondary analysis. Setting One hundred sixteen general practices in the Netherlands. Participants Community-dwelling individuals aged 70 to 78 (N = 2,994). Intervention Nurse-led multidomain intervention targeting cardiovascular risk factors to prevent dementia. Measurements The associations between participant baseline sociodemographic (age, sex, education), clinical (medical history, disability, cardiovascular risk), neuropsychiatric (depressive symptoms (Geriatric Depression Scale-15), and cognitive (Mini-Mental State Examination)) characteristics and dropout from the trial and nonadherence to the trial intervention were explored using multilevel logistic regression models. Results Older age, poorer cognitive function, more symptoms of depression, and greater disability were the most important determinants of dropout of older people. The presence of cardiovascular risk factors was not associated with dropout but was associated with nonadherence. Being overweight was a risk factor for nonadherence, whereas people with high blood pressure or a low level of physical exercise adhered better to the intervention. The association between poorer cognitive function and symptoms of depression and dropout was stronger in the control group than in the intervention group, and vice versa for increased disability. Conclusion In a large dementia prevention trial with 6-year follow-up, dropout was associated with older age, poorer cognitive function, symptoms of depression, and disability at baseline. These findings can help to guide the design of future dementia prevention trials in older adults. The associations found between cardiovascular risk factors and nonadherence need to be confirmed in other older populations receiving cardiovascular prevention interventions. [ABSTRACT FROM AUTHOR]

Background: Engagement with digital health tools ihas not been well‐studied in older populations. We aimed to describe engagement with a preventive eHealth intervention designed to reduce dementia and cardiovascular risk, identify factors associated with engagement, and examine associations between engagement and changes in dementia and cardiovascular risk factors. Method: We analyzed data from the 18‐month randomized controlled 'Healthy Ageing Through Internet Counselling in the Elderly' (HATICE) trial. Participants, enrolled in Finland, France, and the Netherlands, were aged 65+ with at least basic computer literacy and either ≥2 cardiovascular risk factors or history of cardiovascular disease/diabetes. The intervention group (N=1389) received access to an interactive Internet platform, designed to encourage lifestyle changes, with remote support from a lifestyle coach. The control group (N=1335) received access a static Internet platform containing basic health information. Engagement with the intervention platform was assessed via number of logins, lifestyle goals set, messages sent to the coach, monitoring measurements entered, and amount of advice and education materials read. These metrics were combined into a composite engagement score. Result: Most intervention group participants engaged with the platform to some extent: 90% set ≥1 goal, 86% sent ≥1 message and 80% entered ≥1 measurement. The median (IQR) number of logins per participant during follow‐up was 29 (16‐48). Regular computer use was the strongest baseline predictor of engagement. Those already working on or with short‐term plans for lifestyle improvement, and better cognition also engaged more. Compared to the control group, after adjustment, intervention group participants who engaged more with the platform showed significantly more improvement over 18‐months in systolic blood pressure, BMI, physical activity, Mediterranean diet score, and cardiovascular/dementia risk scores. Intervention group participants with a low engagement score showed no improvement compared to the control group. Conclusion: Engaging older people in a digital lifestyle self‐management intervention was feasible. Better engagement led to more improvement in dementia and cardiovascular risk factors. Older adults who are infrequent computer users, have poorer cognition, and no concrete plans to change their lifestyle may need extra support for digital lifestyle interventions. Disparities in engagement may be further emphasized in real‐world settings. [ABSTRACT FROM AUTHOR]

