Brassinosteroids promote etiolated apical structures in darkness by amplifying the ethylene response via the EBF-EIN3/PIF3 circuit.

Germinated plants grow in darkness until they emerge above the soil. To help the seedling penetrate the soil, most dicot seedlings develop an etiolated apical structure consisting of an apical hook and folded, unexpanded cotyledons atop a rapidly elongating hypocotyl. Brassinosteroids (BRs) are necessary for etiolated apical development, but their precise role and mechanisms remain unclear. Arabidopsis thaliana SMALL AUXIN UP RNA17 (SAUR17) is an apical-organ-specific regulator that promotes production of an apical hook and closed cotyledons. In darkness, ethylene and BRs stimulate SAUR17 expression by transcription factor complexes containing PHYTOCHROME-INTERACTING FACTORs (PIFs), ETHYLENE INSENSITIVE 3 (EIN3), and its homolog EIN3-LIKE 1 (EIL1), and BRASSINAZOLE RESISTANT1 (BZR1). BZR1 requires EIN3 and PIFs for enhanced DNA-binding and transcriptional activation of the SAUR17 promoter; while EIN3, PIF3, and PIF4 stability depends on BR signaling. BZR1 transcriptionally downregulates EIN3-BINDING F-BOX 1 and 2 (EBF1 and EBF2), which encode ubiquitin ligases mediating EIN3 and PIF3 protein degradation. By modulating the EBF-EIN3/PIF protein-stability circuit, BRs induce EIN3 and PIF3 accumulation, which underlies BR-responsive expression of SAUR17 and HOOKLESS1 and ultimately apical hook development. We suggest that in the etiolated development of apical structures, BRs primarily modulate plant sensitivity to darkness and ethylene.

Sex and gender differences in risk scores for dementia and Alzheimer's disease among cisgender, transgender, and non-binary adults.

INTRODUCTION: Few studies have explored dementia risk according to sex and gender including for transgender and non-binary adults. This study evaluated dementia risk factors and risk scores among cisgender, transgender, and non-binary adults. METHODS: Observational data were drawn from the 2019 Behavioral Risk Factor Surveillance System. A matched-cohort approach was used to develop sex (male, female) and gender identity cohorts (cisgender men, cisgender women, transgender men, transgender women, and non-binary adults) for comparison. Dementia risk scores were calculated using established mid-life and late-life risk score algorithms. RESULTS: Males had higher overall mid-life dementia risk, and lower late-life Alzheimer's disease risk compared to females. Transgender men, transgender women, and non-binary adults had higher overall late-life risk compared to both cisgender men and women. DISCUSSION: Future research is needed to build the evidence base for specific risk factors that may be contributing to higher overall risk among understudied and underserved gender groups. HIGHLIGHTS: Using data from the 2019 Behavioral Risk Factor Surveillance System, this matched-cohort study found that those assigned female at birth had lower overall mid-life dementia risk and higher overall late-life Alzheimer's disease (AD) risk compared to those assigned male at birth. Transgender men, transgender women, and non-binary adults all showed higher overall late-life AD risk compared to cisgender men and cisgender women. Between-group differences were found in the incidence of specific risk and protective factors for dementia and AD.

Glucosamine suppresses oxidative stress and induces protective autophagy in osteoblasts by blocking the ROS/Akt/mTOR signaling pathway.

Oxidative stress is the crucial pathogenic factor in osteoporosis. Cell autophagy, a major form of self-digestion, plays critical functions in different forms of stress by devouring harmful cytosolic proteins or organelles for the renewal of organelles and to maintain cellular homeostasis. Glucosamine (GlcN) has been widely utilized in treatments for patients with osteoarthritis-related joint pain. It has potential antioxidant effects and its pharmacological effect in osteoblasts remains unclear. The present study aimed to investigate whether autophagy participates in the protective effects of GlcN in osteoblasts under oxidative stress and the possible mechanism. First of all, MC3T3-E1 cells were treated with hydrogen peroxide (H2 O2 ) to induce oxidative stress, as assessed by viability assays, apoptosis, the intracellular reactive oxygen species production. GlcN was capable of inducing autophagy and protected osteoblasts from those cytotoxic effects. Moreover, it significantly attenuated H2 O2 -induced oxidative stress as measured by malondialdehyde, glutathione, nitrite, and superoxide dismutase levels. Importantly, the autophagy level increased in osteoblasts treated with GlcN as represented by an increase in both Beclin1 expression and the LC3 II/I ratio. Immunofluorescence analysis of autophagosomes also confirmed the above results. In addition, GlcN decreased the mammalian target of rapamycin (mTOR) and protein kinase B (Akt). However, the Akt activator (SC79) suppressed the autophagy level induced by GlcN in osteoblasts. Consequently, the antioxidant effects of GlcN were mediated, at least in part, by enhancing autophagy through the Akt/mTOR pathway. These results suggested that GlcN might be a promising candidate for osteoporosis treatment.

