Jacob Brain1,2, Phillip J Tully3, Deborah Turnbull2, Eugene Tang4, Leanne Greene5, Sarah Beach6, Mario Siervo1, Blossom C M Stephan1. 1. Institute of Mental Health, School of Medicine, University of Nottingham, Innovation Park, Jubilee Campus, Nottingham, United Kingdom. 2. Freemasons Foundation Centre for Men's Health, Discipline of Medicine, School of Psychology, The University of Adelaide, Adelaide, Australia. 3. Faculty of Medicine and Health, School of Psychology, University of New England, Armidale, Australia. 4. Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. 5. Clinical Trials Unit, College of Medicine and Health, University of Exeter, St Luke's Campus, Exeter, United Kingdom. 6. University of Nottingham Libraries, University of Nottingham, King's Meadow Campus, Nottingham, United Kingdom.
Abstract
BACKGROUND: Dementia is a major public health priority. Although there is abundant evidence of an association between dementia and poor cardiovascular health, findings have been inconsistent and uncertain in identifying which factors increase dementia risk in those with cardiovascular disease. Indeed, multiple variables including sociodemographic, economic, health, lifestyle and education may indicate who is at higher vs. lower dementia risk and could be used in prediction modelling. Therefore, the aim of this review is to synthesise evidence on the key risk factors for dementia in those with a history of cardiovascular disease. METHODS: This is an overview of reviews protocol, registered on PROSPERO (CRD42021265363). Four electronic databases including MEDLINE, EMBASE, PsycINFO, and the Cochrane Database of Systematic Reviews will be searched. Studies will be included if they are systematic reviews and/or meta-analyses that have investigated the risk of incident dementia (all-cause and subtypes including Alzheimer's disease and vascular dementia) in people with a history of coronary heart disease, heart failure, atrial fibrillation, hypertension, hyperlipidaemia, and vascular stiffness. Study selection will be completed by two independent researchers according to the eligibility criteria, and conflicts resolved by a third reviewer. References will be exported into Covidence for title and abstract sifting, full-text review, and data extraction. Methodological quality will be assessed using the AMSTAR-2 criteria and confidence of evidence will be assessed using the GRADE classification. This overview of reviews will follow PRISMA guidelines. If there is sufficient homogeneity in the data, the results will be pooled, and a meta-analysis conducted to determine the strength of association between each risk factor and incident all-cause dementia and its subtypes for each cardiovascular diagnoses separately. DISCUSSION: We will create a comprehensive summary of the key risk factors linking cardiovascular diseases to risk of incident dementia. This knowledge is essential for informing risk predictive model development as well as the development of risk reduction and prevention strategies.
BACKGROUND: Dementia is a major public health priority. Although there is abundant evidence of an association between dementia and poor cardiovascular health, findings have been inconsistent and uncertain in identifying which factors increase dementia risk in those with cardiovascular disease. Indeed, multiple variables including sociodemographic, economic, health, lifestyle and education may indicate who is at higher vs. lower dementia risk and could be used in prediction modelling. Therefore, the aim of this review is to synthesise evidence on the key risk factors for dementia in those with a history of cardiovascular disease. METHODS: This is an overview of reviews protocol, registered on PROSPERO (CRD42021265363). Four electronic databases including MEDLINE, EMBASE, PsycINFO, and the Cochrane Database of Systematic Reviews will be searched. Studies will be included if they are systematic reviews and/or meta-analyses that have investigated the risk of incident dementia (all-cause and subtypes including Alzheimer's disease and vascular dementia) in people with a history of coronary heart disease, heart failure, atrial fibrillation, hypertension, hyperlipidaemia, and vascular stiffness. Study selection will be completed by two independent researchers according to the eligibility criteria, and conflicts resolved by a third reviewer. References will be exported into Covidence for title and abstract sifting, full-text review, and data extraction. Methodological quality will be assessed using the AMSTAR-2 criteria and confidence of evidence will be assessed using the GRADE classification. This overview of reviews will follow PRISMA guidelines. If there is sufficient homogeneity in the data, the results will be pooled, and a meta-analysis conducted to determine the strength of association between each risk factor and incident all-cause dementia and its subtypes for each cardiovascular diagnoses separately. DISCUSSION: We will create a comprehensive summary of the key risk factors linking cardiovascular diseases to risk of incident dementia. This knowledge is essential for informing risk predictive model development as well as the development of risk reduction and prevention strategies.