Transient ischemic attack (TIA) can be difficult to diagnose. Episodes of acute atypical or nonfocal neurological symptoms, referred to as transient neurological attack (TNA), are as prevalent as TIAs. Diffusion-weighted imaging (DWI) provides evidence of acute cerebral ischemia in a third of TIA patients. We now report that DWI shows acute ischemia in 23% of patients clinically diagnosed as TNA by experienced stroke neurologists. This questions the accuracy of clinically diagnosing TIA and suggests added value for early magnetic resonance imaging after an episode of acute onset atypical or nonfocal neurological symptoms. [ABSTRACT FROM AUTHOR]

Apathy is a frequently reported neuropsychiatric symptom in Parkinson's disease (PD), but its prevalence and clinical correlates are debated. We aimed to address these issues by conducting a systematic review and meta-analysis. Embase, Medline/PubMed, and PsychINFO databases were searched for relevant studies. Data were extracted by two independent observers, using predefined extraction forms tailored specifically to the research question. From 1,702 titles and abstracts, 23 studies were selected. Meta-analysis showed a prevalence of apathy in PD of 39.8% (n = 5,388, 905% CI 34.6-45.0%). Apathy was associated with higher age (3.3 years, 95% CI = 1.7-4.9), lower mean Mini-Mental State Evaluation (MMSE) score (−1.4 points, 95% CI = −2.1 to −0.8), an increased risk of co-morbid depression (relative risk [RR] = 2.3, 95% CI = 1.9-2.8), higher Unified Parkinson's Disease Rating Scale (UPDRS) motor score (6.5 points, 95% CI = 2.6-10.3), and more severe disability (Hedges-G = 0.5, 95% CI = 0.3-0.6). Half of the patients with apathy had concomitant depression (57.2%, 95% CI = 49.4-64.9%), and this estimate was similar after exclusion of patients with cognitive impairment (52.5%, 95% CI = 42.2%-62.8%). In conclusion, we found that apathy affects almost 40% of patients with PD. Several factors influence reported prevalence rates, contributing to the considerable heterogeneity in study results. Half of patients with apathy do not suffer from concomitant depression or cognitive impairment, confirming its status as a separate clinical syndrome in PD. The pervasiveness of apathy in PD warrants research into its treatment, although different underlying pathophysiological mechanisms may require different treatment strategies. Treatment of apathy could improve patient quality of life, reduce caregiver burden, alleviate disability by increasing motivation for self-care, and reduce cognitive impairment by improving executive functioning. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objective Although depression is considered to be associated with cardiovascular disease (CVD), specifically symptoms of apathy have been strongly associated with a history of CVD in recent studies. In this study, we prospectively assess whether symptoms of apathy and depression are independent risk factors for incident CVD and stroke. Methods We carried out a prospective cohort study of 1810 community-dwelling older individuals (70-78 years) without a history of CVD or stroke. Symptoms of apathy and depression were assessed with the 15-item Geriatric Depression Scale. Incident CVD and stroke were assessed after 2 years follow-up. The associations of symptoms of apathy and depression with incident CVD and stroke were analyzed separately using logistic regression analysis. Results Symptoms of apathy and depression were present in 281 (15.5%) and 266 (14.7%) participants, respectively. Incident CVD occurred in 62 (3.5%) participants and stroke in 55 (3.1%) participants. Apathy was associated with incident CVD after adjustment for demographics and cardiovascular risk factors (odds ratio (OR) = 2.60, 95% CI = 1.46-4.65). Exclusion of subjects with depressive symptoms yielded a similar OR (2.94, 95% CI = 1.45-5.96, n = 1544). No association was found between depressive symptoms and incident CVD. Neither apathy symptoms nor depressive symptoms were associated with incident stroke. Conclusions Apathy, but not depression, is a strong, independent risk factor for incident CVD. It may be a marker of underlying vascular disease. By its nature, apathy may cause non-adherence to a healthy lifestyle, diminished activities, and possibly even withdrawal from clinical care aimed at improving vascular risk profiles. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: Although depression is considered to be associated with cardiovascular disease (CVD), specifically symptoms of apathy have been strongly associated with a history of CVD in recent studies. In this study, we prospectively assess whether symptoms of apathy and depression are independent risk factors for incident CVD and stroke. Methods: We carried out a prospective cohort study of 1810 community-dwelling older individuals (70–78 years) without a history of CVD or stroke. Symptoms of apathy and depression were assessed with the 15-item Geriatric Depression Scale. Incident CVD and stroke were assessed after 2 years follow-up. The associations of symptoms of apathy and depression with incident CVD and stroke were analyzed separately using logistic regression analysis. Results: Symptoms of apathy and depression were present in 281 (15.5%) and 266 (14.7%) participants, respectively. Incident CVD occurred in 62 (3.5%) participants and stroke in 55 (3.1%) participants. Apathy was associated with incident CVD after adjustment for demographics and cardiovascular risk factors (odds ratio (OR) = 2.60, 95% CI = 1.46-4.65). Exclusion of subjects with depressive symptoms yielded a similar OR (2.94, 95% CI = 1.45-5.96, n = 1544). No association was found between depressive symptoms and incident CVD. Neither apathy symptoms nor depressive symptoms were associated with incident stroke. Conclusions: Apathy, but not depression, is a strong, independent risk factor for incident CVD. It may be a marker of underlying vascular disease. By its nature, apathy may cause non-adherence to a healthy lifestyle, diminished activities, and possibly even withdrawal from clinical care aimed at improving vascular risk profiles. [ABSTRACT FROM AUTHOR]

Background: Multidomain interventions based on management of vascular and lifestyle risk factors could potentially reduce the risk of dementia and cardiovascular disease. Given the slow progressive nature of these conditions, dementia in particular, clinical endpoints may not be achievable within trials' time‐frame. Well‐established risk scores could be useful surrogate outcomes. In this individual‐participant data meta‐analysis, we assessed the effect of three multidomain dementia prevention interventions on the CAIDE and FINRISK risk scores for dementia and cardiovascular disease, and the impact of baseline characteristics on the response to such interventions. Method: Baseline and 24‐month data from the FINGER, MAPT, and preDIVA dementia/cognitive decline prevention trials carried out in three European cohorts of older adults, were pooled at individual‐participant level (N=6465). Linear mixed‐model with maximum likelihood estimation and random effect by trial and study‐site was used to estimate changes in CAIDE and FINRISK risk scores in the intervention group vs control. Subgroup‐treatment effect interactions were tested to assess the influence of sex, baseline age, education, MMSE, and dementia or cardiovascular disease risk on the response to the interventions. The effect of the interventions on individual modifiable risk factors relevant for both risk scores was also investigated. Result: The interventions led to a significant reduction of both CAIDE (estimated effect: ‐0.173; 95% CI: ‐0.268 to ‐0.077; P<0.001) and FINRISK (estimated effect: ‐0.108; 95% CI: ‐0.181 to ‐0.035; P=0.001) scores. A significantly larger reduction of CAIDE score was reported in women compared to men (P value for interaction=0.007) and a similar, but not significant, pattern was reported for FINRISK score. Interactions by other baseline characteristics were also not significant. Significant reduction of blood pressure (P≤0.001), and waist circumference (P=0.027), but not of BMI nor serum cholesterol, was observed. No baseline characteristic affected the response on these outcomes. Conclusion: Multidomain interventions had beneficial effects on the estimated risk of dementia and cardiovascular disease, measured by the CAIDE and FINRISK scores. Women benefited more than men in terms of dementia risk, whereas effects of baseline age, education, cognitive status, and risk of dementia or cardiovascular disease on the response to the interventions could not be demonstrated. [ABSTRACT FROM AUTHOR]