Cognitive health expectancies of cardiovascular risk factors for cognitive decline and dementia.

BACKGROUND: Cognitive health expectancy estimates the proportion of the lifespan that is lived in good cognitive health at the population level. A number of cardiovascular diseases have been identified to be risk factors for cognitive decline and dementia including diabetes, stroke, heart diseases and hypertension. The aim of this study was to examine how these cardiovascular conditions relate to cognitive health expectancy. METHODS: Longitudinal data were obtained from the US Health and Retirement Study. Multistate modelling was used to estimate total life expectancy (LE), cognitive impairment free life expectancy (CIFLE) and years spent with cognitive impairment (CILE) across self-reported diabetes, hypertension, heart problems and stroke. Individual and cumulative effects of multiple cardiovascular conditions were examined. RESULTS: The presence of cardiovascular disease was associated with a 5- to 9-year decrease in LE and 4- to 8-year decrease in CIFLE at age 55. The outcomes varied in a hierarchical fashion by cardiovascular condition. Relative to other conditions, individuals with stroke had the shortest LE and CIFLE. Analysis of multiple cardiovascular risk factors revealed that each additional cardiovascular condition was associated with an exponential decrease in LE and CIFLE. CONCLUSIONS: Having a cardiovascular condition is associated with a lower CIFLE and higher proportion of life lived with cognitive impairment. However, the outcomes vary depending on the type of cardiovascular condition. Reducing incidence of stroke and minimising exposure to multiple cardiovascular risk factors may be beneficial in helping to improve population estimates of cognitive health expectancy.

Chronic PFOS Exposure Disrupts Thyroid Structure and Function in Zebrafish.

Perfluorooctane sulfonic acid (PFOS), as a potential endocrine disrupting chemical, is widely detected in the environment, wildlife and human. Currently few studies have documented the effects of chronic PFOS exposure on thyroid in aquatic organisms and the underlying mechanisms are largely unknown. The present study assessed the effect of chronic PFOS exposure on thyroid structure and function using zebrafish model. Zebrafish at 8 h post fertilization (hpf) were exposed to PFOS (250 µg/l) until 120 d post fertilization (dpf). Thyroid hormone (T3 and T4) level, thyroid morphology and thyroid function related gene expression were evaluated in zebrafish at 120 dpf. Our findings demonstrated that chronic PFOS exposure altered thyroid hormone level, thyroid follicular cell structure and thyroid hormone related gene expression, suggesting the validity of zebrafish as an alternative model for PFOS chronic toxicity screening.

A Scoping Survey to Inform Design of Digital Dementia Risk Reduction Interventions for Adults Concerned about their Cognitive Health.

Background: Digital dementia risk reduction interventions are cost-effective and scalable. However, it is unknown how they are perceived by people already experiencing cognitive concerns or decline. Objective: To understand the current use, interest, and preferences for online learning courses and interest in learning about factors influencing brain health and dementia risk among adults ≥45. To explore potential differences between individuals experiencing cognitive concerns and those without. Methods: Adults aged 45 and older completed a survey on technology use and healthy ageing (n = 249, Mean age = 65.6, 76.3% female). The Memory Assessment Clinic-Questionnaire was used to assess subjective memory decline, and 153 participants met the study criteria for cognitive concerns (≥25). Results: Almost all participants (98.4%) reported using two or more digital devices, and 51.8% reported increasing device usage following COVID-19. Most (92.1%) were interested in learning about healthy living and memory within an online course, and over 80% indicated a high interest in learning about dementia risk factors. People with cognitive concerns were more likely to report using a 'routine or system' to aid memory than people without (82.4% versus 62.9%, p = 0.001). However, no significant difference was found in technology use, course preferences, or interest in learning about different risk factors. Conclusions: We conclude that adults 45 years and over are interested in online methods for learning about brain health and offer unique insights into adapting dementia prevention programs for cognitive concerns.