Dementia is a leading cause of disability and death globally, affecting around 55 million people, with future projections estimating a rise to 78 million cases in 2030 and 139 million cases in 2050 [1]. The cost of dementia is significant, estimated at US$ 1.3 trillion in 2020, equivalent to over 1% of the world’s gross domestic product [1]. At present, dementia is incurable and, consequently, there has been a push toward risk reduction and prevention [2, 3]. Indeed, recent evidence suggests that risk of dementia may be declining, at least in some high-income countries [2, 4]. This is thought to be linked to several factors, including for example, improved education, better risk factor control (e.g., linked to cardio-metabolic health), increased access to resources, information and digital technologies all leading to improvements in health, healthcare and cognitive reserve [5-13].Epidemiological and clinical studies consistently show strong links between cardiovascular health (e.g., presence of coronary heart disease (CHD)) and neurological conditions (e.g., dementia) [14, 15]. Moreover, those who present with multiple cardiovascular conditions in mid-life are increasingly likely to develop dementia [16]. The 2020 Lancet Commission on Dementia Prevention, Intervention and Care, highlighted a number of key modifiable factors including early life low education; midlife hearing loss, traumatic brain injury, hypertension, high alcohol consumption and obesity; and, later-life smoking, depression, social isolation, physical inactivity, air pollution and diabetes that together account for approximately 40% of dementia cases globally [2]. Preventative strategies to remove cardiovascular disease (e.g., hypertension) and its risk factors including high alcohol intake, diabetes, smoking and physical inactivity would individually eliminate approximately 1–2% of dementia cases globally [2], with greater effects in Low and Middle Income Countries [17]. Key non-modifiable factors including age [18, 19], gender [20, 21], genetics [22], and ethnicity [23, 24] may also modify the association between cardiovascular disease and risk of dementia. Regarding age, the associations between cardiovascular disease and dementia in midlife are not always replicated in later-life, with mid-life cardiovascular disease associated with increased dementia risk, and an inverse relationship reported in later-life [25-27]. Genetic factors, such as the presence of the apolipoprotein e4 allele (ApoE4), have also been found to modify the association between cardiovascular disease (e.g., CHD and AF), and dementia [22, 28, 29]. Regarding ethnicity, underrepresented groups, such as those who identify as Black or Hispanic, often have greater risk of dementia compared to Caucasians, with these differences often associated with socioeconomic and structural factors that often drive comorbidity, including the presence of cardiovascular disease [30].Yet, what drives the link between poor heart and brain health and the strategies to best maintain each system, jointly and independently, are not entirely clear. While the link between vascular dementia and cardiovascular health is well understood (i.e., reduced blood flow deprives brain cells of oxygen and nutrients, resulting in cerebral atrophy), the mechanisms underpinning other types of dementia (e.g., Alzheimer’s disease) are less understood. One theory suggests an association between poor cardiovascular health and the development of Alzheimer’s disease due to compromised blood flow to the brain, metabolic dysfunction and neuroinflammation [31, 32]. This is postulated to be mediated by various physiological pathways, such as the nitric oxide pathway, that is significantly associated with neurodegenerative disease.A comprehensive approach to dementia risk reduction and prevention is urgently needed. To achieve this, further knowledge of the risk factors for developing dementia in different populations, for example, people with cardiovascular disease, is warranted. This information could then be used to inform the development of new dementia risk prediction models to aid clinical decision making, new policy and public health campaigns targeting the link between heart and brain health, development of more effective clinical trials, and risk reduction and preventative strategies.
Objective
This review will synthesise existing literature that explores the link between cardiovascular health and dementia risk to determine, in people with cardiovascular disease, what factors increase their risk of future dementia. Six conditions will be included: CHD, heart failure, atrial fibrillation (AF), hypertension, hyperlipidaemia, and vascular stiffness.
Materials and methods
Research question
What factors are associated with an increased risk of all-cause dementia and its subtypes in individuals with a history of cardiovascular disease?
Registration and reporting information
The review will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [33]. The protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) database [CRD42021265363]. This protocol follows PRISMA-Protocol (PRISMA-P) guidelines (S1 File).