Background: With no effective pharmacological therapies, risk factor modification may be a suitable intervention for dementia prevention. To date, no single‐domain intervention has convincingly shown to reduce the risk of developing dementia. Targeting more than one risk factor might have additive or even synergistic effects. In this Cochrane systematic review, we investigated the effect of multidomain intervention studies on the prevention of dementia and cognitive decline Method: We searched ALOIS (the Cochrane Dementia and Cognitive Improvement Group's register), MEDLINE, Embase, PsycINFO, CINAHL, Web of Science Core Collection, LILACS, and ClinicalTrials.gov from origin to April 2020. We included randomized controlled trials (RCTs) targeting at least two dementia risk factors simultaneously, with >400 participants and >12 months of follow‐up. Data were pooled using random‐effect models. This abstract is based on a pre‐peer review version of a Cochrane Review (protocol DOI: 10.1002/14651858.CD013572). Result: The search identified 13.039 studies. Nine RCTs fulfilled the inclusion criteria and could be included in the review and meta‐analysis; two studies reported incident dementia as outcome, all nine studies reported a measure for cognitive decline. Overall pooled risk ratio (RR) for dementia was 0.94 (95% confidence interval (CI) 0.76‐1.18, I2<10%) and standardised mean difference (SMD) for cognitive decline measured with a neurological test battery (NTB) 0.03 (95% CI 0.01‐0.06, I2<10%). SMD in mini‐mental state examination (MMSE) score was 0.00 (95% CI ‐0.03‐0.04). Subgroup analyses suggested modest favourable outcomes on cognitive decline (NTB) for participants with worse baseline cognitive status (SMD 0.06 (0.01‐ 0.11) for low baseline MMSE vs. SMD 0.01 (‐0.01‐0.04) for high baseline MMSE), though this difference was not significant (p=0.12). There was no difference between groups with respect to adverse events (mortality, cardiovascular disease and stroke). The overall quality of evidence was moderate to high. Conclusion: Multidomain interventions did not improve the overall risk of dementia. There was a modest effect on cognitive decline measured with a NTB, though this effect was not convincingly supported by other cognitive assessment scores. Future research in populations at increased risk could have important implications for dementia prevention strategies. [ABSTRACT FROM AUTHOR]

Background: High visit‐to‐visit blood pressure variability (BPV) is associated with an increased risk of cardiovascular disease. However, for incident dementia, conflicting results are reported. Our objective was to assess the association of very long‐term visit‐to‐visit BPV and the risk of all‐cause dementia in community‐dwelling individuals. Method: Community‐dwelling individuals aged 65 years or older and free from dementia were randomly sampled from 1994 onwards from Kaiser Permanente Washington (KPW), Seattle, USA, and included in the Adult Changes in Thought (ACT) study. After enrollment, participants were followed‐up biannually. We retrospectively collected yearly data on blood pressure measurements and medical history from the age of 50 up to recruitment into the ACT study, through KPW electronic databases. Visit‐to‐visit BPV was defined as coefficient of variation (SD/mean*100) calculated with systolic blood pressure measurements. Dementia was diagnosed by an expert panel based on DSM‐IV and NINCDS‐ADRDA criteria. We used Cox regression adjusted for sex, blood pressure trend, antihypertensive medication use and cardiovascular risk factors. Subgroup analyses were performed for midlife (50‐64) and later life (≥65). Result: We included 1174 individuals with a median age of 78 years [IQR=72‐83] at inclusion in the ACT study. Systolic blood pressure measurements (mean=27.9, SD=8.5, range: 2‐50) were collected over 2 to 54 years (mean=31.8, SD=9.4), and 483 (41.1%) individuals developed dementia. There was no significant association between very long term visit‐to‐visit BPV (mean=12.15; SD=2.67) and incident all‐cause dementia (HR=0.98; 95%CI=0.94‐1.02). Competing risk of death analyses (combined outcome dementia/death) showed a dementia/mortality risk reduction of 4% per point visit‐to‐visit BPV increase (HR=0.96; 95%CI=0.94‐0.99). The associations were similar for visit‐to‐visit BPV in later life (dementia: HR=0.99; 95%CI=0.95‐1.02, dementia/death: HR=0.96; 95%CI=0.93‐0.99). Visit‐to‐visit BPV in midlife was not associated with incident dementia (dementia: HR=0.99; 95%CI=0.96‐1.02, dementia/death: HR=1.01; 95%CI=0.99‐1.02). Conclusion: In our sample, higher very long‐term visit‐to‐visit BPV is associated with lower incident all‐cause dementia risks. This association might be stronger in later life than in midlife. [ABSTRACT FROM AUTHOR]