A Technology-Enriched Approach to Studying Microlongitudinal Aging Among Adults Aged 18 to 85 Years: Protocol for the Labs Without Walls Study.

BACKGROUND: Traditional longitudinal aging research involves studying the same individuals over a long period, with measurement intervals typically several years apart. App-based studies have the potential to provide new insights into life-course aging by improving the accessibility, temporal specificity, and real-world integration of data collection. We developed a new research app for iOS named Labs Without Walls to facilitate the study of life-course aging. Combined with data collected using paired smartwatches, the app collects complex data including data from one-time surveys, daily diary surveys, repeated game-like cognitive and sensory tasks, and passive health and environmental data. OBJECTIVE: The aim of this protocol is to describe the research design and methods of the Labs Without Walls study conducted between 2021 and 2023 in Australia. METHODS: Overall, 240 Australian adults will be recruited, stratified by age group (18-25, 26-35, 36-45, 46-55, 56-65, 66-75, and 76-85 years) and sex at birth (male and female). Recruitment procedures include emails to university and community networks, as well as paid and unpaid social media advertisements. Participants will be invited to complete the study onboarding either in person or remotely. Participants who select face-to-face onboarding (n=approximately 40) will be invited to complete traditional in-person cognitive and sensory assessments to be cross-validated against their app-based counterparts. Participants will be sent an Apple Watch and headphones for use during the study period. Participants will provide informed consent within the app and then begin an 8-week study protocol, which includes scheduled surveys, cognitive and sensory tasks, and passive data collection using the app and a paired watch. At the conclusion of the study period, participants will be invited to rate the acceptability and usability of the study app and watch. We hypothesize that participants will be able to successfully provide e-consent, input survey data through the Labs Without Walls app, and have passive data collected over 8 weeks; participants will rate the app and watch as user-friendly and acceptable; the app will allow for the study of daily variability in self-perceptions of age and gender; and data will allow for the cross-validation of app- and laboratory-based cognitive and sensory tasks. RESULTS: Recruitment began in May 2021, and data collection was completed in February 2023. The publication of preliminary results is anticipated in 2023. CONCLUSIONS: This study will provide evidence regarding the acceptability and usability of the research app and paired watch for studying life-course aging processes on multiple timescales. The feedback obtained will be used to improve future iterations of the app, explore preliminary evidence for intraindividual variability in self-perceptions of aging and gender expression across the life span, and explore the associations between performance on app-based cognitive and sensory tests and that on similar traditional cognitive and sensory tests. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47053.

Gender specific factors contributing to cognitive resilience in APOE ɛ4 positive older adults in a population-based sample.

Although APOE ɛ4 has been identified as the strongest genetic risk factor for Alzheimer's Disease, there are some APOE ɛ4 carriers who do not go on to develop Alzheimer's disease or cognitive impairment. This study aims to investigate factors contributing to this "resilience" separately by gender. Data were drawn from APOE ɛ4 positive participants who were aged 60 + at baseline in the Personality and Total Health Through Life (PATH) Study (N = 341, Women = 46.3%). Participants were categorised into "resilient" and "non-resilient" groups using Latent Class Analysis based on their cognitive impairment status and cognitive trajectory across 12 years. Logistic regression was used to identify the risk and protective factors that contributed to resilience stratified by gender. For APOE ɛ4 carriers who have not had a stroke, predictors of resilience were increased frequency of mild physical activity and being employed at baseline for men, and increased number of mental activities engaged in at baseline for women. The results provide insights into a novel way of classifying resilience among APOE ɛ4 carriers and risk and protective factors contributing to resilience separately for men and women.

Experiences of Performing Daily Activities in Middle-Aged and Older Autistic Adults: A Qualitative Study.