Study design
As numerous reviews on the association between cardiovascular health and dementia have been published, an ‘umbrella review’ or a ‘systematic review of systematic reviews’ approach will be used. This is considered one of the highest levels of evidence [34], presenting information both succinctly and effectively, providing an overall examination of the subject matter [35]. The current authors will look to emulate Déry et al’s. [36] approach of basing our methodology on previous works [37-41] and the Cochrane Training Handbook [42].
Search strategy
Four electronic databases will be searched from inception onwards including MEDLINE (Ovid), EMBASE (Ovid), PsycINFO (Ovid) and the Cochrane Database for Systematic Reviews. MeSh terms (e.g. ‘Dementia’, ‘Heart Failure’, ‘Hypertension’, ‘Arrhythmias’, and ‘Vascular Stiffness’), keywords and subject headings will be used together with Boolean operators of ‘OR’ and ‘AND’. Search filters, or hedges, will be employed to further retrieve methodologically sound systematic reviews or meta-analyses [43]. Searches will be prepared with the assistance of a specialist librarian and tailored to each database. The search strategy for each database is available in the S2 File. Backwards citation chaining will also be used to ensure relevant articles are not missed.
Eligibility criteria
All systematic reviews and/or meta-analyses that have synthesised evidence on the association between dementia and one of the following cardiovascular diseases or associated risk factors including CHD, heart failure, AF, hypertension, hyperlipidaemia, or vascular stiffness, will be included. The empirical studies for inclusion must be population-based or record-based. Reviews of clinical studies including trials will be excluded. Intervention and treatment studies, editorial, narrative reviews, opinion pieces and cross-sectional studies of dementia prevalence will also be excluded. Articles must be published in English. There will be no exclusion based on date of publication. As recommended when conducting an aetiology and/or risk review, this overview of reviews will follow a PEO framework [44, 45].Population. The population of interest is restricted to the general population with or without a history of cardiovascular disease or its risk factors, with information on incident dementia status. In line with similar reviews [46], we will include all ages at baseline. Indeed, the strongest associations between poor cardiovascular health and dementia appear in mid-life with often mixed results in later-life cohorts [47, 48]. However, we will exclude individuals with a diagnosis of dementia before the age of 65 (e.g., individuals with young- or early-onset dementia [49]).Exposure. The exposure will be a diagnosis of any or the following conditions: CHD, heart failure, AF, hypertension, hyperlipidaemia, or vascular stiffness. These conditions may be either self-reported or clinically diagnosed.Outcome. The primary outcome will be all-cause dementia and it subtypes including Alzheimer’s disease and vascular dementia, diagnosed through an operationalised clinical diagnosis (e.g., in accordance with established criteria such as the Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases) [50, 51].
Study selection and data extraction
All references will be imported into Covidence which has an automatic de-duplication function [52]. Two researchers (JB and ET) will independently screen the title and abstracts against the eligibility criteria. All eligible papers from initial screening will be read in full to determine inclusion. Any conflicts regarding study inclusion will be resolved by a third researcher (BS). Information extracted will include lead author; year of publication; number of included studies (with sample size); study methodology (e.g., sampling, response bias, attrition); socio-demographics; diagnostic criteria for dementia; the cardiovascular condition (CHD, heart failure, AF, hypertension, hyperlipidaemia, and vascular stiffness); statistical methodology (including control of covariance); follow-up duration; and significant/non-significant risk factors for incident dementia. Where reported, hazard/risk ratio’s and/or meta-analyses will also be extracted for analysis.
Quality assessment and evidence grading
Critical appraisal will be conducted independently by two researchers (JB and ET) using A MeaSurement Tool to Assess Systematic Reviews (AMSTAR-2) [53] tool. Any discrepancies will be resolved by discussion or a third reviewer (BS) if needed. The AMSTAR-2 has 16-domains covering topics including review registration, comprehensiveness of the literature search, inclusion/exclusion strategy, critical appraisal/results synthesis, and risk of bias (e.g., assessment and publication bias). Each domain is rated ‘yes’, ‘partial yes’, or ‘no’, and the overall quality of the study will be rated as ‘high’, ‘moderate’, ‘low’, or ‘critically low’. All studies that meet the eligibility criteria will be included regardless of their reported quality.To assess the certainty/quality of evidence of the included studies, we will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification [54]. This allows assessment of the certainty of estimate for each systematic review/meta-analysis outcome and present the conclusions in an accessible tabular format. Ratings will be completed independently by two reviewers (JB and ET). Using the GRADE classification, studies will be categorised into having ‘high’, ‘moderate’, ‘low’, or ‘very low’ certainty of evidence.
