Economic evaluations &nbsp;of strategies targeting pre-diagnosis dementia &nbsp;populations: Protocol for a systematic review

Men Thi Hoang; Alina Zenker; Sanjib Saha; Ulf-Göran Gerdtham; Dominic Trepel

doi:10.12688/hrbopenres.14064.3

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Study Protocol

Revised

Economic evaluations of strategies targeting pre-diagnosis dementia populations: Protocol for a systematic review

[version 3; peer review: 2 approved, 1 approved with reservations]

Men Thi Hoang ^1-3, Alina Zenker^2,4, Sanjib Saha⁴, Ulf-Göran Gerdtham^4,5, Dominic Trepel^1,2,6

Men Thi Hoang ^1-3, Alina Zenker^2,4, [...] Sanjib Saha⁴, Ulf-Göran Gerdtham^4,5, Dominic Trepel^1,2,6

PUBLISHED 29 Sep 2025

Author details Author details

¹ Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Leinster, Ireland
² School of Medicine, Trinity College Dublin, Dublin, Leinster, Ireland
³ Faculty of Business Administration, Van Lang University, Ho Chi Minh City, Vietnam
⁴ Health Economics Unit, Department of Clinical Science (Malmö), Lund University, Lund, Sweden
⁵ Department of Economics, Lund University, Lund, Sweden
⁶ Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland

Men Thi Hoang
Roles: Conceptualization, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing

Alina Zenker
Roles: Conceptualization, Methodology, Project Administration, Writing – Review & Editing

Sanjib Saha
Roles: Conceptualization, Investigation, Supervision, Writing – Review & Editing

Ulf-Göran Gerdtham
Roles: Supervision, Writing – Review & Editing

Dominic Trepel
Roles: Conceptualization, Funding Acquisition, Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Introduction

Dementia remains incurable, and treatment trials are typically conducted after the symptoms manifest, potentially too late in the disease process to alter its course. Thus, it is essential to identify and implement cost-effective strategies targeting individuals who have not yet been formally diagnosed with dementia. This review aims to scrutinise emerging evidence and present a comprehensive summary of cost-effectiveness estimates of all strategies targeting the pre-diagnosis dementia populations.

Method and analysis

A systematic search will be conducted across six electronic databases. All articles will be assessed against pre-defined eligibility criteria through title and abstract screening, and full-text screening phases. Data from the included articles will be extracted using a standardized template. A newly established framework based on the CHEERS 2022 checklist will be applied to assess the reporting quality of the included articles. The entire review process, from screening to data extraction and quality assessment, will be a dual process conducted by two reviewers. Disagreements will be resolved by a third senior reviewer. The extracted data will be synthesised and presented in tables and figures.

Conclusion

This systematic review will present evidence of cost-effectiveness, along with the strengths and limitations of the existing literature. These findings aim to identify existing gaps, thereby informing and guiding the design of future studies in this domain.

Ethics and dissemination

Since this is a systematic review protocol, ethical approval is not required. The results will be published in a peer-reviewed journal, with both raw and summarised data shared through the journal or other open platforms.

Systematic review registration

PROSPERO - CRD42024521521.

Keywords

Cost-effectiveness Analysis, economic evaluation, dementia, Alzheimer's Disease, identification, treatment,

Corresponding author: Men Thi Hoang

Competing interests: No competing interests were disclosed.

Grant information: This study was funded by the Global Brain Health Institute, Economics of Brain Health Project (Project no. 212322).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2025 Hoang MT et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Hoang MT, Zenker A, Saha S et al. Economic evaluations of strategies targeting pre-diagnosis dementia populations: Protocol for a systematic review [version 3; peer review: 2 approved, 1 approved with reservations]. HRB Open Res 2025, 8:11 (https://doi.org/10.12688/hrbopenres.14064.3) First published: 23 Jan 2025, 8:11 (https://doi.org/10.12688/hrbopenres.14064.1) Latest published: 29 Sep 2025, 8:11 (https://doi.org/10.12688/hrbopenres.14064.3)

Revised Amendments from Version 2

We thank the reviewers for their thoughtful comments, which have helped us enhance the clarity and transparency of this protocol.
In the introduction, we included our definition of pre-diagnosis populations.
In the methods section, we specified the search dates within the search strategies, revised the PICO criteria for inclusion and exclusion, and updated the category labels.
Additionally, we expanded the description of the data synthesis by providing further details on cost adjustments and the willingness-to-pay thresholds used to illustrate the cost-effectiveness plane.