Background: Midlife hypertension is a risk factor for all‐cause dementia. Treatment of hypertension with antihypertensive medication (AHM) may therefore be a promising strategy to delay or prevent dementia. Recent reports have suggested that AHM are associated with differential effects on dementia risk, due to class‐specific mechanisms. In this study, we assess the association between different AHM‐classes and incident dementia, using data from the preDIVA observational extension (POE) study. Method: All participants who reported use of AHM at baseline were included in the analyses. We distinguished angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta‐blockers, calcium channel blockers (CCBs), and diuretics. Data on incident dementia was collected during the randomised phase at 2, 4, 6‐8 and, after discontinuation of the intervention, 10‐12 years after baseline. Cox proportional hazards regression was used to study the association between use of different AHM‐classes, compared with use of any other AHM class, and incident dementia. A post‐hoc analysis was performed, dividing follow‐up time in two periods (preDIVA median follow‐up acting as cut‐off point) to account for the effect of time between exposure and dementia. Result: 1953 participants who reported AHM use at baseline were included, with a mean age of 74.5 (±2.5) and a mean systolic blood pressure of 156.4 mmHg (±21.5). After a median follow‐up of 10.4 years (IQR 6.7‐11.0), 228 (11.7%) participants had developed dementia. Adjusted hazard ratios (HR) for dementia were 1.07 (95%CI 0.80‐1.42) for ACE inhibitors, 0.75 (95%CI 0.53‐1.06) for ARBs, 1.00 (95%CI 0.77‐1.31) for beta‐blockers, 0.92 (95%CI 0.68‐1.24) for CCBs, and 1.02 (95%CI 0.78‐1.33) for diuretics. ARBs and CCBs were inversely associated with dementia during the first time period (HR 0.46, 95%CI 0.25‐0.84 and HR 0.62, 95%CI 0.38‐0.99 respectively), which was not apparent anymore during the second one. Conclusion: Despite short‐term beneficial associations of CCBs and ARBs and a promising HR for ARBs also after longer follow‐up, associations between any AHM‐class and incident dementia were not convincing after complete follow‐up. These findings are possibly best explained by the long follow‐up in older participants with high mortality‐ and dementia rates, possibly attenuating AHM‐class effects on dementia incidence. [ABSTRACT FROM AUTHOR]

Background: Older people with symptoms of subjective memory complaints (SMC) and impairments in instrumental activities of daily living (IADL) have an increased risk of developing dementia. The predictive value of SMC and IADL‐impairments may be modified by sex. This could have consequences for personalized risk prediction and prognosis. Methods: From the Prevention of Dementia by Intensive Vascular care study (preDIVA), 3495 community‐dwelling older people, aged 70‐78 years (mean=74.3±2.5) without dementia, were investigated over a median follow‐up of 6.7 years. SMC at baseline were assessed using the memory question from the 15‐item Geriatric Depression Scale. IADL‐impairments were assessed using the Academic Medical Center Linear Disability Score (ALDS). Potential sex‐differences in the predictive value of SMC and IADL‐impairments for incident dementia were assessed using Cox regression models with an interaction term for sex*ALDS_SMC. Results: Women with isolated SMC (HR=2.10,95%CI=0.94‐4.69) and SMC combined with IADL‐impairments (HR=2.96,95%CI=1.66‐5.28) were at greater risk of developing dementia than men (HR=1.51,95%CI=0.83‐2.75; HR=1.24,95%CI=0.59‐2.61 respectively), but these differences were not significant (p‐interaction=0.67 and 0.13). Isolated IADL‐impairments were associated with a significantly higher risk of mortality (HR=1.36,95%CI=1.09‐1.68), and a lower risk of dementia (HR=0.70,95%CI=0.48‐1.00). These associations were particularly prominent in men, but were not significantly different compared to women (p‐interaction=0.25 and 0.83). Conclusion: SMC increase dementia risk, especially when occurring together with IADL‐impairments. This relation may be somewhat stronger in women. Isolated IADL‐impairments do not increase dementia risk. Competing mortality risk may strongly influence these associations, especially in men, suggesting it is essential to assess when comparing sex‐differences in dementia risk. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To investigate whether vascular care slows dementia progression in patients with Alzheimer's disease with cerebrovascular lesions on neuroimaging. DESIGN: Multicenter randomized controlled clinical trial with 2-year follow-up. SETTING: Neurological and geriatric outpatient clinics in 10 Dutch hospitals: three academic, five teaching, and two midsize community hospitals. PARTICIPANTS: One hundred thirty community-dwelling patients with mild dementia fulfilling clinical criteria for Alzheimer's disease with cerebrovascular lesions on neuroimaging. INTERVENTION: Patients randomized to vascular care were treated according to strict guidelines for hypercholesterolemia and hypertension. Acetylsalicylic acid, folic acid, and pyridoxine were prescribed. During visits every 3 months special attention was paid to smoking cessation, losing weight, and stimulating physical exercise. MEASUREMENTS: Primary outcome was disability, measured according to the Interview for Deterioration in Daily activities in Dementia (IDDD). Secondary outcomes were changes on the Mini-Mental State Examination (MMSE), the Revised Memory and Behavioural Problems Checklist (RMBPC), a composite measure of “poor outcome” (death, institutionalization, or severe clinical decline), and costs. RESULTS: Patients in the vascular and standard care condition declined equally on the IDDD (13.7 vs 11.0 points; difference 2.7, 95% confidence interval =−3.1–8.6). There was no treatment effect on the MMSE or RMBPC. There were no differences in institutionalization rate, “poor outcome” (41.4% vs 35.4%, P=.50), or costs. In the intervention group, there were three intracerebral hemorrhages and one gastrointestinal hemorrhage, versus none in the control group. CONCLUSION: Multicomponent vascular care, combining pharmacological and nonpharmacological interventions, does not slow decline in patients with Alzheimer's disease with cerebrovascular lesions. [ABSTRACT FROM AUTHOR]

Background: Dyslipidaemia in mid‐life is associated with incident dementia but evidence is conflicting on whether dyslipidaemia in late‐life increases dementia risk. This may be due to the large heterogeneity in cholesterol measures and study designs employed. We used detailed data from a large prospective cohort of older people to comprehensively assess the relation between a broad range of cholesterol measures and incident dementia, addressing potential biases, confounders and modifiers. Method: In 3392 community‐dwelling individuals, without dementia, aged 70‐78 years, total cholesterol, low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), triglycerides and apolipoprotein A1 and B were assessed. Over a median of 6.7 years follow‐up, dementia was established by clinical diagnosis confirmed by independent outcome adjudication. Hazard ratios (HR) for dementia and mortality were calculated using Cox regression. Result: Dementia occurred in 231 (7%) participants. Dyslipidaemia, particularly high LDL‐C/HDL‐C, was associated with lower dementia risk, independent of age, cardiovascular risk factors, cognitive function, apolipoprotein E genotype and cholesterol lowering drugs. This association was not influenced by the competing risk of mortality. One SD increase in LDL/HDL conveyed a 19% lower dementia risk (HR=0.81, 95%CI=0.69‐0.96) and a 10% lower risk of dementia/mortality combined (HR=0.90, 95%CI=0.82‐0.98). Strong and consistent interactions suggested these associations were predominant in individuals with low BMI and education and potentially reversed in high BMI and education subgroups. Conclusion: Dyslipidaemia in older individuals conveyed a lower risk of dementia. Differentiating between subgroups seems essential when assessing the risk of poor outcome associated with dyslipidaemia. This may have important implications for dementia risk prediction. [ABSTRACT FROM AUTHOR]