Data synthesis
A results table will be created including key study characteristics, overall findings, the review conclusion(s) and risk of bias/quality of evidence scores. A narrative synthesis will first be undertaken to determine the pattern of risk/protective factors for incident dementia in people with cardiovascular conditions. If there is sufficient homogeneity (I2≤75%, low and moderate) in the data, we will extract the relative risks with 95% confidence intervals for dementia risk for each cardiovascular condition. For each cardiovascular disease, these will be pooled in a separate meta-analysis using an inverse variance weighted random effects model. Forest plots will be generated for graphical presentations of the dementia relative risk for each cardiovascular condition. Statistical heterogeneity across studies will be assessed using the I2 and Q tests according to specific categories (low 0–25%, moderate 26–75% and high 76–100%) and significance level (P < 0.10), respectively [55]. Funnel plots and Egger’s regression test will be used to evaluate presence of potential publication bias. Where possible analysis will be stratified on key dementia risk characteristics including age, gender, ethnicity, and presence of cardiovascular comorbidities, for example, AF and valvular disease. To determine whether the quality of studies impacts the results we will undertake sensitivity analysis excluding studies rated as being of poor quality/high risk of biases. Additional sensitivity analyses will be conducted to evaluate whether effect size differs by methodological and study characteristics such as type of diagnosis of cardiovascular risk factors, study design or sample size.
Ethics and dissemination
No ethical approval is required. The results will be published in a peer-reviewed journal, presented at national and international conferences, disseminated through social media, e.g., Twitter, and will form a component of the first authors PhD.
Discussion
There are numerous systematic reviews and meta-analyses focused on the link between cardiovascular health and dementia risk [56-58]. However, none has focused specifically on identifying which factors increase dementia risk in those with cardiovascular disease.There are strengths and weaknesses with our proposed methodology. The key strength is that the review will build upon existing literature and provide a single report synthesising current knowledge on dementia risk in people with cardiovascular disease for informing new research directions [59]. There are also some weaknesses. First, the results will be limited to the number of systematic reviews/meta-analyses published. The use of search filters, broad search terms, and backwards citation chaining will, however, ensure that articles are not missed. Second, the review will be constrained by the quality of the included studies. To address this, we will use different tools to assess the quality of the included studies as well as undertaking sensitivity analyses by excluding studies of poor quality. Last, we are including only studies published in English. Therefore, relevant studies in other languages will be missed.This overview of reviews will provide, for the first time, a systematic investigation of the key factors that increase risk of all-cause dementia and its subtypes in individuals with cardiovascular disease. This information is urgently needed to ensure that the right people are targeted for treatment and to allow for better planning of care [60, 61]. Further, disentangling the mechanisms underpinning the association between dementia and cardiovascular disease may guide future research strategies for the development of composite risk scores for use in research and clinical practice.
PRISMA-P checklist.
(ZIP)Click here for additional data file.
Search strategy.
(ZIP)Click here for additional data file.31 May 2022
PONE-D-22-04170
Risk factors for dementia in the context of cardiovascular disease: a protocol of an overview of reviews
PLOS ONE
Dear Dr. Greene,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.I agree with the reviewers' assessment that this is a well written study protocol as well as with their comments to improve the paper further.
