Dementia is a neurodegenerative disorder with global impact, with the largest proportion of cases occurring in low- and middle-income countries. It is estimated that there are 46.8 million cases globally with approximately 10 million new cases each year or a new case occurring every 3 sec (Prince et al., 2015). For comparison there are 36.7 million HIV cases with an estimated 2 million new cases each year (WHO, 2017). The rise in dementia prevalence is largely due to population ageing, with the oldest being at highest risk. To date there are no diseases modifying medications for Alzheimer's disease or the other causes of dementia. Academics and research groups are increasingly focused on prevention or delay of dementia (Brayne and Miller, 2017) and a number of organizations now prioritize dementia, indicating a strong and coherent international effort to address this problem. Examples include the World Health Organisation (WHO), which has established a Global Dementia Observatory; the World Dementia Council; the Organisation for Economic Co-operation and Development (OECD); the U.S. National Alzheimer's Project Act (NAPA); and the Global Council on Brain Health.

In the past decade a large body of evidence has accumulated on risk factors for dementia, primarily from Europe and North America. Drawing on recent integrative reviews and a consensus workshop, the International Research Network on Dementia Prevention developed a consensus statement on priorities for future research. Significant gaps in geographical location, representativeness, diversity, duration, mechanisms, and research on combinations of risk factors were identified. Future research to inform dementia risk reduction should fill gaps in the evidence base, take a life-course, multi-domain approach, and inform population health approaches that improve the brain-health of whole communities.

Introduction

Current efforts to reduce dementia focus on prevention and risk reduction by targeting modifiable risk factors. As dementia and cardiometabolic non-communicable diseases (NCDs) share risk factors, a single risk-estimating tool for dementia and multiple NCDs could be cost-effective and facilitate concurrent assessments as compared with a conventional single approach. The aim of this study is to develop and validate a new risk tool that estimates an individual's risk of developing dementia and other NCDs including diabetes mellitus, stroke and myocardial infarction. Once validated, it could be used by the public and general practitioners.

Methods and analysis

Ten high-quality cohort studies from multiple countries were identified, which met eligibility criteria, including large representative samples, long-term follow-up, data on clinical diagnoses of dementia and NCDs, recognised modifiable risk factors for the four NCDs and mortality data. Pooled harmonised data from the cohorts will be used, with 65% randomly allocated for development of the predictive model and 35% for testing. Predictors include sociodemographic characteristics, general health risk factors and lifestyle/behavioural risk factors. A subdistribution hazard model will assess the risk factors' contribution to the outcome, adjusting for competing mortality risks. Point-based scoring algorithms will be built using predictor weights, internally validated and the discriminative ability and calibration of the model will be assessed for the outcomes. Sensitivity analyses will include recalculating risk scores using logistic regression.

Ethics and dissemination

Ethics approval is provided by the University of New South Wales Human Research Ethics Committee (UNSW HREC; protocol numbers HC200515, HC3413). All data are deidentified and securely stored on servers at Neuroscience Research Australia. Study findings will be presented at conferences and published in peer-reviewed journals. The tool will be accessible as a public health resource. Knowledge translation and implementation work will explore strategies to apply the tool in clinical practice.

This article describes the protocol for the Systematic Multi-domain Alzheimer's Risk Reduction Trial (SMARRT), a single-blind randomized pilot trial to test a personalized, pragmatic, multi-domain Alzheimer's disease (AD) risk reduction intervention in a US integrated healthcare delivery system. Study participants will be 200 higher-risk older adults (age 70-89 years with subjective cognitive complaints, low normal performance on cognitive screen, and ≥ two modifiable risk factors targeted by our intervention) who will be recruited from selected primary care clinics of Kaiser Permanente Washington, oversampling people with non-white race or Hispanic ethnicity. Study participants will be randomly assigned to a two-year Alzheimer's risk reduction intervention (SMARRT) or a Health Education (HE) control. Randomization will be stratified by clinic, race/ethnicity (non-Hispanic white versus non-white or Hispanic), and age (70-79, 80-89). Participants randomized to the SMARRT group will work with a behavioral coach and nurse to develop a personalized plan related to their risk factors (poorly controlled hypertension, diabetes with evidence of hyper or hypoglycemia, depressive symptoms, poor sleep quality, contraindicated medications, physical inactivity, low cognitive stimulation, social isolation, poor diet, smoking). Participants in the HE control group will be mailed general health education information about these risk factors for AD. The primary outcome is two-year cognitive change on a cognitive test composite score. Secondary outcomes include: 1) improvement in targeted risk factors, 2) individual cognitive domain composite scores, 3) physical performance, 4) functional ability, 5) quality of life, and 6) incidence of mild cognitive impairment, AD, and dementia. Primary and secondary outcomes will be assessed in both groups at baseline and 6, 12, 18, and 24 months.

We characterized the relationship between late life cholesterol exposure and neuropathological outcomes in a community-based, older adult cohort. Adult Changes in Thought (ACT) is a cohort study that enrolls consenting, randomly selected, non-demented people aged ≥65 from a healthcare delivery system. We used late life HDL and total cholesterol lab values from Group Health computerized records, and calculated HDL and non-HDL levels. We evaluated neuropathological outcomes of Alzheimer's disease, cerebral amyloid angiopathy, vascular brain injury, and Lewy body disease. Using linear mixed models with age and antilipemic medication as predictors, we obtained predicted cholesterol values at age 70 and 10 years prior to death for individuals with available cholesterol data in 10-year exposure windows. We used logistic regression to determine whether predicted late life cholesterol levels were associated with neuropathological outcomes controlling for age at death, APOE genotype, sex, and their interactions with cholesterol levels. 525 decedents came to autopsy by 08/2014. Of these, plasma cholesterol concentration was available for 318 (age 70, model 1) and 396 (10 years prior to death, model 2) participants. We did not find associations between late life cholesterol and Alzheimer's disease neuropathological changes, and there were no associations between cholesterol levels and amyloid angiopathy or vascular brain injury. We observed an association between predicted non-HDL cholesterol at age 70 and Lewy body disease. Our study suggests an association between late life non-HDL cholesterol exposure and Lewy body disease. We did not observe associations between late life cholesterol levels and Braak stage or CERAD score.