Background: Although not designed as such, dementia risk scores, such as the CAIDE or LIBRA, might be useful as surrogate outcome measures for dementia prevention trials conducted from midlife onwards. In the risk scores' original categorical scoring systems, changes in risk factors are only taken into account when crossing cut‐off values, which may limit responsiveness and ability to detect intervention effects. We hypothesized that scoring systems based on continuous z‐score measures of risk factors may improve the performance of risk scores in this respect. Method: In three large multidomain dementia prevention trials (MAPT, preDIVA and HATICE) with 1.5‐2 years of follow up, we assessed of the original and z‐score versions of the CAIDE and LIBRA scores: 1) responsiveness and 2) actual and simulated intervention effects. Result: Across the three trials, 48 to 58% of intervention group participants underwent change on the CAIDE score between baseline and follow‐up. The LIBRA index was more responsive: 61 to 79% of participants changed over time. The z‐score versions registered changes in risk factors that were not detected by the original scores: subjects with no change over time in the original score showed great variability in their change in z‐scores, ranging from as much as ‐1.25 to 1.25 for the CAIDE. Conversely, for very small changes in z‐score, the change in original CAIDE or LIBRA scores was as much as ‐5 to 5 points, indicating multiple small changes in risk factors just across the cut‐off values for the original scoring system. Original scores and z‐scores were equally able to detect modest but significant intervention effects. When simulating very large intervention effects, mean between‐group differences of ‐0.50 points (23% of potential for improvement) could be attained for original CAIDE score and ‐0.52 points for original LIBRA index (15% of potential for improvement). Their z‐score versions could attain a maximum of ‐0.24 standard deviations for CAIDE and ‐0.15 standard deviations for the LIBRA index. Conclusion: Dementia risk scores as well as their z‐score versions show potential as surrogate outcomes. How changes in risk scores affect long‐term dementia incidence rates remains to be determined. [ABSTRACT FROM AUTHOR]

Background: To date, there is no gold standard for diagnosing dementia and diagnostic strategies vary widely between specialists and hospitals. More insight into diagnostic practice variation can be used to improve quality of diagnostics. Aim: To determine variation in diagnostic strategies between Dutch hospitals. Method: In the Netherlands, all health insurance claim data are centrally registered. Information on diagnostic ancillary services carried out from 2015 to 2018 was collected via national‐level insurance claims for patients that received a (new) diagnose‐coding for dementia in 2018. Hospitals were included in the analysis if they diagnosed >50 patients with dementia and were divided in academic medical centres (AMC), non‐academic training hospitals (TH) and general hospitals (GH). Result: 71 of 98 (72%) Dutch hospitals fulfilled the inclusion criterion, accounting for a total of 20.073 new dementia diagnoses in 2018. Nearly all patients underwent some form of ancillary diagnostic services (n=20.068) in the preceding 3‐4 years, however frequencies and diagnostic modalities differed widely between hospitals. The range of percentages between hospitals that performed MRI/CT‐imaging ranged from 37 to 99% (median 76.7%) of all patients that were diagnosed with dementia, neuropsychological assessment from 0‐89% (median 31.8%), cerebrospinal fluid examination from 0‐14% (median 2.4%), PET/SPECT‐imaging from 0‐16% (median 6.2%) and electroencephalography from 1‐20% (median 5.8%). The percentage of patients subjected to ancillary diagnostic investigations decreased sharply with increasing age (approximately 2 times for patients >90 years when compared to patients of 70‐80 years old). There were no distinct differences according to gender, or number of patients that were diagnosed, whereas PET/SPECT‐imaging was slightly more frequently used in academic centres (8% in AMCs versus 5% in GHs, p=0.003). Conclusion: In the Netherlands, diagnostic ancillary methods used vary widely between hospitals both in frequency and modality. This variation may be driven by the flexibility in national guidelines due to limited evidence of diagnostic accuracy and added value of different diagnostic tests, varying doctor and patient preferences and differences in available diagnostic techniques per hospital. Future research could explore this heterogeneity further and help to identify a practice strategy that combines the most benefit with the least burden for patients. [ABSTRACT FROM AUTHOR]