This is the first study to investigate instrumental activities of daily living in older autistic adults. We conducted interviews with fifteen adults (mean age = 60.1, SD = 7.4, range = 50-73) from Australia with no intellectual disability. Analysis included both deductive and inductive steps, to categorise responses using the Occupational Performance Model Australia and identify themes across participants' experiences. Strengths and challenges were unique to the individual, as were the methods they had developed to manage tasks. Challenges occurred mostly at the interaction between aspects of the environment (sensory, cognitive, social and cultural) and personal factors such as health conditions and sensory sensitivities. Enhanced person-environment fit is needed, as is a shift in wider sociocultural attitudes to enable comfort and autonomy in later life.

MyCOACH (COnnected Advice for Cognitive Health): a digitally delivered multidomain intervention for cognitive decline and risk of dementia in adults with mild cognitive impairment or subjective cognitive decline-study protocol for a randomised controlled trial.

INTRODUCTION: Digital health interventions are cost-effective and easily accessible, but there is currently a lack of effective online options for dementia prevention especially for people at risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). METHODS AND ANALYSIS: MyCOACH (COnnected Advice for Cognitive Health) is a tailored online dementia risk reduction programme for adults aged ≥65 living with MCI or SCD. The MyCOACH trial aims to evaluate the programme's effectiveness in reducing dementia risk compared with an active control over a 64-week period (N=326). Eligible participants are randomly allocated to one of two intervention arms for 12 weeks: (1) the MyCOACH intervention programme or (2) email bulletins with general healthy ageing information (active control). The MyCOACH intervention programme provides participants with information about memory impairments and dementia, memory strategies and different lifestyle factors associated with brain ageing as well as practical support including goal setting, motivational interviewing, brain training, dietary and exercise consultations, and a 26-week post-intervention booster session. Follow-up assessments are conducted for all participants at 13, 39 and 65 weeks from baseline, with the primary outcome being exposure to dementia risk factors measured using the Australian National University-Alzheimer's Disease Risk Index. Secondary measures include cognitive function, quality of life, functional impairment, motivation to change behaviour, self-efficacy, morale and dementia literacy. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of New South Wales Human Research Ethics Committee (HC210012, 19 February 2021). The results of the study will be disseminated in peer-reviewed journals and research conferences. TRIAL REGISTRATION NUMBER: ACTRN12621000977875.

Arabidopsis SYP121 acts as an ROP2 effector in the regulation of root hair tip growth.

Tip growth is an extreme form of polarized cell expansion that occurs in all eukaryotic kingdoms to generate highly elongated tubular cells with specialized functions, including fungal hyphae, animal neurons, plant pollen tubes, and root hairs (RHs). RHs are tubular structures that protrude from the root epidermis to facilitate water and nutrient uptake, microbial interactions, and plant anchorage. RH tip growth requires polarized vesicle targeting and active exocytosis at apical growth sites. However, how apical exocytosis is spatially and temporally controlled during tip growth remains elusive. Here, we report that the Qa-Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) SYP121 acts as an effector of Rho of Plants 2 (ROP2), mediating the regulation of RH tip growth. We show that active ROP2 promotes SYP121 targeting to the apical plasma membrane. Moreover, ROP2 directly interacts with SYP121 and promotes the interaction between SYP121 and the R-SNARE VAMP722 to form a SNARE complex, probably by facilitating the release of the Sec1/Munc18 protein SEC11, which suppresses the function of SYP121. Thus, the ROP2-SYP121 pathway facilitates exocytic trafficking during RH tip growth. Our study uncovers a direct link between an ROP GTPase and vesicular trafficking and a new mechanism for the control of apical exocytosis, whereby ROP GTPase signaling spatially regulates SNARE complex assembly and the polar distribution of a Q-SNARE.

The use of everyday and assistive technology in the lives of older autistic adults.

LAY ABSTRACT: Technology has the potential to help people with various support needs live more autonomous lives. This includes autistic individuals. In this article, we look at how older autistic adults use technology in their daily lives. Past research examining technology use and autism has mainly focused on helping children to learn new skills. To date, very little research has been conducted looking at how to create and design technology for use by older autistic adults. This is concerning because older autistic adults will likely have supports needs that match or exceed those of similarly aged non-autistic individuals. In this article, we spoke to autistic adults over 50 years about their daily experiences and how they use technology. We identified some important ways that older autistic adults use technology in their daily lives, as well as a number of support needs and barriers to technology use. Based on the findings, we were able to provide some guidelines and recommendations for technology developers and service providers to assist with designing, creating and using technology with older autistic adults.