Background

Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective.

Objective

The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator.

Methods

Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored.

Results

Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012).

Conclusion

Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

AIM: To synthesize international findings on the alcohol-dementia relationship, including representation from low- and middle-income countries. METHODS: Individual participant data meta-analysis of 15 prospective epidemiological cohort studies from countries situated in six continents. Cox regression investigated the dementia risk associated with alcohol use in older adults aged over 60 years. Additional analyses assessed the alcohol-dementia relationship in the sample stratified by sex and by continent. Participants included 24 478 community dwelling individuals without a history of dementia at baseline and at least one follow-up dementia assessment. The main outcome measure was all-cause dementia as determined by clinical interview. RESULTS: At baseline, the mean age across studies was 71.8 (standard deviation = 7.5, range = 60-102 years), 14 260 (58.3%) were female and 13 269 (54.2%) were current drinkers. During 151 636 person-years of follow-up, there were 2124 incident cases of dementia (14.0 per 1000 person-years). When compared with abstainers, the risk for dementia was lower in occasional [hazard ratio (HR) = 0.78; 95% confidence interval (CI) = 0.68-0.89], light-moderate (HR = 0.78; 95% CI = 0.70-0.87) and moderate-heavy drinkers (HR = 0.62; 95% CI = 0.51-0.77). There was no evidence of differences between life-time abstainers and former drinkers in terms of dementia risk (HR = 0.98; 95% CI = 0.81-1.18). In dose-response analyses, moderate drinking up to 40 g/day was associated with a lower risk of dementia when compared with lif-time abstaining. Among current drinkers, there was no consistent evidence for differences in terms of dementia risk. Results were similar when the sample was stratified by sex. When analysed at the continent level, there was considerable heterogeneity in the alcohol-dementia relationship. CONCLUSIONS: Abstinence from alcohol appears to be associated with an increased risk for all-cause dementia. Among current drinkers, there appears to be no consistent evidence to suggest that the amount of alcohol consumed in later life is associated with dementia risk.

Background

Besides physical activity as a target for dementia prevention, sedentary behaviour is hypothesized to be a potential target in its own right. The rising number of persons with dementia and lack of any effective treatment highlight the urgency to better understand these modifiable risk factors. Therefore, we aimed to investigate whether higher levels of sedentary behaviour are associated with reduced global cognitive functioning and slower cognitive decline in older persons without dementia.

Methods

We used five population cohorts from Greece, Australia, USA, Japan, and Singapore (HELIAD, PATH, SALSA, SGS, and SLAS2) from the Cohort Studies of Memory in an International Consortium. In a coordinated analysis, we assessed the relationship between sedentary behaviour and global cognitive function with the use of linear mixed growth model analysis (mean follow-up range of 2.0-8.1 years).

Results

Baseline datasets combined 10,450 older adults without dementia with a mean age range between cohorts of 66.7-75.1 years. After adjusting for multiple covariates, no cross-sectional association between sedentary behaviour and cognition was found in four studies. One association was detected where more sedentary behaviour was cross-sectionally linked to higher cognition levels (SLAS2, B = 0.118 (0.075; 0.160), P < 0.001). Longitudinally, there were no associations between baseline sedentary behaviour and cognitive decline (P > 0.05).

Conclusions

Overall, these results do not suggest an association between total sedentary time and lower global cognition in older persons without dementia at baseline or over time. We hypothesize that specific types of sedentary behaviour may differentially influence cognition which should be investigated further. For now, it is, however, too early to establish undifferentiated sedentary time as a potential effective target for minimizing cognitive decline in older adults without dementia.

Introduction

Numerous studies have found associations between characteristics of urban environments and risk factors for dementia and cognitive decline, such as physical inactivity and obesity. However, the contribution of urban environments to brain and cognitive health has been seldom examined directly. This cohort study investigates the extent to which and how a wide range of characteristics of urban environments influence brain and cognitive health via lifestyle behaviours in mid-aged and older adults in three cities across three continents.

Methods and analysis

Participants aged 50-79 years and living in preselected areas stratified by walkability, air pollution and socioeconomic status are being recruited in Melbourne (Australia), Barcelona (Spain) and Hong Kong (China) (n=1800 total; 600 per site). Two assessments taken 24 months apart will capture changes in brain and cognitive health. Cognitive function is gauged with a battery of eight standardised tests. Brain health is assessed using MRI scans in a subset of participants. Information on participants' visited locations is collected via an interactive web-based mapping application and smartphone geolocation data. Environmental characteristics of visited locations, including the built and natural environments and their by-products (e.g., air pollution), are assessed using geographical information systems, online environmental audits and self-reports. Data on travel and lifestyle behaviours (e.g., physical and social activities) and participants' characteristics (e.g., sociodemographics) are collected using objective and/or self-report measures.

Ethics and dissemination

The study has been approved by the Human Research Ethics Committee of the Australian Catholic University, the Institutional Review Board of the University of Hong Kong and the Parc de Salut Mar Clinical Research Ethics Committee of the Government of Catalonia. Results will be communicated through standard scientific channels. Methods will be made freely available via a study-dedicated website.

Trial registration number

ACTRN12619000817145.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.