Background: Hypertension is an important risk factor for dementia. Specific antihypertensive medication (AHM) classes may lower dementia risk more effectively than others. We aim to systematically review and synthesize the evidence on differential associations between AHM classes and the risk of dementia, using network meta‐analysis. Method: Embase, MEDLINE and the Cochrane library were searched from origin to December 2019. We included randomized controlled trials and prospective cohort studies, including non‐demented participants with ≥one year of follow‐up. Data were extracted following PRISMA guidelines. Data on individual AHM classes were pooled using random effects frequentist network meta‐analysis. Result: Fifteen observational studies and seven RCTs were included. Dementia occurred in 19,600/649,790 (3.02%) individuals. In observational studies, treatment with calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs) conveyed lower dementia risks than treatment with other antihypertensives: CCBs compared to ACE‐inhibitors (HR=0.84, 95%CI 0.74‐0.95), beta blockers (BB) (HR=0.83, 95%CI 0.73‐0.95) and diuretics (HR=0.89, 95%CI 0.78‐1.01); ARBs compared to ACE‐inhibitors (HR=0.88, 95%CI 0.81‐0.97), BB (HR=0.87, 95%CI 0.77‐0.99) and diuretics (HR=0.93, 95%CI 0.83‐1.05). There were too few RCTs to create a robust network based on randomized data but similar conclusions were suggested. Conclusion: Recommending CCBs or ARBs as preferred first‐line antihypertensive treatment may significantly reduce the risk of dementia. If confirmed in randomized trials, these findings reflect a low‐cost and scalable opportunity to reduce dementia incidence world‐wide. [ABSTRACT FROM AUTHOR]

Background: Hypertension is an important risk factor for all‐cause dementia and Alzheimer's disease (AD). Reports about the relation between mid‐life hypertension and AD‐related neuropathology are sparse and inconsistent. We conducted a systematic review to collate and synthesize the literature on the relation between hypertension and AD neuropathology. Methods: Search terms included dementia, Alzheimer's disease, hypertension, autopsy, obduction and neuropathology. The main outcome was AD‐related neuropathological changes at autopsy (including amyloid plaques and neurofibrillary tangles) with hypertension as exposure, either collected retrospectively from medical records or prospectively measured at clinical evaluation(s). We included prospective and retrospective cohort studies with individuals from general and selected (e.g. memory clinic) populations. We excluded case‐control studies. Results: We found 10 studies (total N = 3054, median 231 participants, range 50‐1288) that were very heterogeneous concerning populations, methodological approach and statistical analysis. Most studies reported no association between midlife hypertension and AD‐changes at autopsy. Two studies (total n = 1531) reported an association between hypertension and elevated numbers of neurofibrillary tangles and neuritic plaques. Of those studies, one reported that both a low and a high BP in late‐life was associated with an increased burden of amyloid plaques and tangles (U‐shape). Conclusions: Our study shows no consistent association between blood pressure and AD‐neuropathology. However, based on our results, we speculate that the association between hypertension and AD‐neuropathology is age‐dependent, and that U‐shaped relations may have been obscured in linear analyses. Future studies could take this phenomenon into account when investigating the relation between hypertension and AD neuropathology. [ABSTRACT FROM AUTHOR]

A response by Edo Richard and Willem A. Van Gool to a letter to the editor about their article "Vascular care in patients with Alzheimer’s disease with cerebrovascular lesions-a randomized clinical trial” in a previous issue is presented.