The consideration of sex/gender differences, ethnicity and possibly other determinants such as educational attainment as mentioned by reviewer #1 could increase the value of the review (and if only to point out a lack of knowledge on these factors in the relationship between cardiovascular risk and dementia).Please submit your revised manuscript by Jul 15 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please include the following items when submitting your revised manuscript:
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Comments to the Author1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: YesReviewer #2: Yes********** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: YesReviewer #2: Yes********** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: YesReviewer #2: Yes********** 4. Have the authors described where all data underlying the findings will be made available when the study is complete?The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: YesReviewer #2: Yes********** 5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: YesReviewer #2: Yes********** 6. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I would like to thank the authors for submitting this well-written protocol. Below is a list of minor suggestions and points that can be better contextualized in the protocol:Background - This section could be better contextualized. For instance, the 2020 Lancet commission highlighted 12 risk factors for dementia prevention. Which could be identified as, or associated with cardiovascular risk factors? What is the approximate percentage reduction in dementia prevalence if these risk factors were eliminated in this context?Are there any possible policies that can be developed with the findings of this systematic review?Briefly report whether gender, ethnicity, and other factors could influence the cardiovascular risk factors.Search strategy – In this section, it would be necessary to clearly state that MeSH terms will be used, and that search strategy will be adapted for each database.Data synthesis - How these results will be organized? Will the authors provide tables including sample characteristics, overall results, and other possible descriptions?Discussion – As there are other risk factors associated with dementia, the authors should rephrase the following statement: “ Reducing the number of people with dementia.”Finally, other systematic review references could be included:Purnell, C., Gao, S., Callahan, C. M., & Hendrie, H. C. (2009). Cardiovascular risk factors and incident Alzheimer disease: a systematic review of the literature. Alzheimer disease and associated disorders, 23(1), 1–10. https://doi.org/10.1097/WAD.0b013e318187541cAnstey, K. J., Lipnicki, D. M., & Low, L. F. (2008). Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis. The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry, 16(5), 343–354. https://doi.org/10.1097/JGP.0b013e31816b72d4Reviewer #2: In this manuscript, the authors present the protocol for an overview of systematic reviews aimed to provide a synthesis of the evidence on the main dementia risk factors in people with a history of cardiovascular disease. The link between cardiovascular disease and dementia risks is a key question for dementia prevention. On this regard, this rigorously planned study aims to/will likely provide clarifications in the large body of evidence currently available, as well as important insights for future dementia-focused research.The manuscript is well written, and the study premises and design are clearly presented. I have only a few minor comments related to specific information to be provided ad their location in the manuscript:- At the end of the methods section of the abstract different “cardiovascular groups” are mentioned (line 41-42). I assume that this refers to the different CVD diagnoses mentioned above (lines 33-34). However, the term cardiovascular group is fairly vague and used only in this instance. Another wording, e.g., “cardiovascular diagnoses” would more clearly explain what these groups include.- Please, state also in the abstract that the overview of systematic review will follow the PRISMA statement/guidelines .- In the “Quality assessment and evidence grading” section, it is not clear whether the result of the AMSTAR assessment will be used to further select studies (e.g., for inclusion/exclusion in the data synthesis). However, in the discussion section (lines 190-192) the potential low quality of the studies included is listed as one of the limitations, which suggest that this criterion will not be applied and low quality studies will be excluded only in sensitivity analysis. Regardless of whether studies will be selected based on the results of the AMSTAR assessment, the authors strategy on this regard should be clearly stated in the methods section and not only in the discussion. In the discussion, a clear explanation of the rationale whereby studies will be included regardless of their quality assessment, which means also studies with quality rated as “low”/”critically low” could be included in the data synthesis, should be provided.- The section “Data Synthesis” lacks crucial details that should be prospectively provided in relation to the data synthesis methods and that are either missing from or presented in other sections (e.g., discussion) of the manuscript. In particular, these include: 1. specific statistics methods that will be applied to assess homogeneity/heterogeneity of the data to select studies for pooling, 2. criteria/cut-offs used to make this selection based on the results of the assessments mentioned in point 1, and 3. planned sensitivity analyses.********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: NoReviewer #2: No[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. 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23 Jun 2022See 'Response to Reviewers' documentSubmitted filename: Response to Reviewers.docxClick here for additional data file.4 Jul 2022Risk factors for dementia in the context of cardiovascular disease: a protocol of an overview of reviewsPONE-D-22-04170R1Dear Dr. Greene,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.Kind regards,Anja K Leist, Professor Dr.Academic EditorPLOS ONEAdditional Editor Comments (optional):Thank you for the careful revision. The manuscript reads very well and contains all elements that have been raised by the reviewers.Reviewers' comments:12 Jul 2022PONE-D-22-04170R1Risk factors for dementia in the context of cardiovascular disease: a protocol of an overview of reviewsDear Dr. Greene:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.If we can help with anything else, please email us at plosone@plos.org.Thank you for submitting your work to PLOS ONE and supporting open access.Kind regards,PLOS ONE Editorial Office Staffon behalf ofProf. Dr. Anja K LeistAcademic EditorPLOS ONE
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