See the authors' detailed response to the review by Jiaer Lin
See the authors' detailed response to the review by Joseph Kane
See the authors' detailed response to the review by Amritpal Rehill

Introduction

Dementia is a group of conditions characterised by deterioration of multiple cognitive domains that significantly affects daily functioning. According to the World Health Organization (WHO) over 55 million people worldwide live with dementia, with approximately 10 million new cases emerging annually¹. It is the seventh leading cause of death and contributes to disability and dependency, affecting individuals, caregivers, and society¹.

Currently, there is no cure for dementia, and treatment trials are typically conducted after symptoms manifest, often too late to alter disease progression². Early identification of dementia is crucial for implementing effective treatment and care strategies; however, achieving this remains elusive due to the high prevalence of undiagnosed cases. In high-income countries, the diagnosis rate is approximately 42%, while globally, up to 75% of dementia cases may remain undiagnosed^3,4. Thus, it is essential to identify and implement cost-effective strategies targeting individuals who have not yet been formally diagnosed (i.e., those in the pre-diagnosis dementia populations) to help reduce the rising impact of dementia.

A systematic review is well-suited to examine common characteristics and evaluate the quality of existing literature, thereby aiding in the identification of research gaps and guiding future studies. Previous systematic reviews on the economic evaluation (EE) of dementia have predominantly focused on specific strategies or categories for mild cognitive impairment (MCI) and dementia^5–7, Alzheimer’s disease^8,9 or the examination of methodological techniques employed in EEs, such as model-based EE^10,11. However, a comprehensive review encompassing all strategies specifically targeting pre-diagnosis dementia populations, which include the general population, at-risk groups, and individuals with MCI without detectable AD pathology, is lacking in the literature. Furthermore, most existing reviews are outdated and were conducted between 2008 and 2017^6–11. This systematic review aimed to address these gaps by critically identifying evidence and providing a comprehensive summary of EEs for strategies targeting the pre-diagnosis dementia population.

Method

Registration

This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines¹². The PRISMA-P checklist is provided as part of the Extended Data¹³. The review was registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42024521521). The results will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines¹⁴.

Eligibility criteria

Population: The target population includes individuals at any stage prior to having a formal diagnosis of dementia, such as the general population, people at risk of dementia, those with mild cognitive impairment (MCI), caregivers, and patient-caregiver dyads. The pre-diagnosis dementia population is typically defined by authors who explicitly state that their studies start with a cohort described as having “no dementia,” or as comprising individuals with mild cognitive impairment (MCI) or at-risk population.

Intervention: All strategies targeting individuals in the pre-diagnosis phase of dementia will be considered. To be eligible, interventions needed to demonstrate an intended impact prior to the formal confirmation of dementia. The strategies encompassed: (1) Strategies for identifying people at risk of developing dementia; (2) strategies aimed at modifiable risk factors (such as exercise, nutrition, or cognitive training); and (3) Management-related initiatives, including models of healthcare delivery applied before a dementia diagnosis. Inclusion required that the intervention influence outcomes during the pre-diagnostic period, rather than solely detecting undiagnosed cases for later treatment.

Comparator: The comparison group will contain any of the following: (1) usual care or standard of care or conventional interventions, (2) placebo, (3) doing nothing or without intervention, or (4) any treatment aimed at the pre-defined populations.

Outcomes: Our primary outcomes will be cost-effectiveness assessments, such as incremental cost-effectiveness ratio (ICER), total costs, intervention costs, incremental cost, total effectiveness such as quality-adjusted life-year (QALY), and incremental effectiveness (e.g., incremental QALY).

Study design: Full EEs will be selected for this review. Full EEs were pre-defined according to Drummond’s classification scheme¹⁵. Accordingly, this review will include (1) Cost-Effectiveness Analysis (CEA), cost-utility analysis (CUA), and Cost-Benefit Analysis (CBA), and Cost-Consequence Analysis (CCA).

Settings: The review includes studies conducted in all countries globally, and includes all types of clinical settings.

Exclusion criteria

Articles will be excluded from the review if their:

Populations: do not target pre-diagnosis dementia, or populations with unclear boundaries surrounding diagnosis (i.e., some pre- and some post-diagnosis) or individuals who may only exhibit MCI symptomatology but where neuropathology of dementia has been established (i.e., MCI due to Alzheimer’s Disease (AD)). This is because the criteria for MCI due to AD must be confirmed by biomarkers to determine the likelihood that the syndrome results from the underlying pathophysiology of AD¹⁶.