Dementia Risk Scores and Their Role in the Implementation of Risk Reduction Guidelines.

Dementia prevention is a global health priority. In 2019, the World Health Organisation published its first evidence-based guidelines on dementia risk reduction. We are now at the stage where we need effective tools and resources to assess dementia risk and implement these guidelines into policy and practice. In this paper we review dementia risk scores as a means to facilitate this process. Specifically, we (a) discuss the rationale for dementia risk assessment, (b) outline some conceptual and methodological issues to consider when reviewing risk scores, (c) evaluate some dementia risk scores that are currently in use, and (d) provide some comments about future directions. A dementia risk score is a weighted composite of risk factors that reflects the likelihood of an individual developing dementia. In general, dementia risks scores have a wide range of implementations and benefits including providing early identification of individuals at high risk, improving risk perception for patients and physicians, and helping health professionals recommend targeted interventions to improve lifestyle habits to decrease dementia risk. A number of risk scores for dementia have been published, and some are widely used in research and clinical trials e.g., CAIDE, ANU-ADRI, and LIBRA. However, there are some methodological concerns and limitations associated with the use of these risk scores and more research is needed to increase their effectiveness and applicability. Overall, we conclude that, while further refinement of risk scores is underway, there is adequate evidence to use these assessments to implement guidelines on dementia risk reduction.

Exploration of the cortical pathophysiology underlying visual disturbances in schizophrenia comorbid with depressive disorder-An evidence from mouse model.

INTRODUCTION: Patients with schizophrenia frequently present with visual disturbances including hallucination, and this symptom is particularly prevalent in individuals with comorbid depressive disorders. Currently, little is known about the neurobiological mechanisms of such psychiatric symptoms, and few explanations for the co-occurrence of schizophrenia, depression, and visual disturbances are available. METHODS: In this study, we generated a mouse schizophrenia model in which depressive symptoms were also induced. We adopted in vivo two-photon calcium imaging and ex vivo electrophysiological recording of the primary visual cortex to reveal the synaptic transmission and neural activity in the mouse schizophrenia model. RESULTS: In vivo two-photon calcium imaging and ex vivo electrophysiological recording of the primary visual cortex revealed impaired synaptic transmission and abnormal neural activity in the schizophrenia model, but not in the depression model. These functional deficits were most prominent in the combined schizophrenia and depression model. CONCLUSION: Overall, our data support a mechanism by which the visual cortex plays a role in visual disturbances in schizophrenia.

Development of the First WHO Guidelines for Risk Reduction of Cognitive Decline and Dementia: Lessons Learned and Future Directions.

The first WHO guidelines for risk reduction of cognitive decline and dementia marked an important milestone in the field of dementia prevention. In this paper, we discuss the evidence reviewed as part of the guidelines development and present the main themes emerged from its synthesis, to inform future research and policies on dementia risk reduction. The role of intervention effect-size; the mismatch between observational and intervention-based evidence; the heterogeneity of evidence among intervention trials; the importance of intervention duration; the role of timing of exposure to a certain risk factor and interventions; the relationship between intervention intensity and response; the link between individual risk factors and specific dementia pathologies; and the need for tailored interventions emerged as the main themes. The interaction and clustering of individual risk factors, including genetics, was identified as the overarching theme. The evidence collected indicates that multidomain approaches targeting simultaneously multiple risk factors and tailored at both individual and population level, are likely to be most effective and feasible in dementia risk reduction. The current status of multidomain intervention trials aimed to cognitive impairment/dementia prevention was also briefly reviewed. Primary results were presented focusing on methodological differences and the potential of design harmonization for improving evidence quality. Since multidomain intervention trials address a condition with slow clinical manifestation-like dementia-in a relatively short time frame, the need for surrogate outcomes was also discussed, with a specific focus on the potential utility of dementia risk scores. Finally, we considered how multidomain intervention could be most effectively implemented in a public health context and the implications world-wide for other non-communicable diseases targeting common risk factors, taking into account the limited evidence in low-middle income countries. In conclusion, the evidence from the first WHO guidelines for risk reduction of cognitive decline and dementia indicated that "one size does not fit all," and multidomain approaches adaptable to different populations and individuals are likely to be the most effective. Harmonization in trial design, the use of appropriate outcome measures, and sustainability in large at-risk populations in the context of other chronic disorders also emerged as key elements.

Dementia risk reduction in practice: the knowledge, opinions and perspectives of Australian healthcare providers.

This study examined Australian primary healthcare providers' knowledge about dementia risk factors and risk reduction and their perspectives on barriers and enablers to risk reduction in practice. Primary healthcare providers were recruited through Primary Health Networks across Australia (n=51). Participants completed an online survey that consisted of fixed-responses and free-text components to assess their knowledge, attitudes and current practices relating to dementia risk factors and risk reduction techniques. The results showed that Australian primary healthcare providers have good knowledge about the modifiable risk factors for dementia; however, face several barriers to working with patients to reduce dementia risk. Commonly reported barriers included low patient motivation and healthcare system level limitations. The most commonly reported recommendations to helping primary healthcare providers to work with patients to reduce dementia risk included increasing resources and improving dementia awareness and messaging. While the results need to be interpreted in the context of the limitations of this study, we conclude that collaborative efforts between researchers, clinicians, policy makers and the media are needed to support the uptake of risk reduction activities in primary care settings.

Reducing the Risk of Cognitive Decline and Dementia: WHO Recommendations.

With population ageing worldwide, dementia poses one of the greatest global challenges for health and social care in the 21st century. In 2019, around 55 million people were affected by dementia, with the majority living in low- and middle-income countries. Dementia leads to increased costs for governments, communities, families and individuals. Dementia is overwhelming for the family and caregivers of the person with dementia, who are the cornerstone of care and support systems throughout the world. To assist countries in addressing the global burden of dementia, the World Health Organisation (WHO) developed the Global Action Plan on the Public Health Response to Dementia 2017-2025. It proposes actions to be taken by governments, civil society, and other global and regional partners across seven action areas, one of which is dementia risk reduction. This paper is based on WHO Guidelines on risk reduction of cognitive decline and dementia and presents recommendations on evidence-based, multisectoral interventions for reducing dementia risks, considerations for their implementation and policy actions. These global evidence-informed recommendations were developed by WHO, following a rigorous guideline development methodology and involved a panel of academicians and clinicians with multidisciplinary expertise and representing geographical diversity. The recommendations are considered under three broad headings: lifestyle and behaviour interventions, interventions for physical health conditions and specific interventions. By supporting health and social care professionals, particularly by improving their capacity to provide gender and culturally appropriate interventions to the general population, the risk of developing dementia can be potentially reduced, or its progression delayed.

Neural mechanisms underlying visual and auditory processing impairments in schizophrenia: insight into the etiology and implications for tailoring preventive and therapeutic interventions.

Schizophrenia is a complex and devastating neuropsychiatric disorder with an unknown etiology. Patients with schizophrenia have a high prevalence of visual disturbances, commonly accompanied by auditory impairments. In recent review articles, the perceptual deficits of visual and auditory sensory processing have been downplayed. However, visual and auditory impairments are associated with hallucinations, which is characteristic of schizophrenia across all cultures. Despite decades of research, the common neural mechanisms underlying hallucinations remain largely unknown. In recent years, neuroimaging technologies have empowered researchers to investigate the underlying neural mechanisms. In this review article, we performed a literature search of studies that assessed visual and auditory processing impairments, along with their relationship to visual disturbances and auditory hallucinations, in schizophrenia. We proposed that the pulvinar may play a critical role. In addition, disrupted visual and auditory projections from the pulvinar to the visual and auditory cortices could be shared pathways in relation to visual disturbances and auditory hallucinations in schizophrenia. Our findings suggest that early visual and auditory processing deficits may occur before the onset of the initial psychotic episode, including hallucinations, and the full manifestation of schizophrenia. Furthermore, we discussed the directions for future studies. Our findings from this review offer unique insights into the distinct underlying neural mechanisms of schizophrenia, which may help develop tailored preventive and therapeutic interventions in the future.

Future Directions for Dementia Risk Reduction and Prevention Research: An International Research Network on Dementia Prevention Consensus.

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.