Interventions: (1) do not specifically target the defined pre-diagnosis populations; (2) the interventions solely detect individuals without a dementia diagnosis and provided risk-reduction or management strategies afterward, meaning they do not generate any impact during the pre-diagnostic phase; (3) studies encompass both the pre-diagnosis and post-diagnosis phases within the same design (for instance, integrating early detection with treatment for individuals already diagnosed). Such studies will be examined in a separate review.

Comparator: do not include any comparator.

Outcomes: do not report economic outcomes.

Study design: (1) partial EEs such as cost-of-illness analysis, efficacy effectiveness evaluation, cost-outcome description; (2) reviews, editorials, letters, commentaries, viewpoint/perspective, conference abstracts; (3) proceedings, protocols, case studies, and (4) are not reported in English.

Search strategy

Potentially relevant literature was identified by systematically searching six electronic databases: Embase, PubMed, Econlit, Web of Science, Cumulative Index to Nursing and Allied Health (CINAHL) and The NHS Economic Evaluation Database (NHS EED). We searched for articles published between January 1, 2000, and January 14, 2025. The details of the search terms are provided in Extended Data¹³.

Study selection

References exported from the six databases will be transferred to EndNote, deduplicated, and then imported into the Covidence (https://www.covidence.org).

The study selection process will be conducted independently by two reviewers. Any disagreement will be resolved by a third reviewer. During the screening process, all titles and abstracts will be independently scanned for relevance, and the full texts of eligible articles will be assessed according to pre-defined inclusion and exclusion criteria.

Data extraction

The data will be extracted into a pre-defined template using Covidence. This process will be conducted independently by two reviewers, and any disagreements will be resolved by a third reviewer.

The extracted items will include:

Study details: Title, author, publication information, country, funding source, study design, population, intervention, comparator, and settings.

Methodology: Type of EEs, type of model (if applicable), time horizon, perspective, type of sensitivity analysis, currency, price, discount rate, method to measure and value costs, and method to measure and value outcomes.

Results: Total costs, incremental cost, total outcomes, incremental outcomes, ICER, NMB, and authors’ conclusions on the cost-effectiveness of the strategies.

Data synthesis

Pre-diagnosis dementia strategies will be categorised into three groups: identification, risk reduction, and others.

Qualitative synthesis will report the number of EE studies in each subgroup. Where studies report both incremental costs and incremental outcomes expressed in QALYs, the incremental cost will be converted to international dollars (value in 2024) using the purchasing power parity from the International Monetary Fund dataset¹⁷, and visually presented on a cost-effectiveness plane to facilitate comparison. Two willingness-to-pay (WTP) benchmarks were used to demonstrate the comparative cost-effectiveness of the strategies: $150,000 per QALY, indicative of the relatively unregulated market context in the United States (US)¹⁸, and £12,936 per QALY, representing the more resource-limited system in the United Kingdom (UK)¹⁹. These values were selected to capture the range between higher and lower reference points. The cost-effectiveness plane is used solely for illustrative purposes, we will not alter the original conclusion regarding the cost-effectiveness of the included articles.

According to the available data and the variation in study quality, method, or design, narrative synthesis provides guidance on the interpretation and reliability of estimates to inform allocation decisions. The extracted data will be presented in a summary table of the key extracted items. Figures will be used to portray the production of studies over time and geographic location.

All systematic review processes aim to adhere to standards set out in the Cochrane Handbook and specifically Chapter 20: Economic evidence²⁰. The results are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines¹⁴. The template for summarising data extracted from each individual study was based on the former template of CRD NHS EED database.

Quality appraisal

The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 checklist was initially piloted to evaluate the reporting quality²¹. However, discrepancies arose during this process owing to varying interpretations by the two reviewers, leading to inconsistencies across items. To address these issues, several meetings were held with senior reviewers (DT and SS), resulting in a modified CHEERS 2022 framework comprising 67 sub-items, categorized as follows: title (two items), abstract (four items), introduction (three items), methods (38 items), results (11 items), discussion (six items), and other relevant information (two items). This adapted framework will be applied to assess reporting quality. Two reviewers will independently assess the reporting quality of the included articles using this framework, with a third reviewer resolving disagreements. All processes will be performed using Covidence.

Results of the reporting quality of included articles will be summarised using the traffic light system (i.e., green: fully satisfied, amber: partially satisfied, or red: where the standard was not achieved). Scoring of individual studies, in line with the framework, will be summarised in the summaries of each paper.

Discussion

EE is a useful analytical technique for informing policy decisions on resource allocation by providing cost-effective evidence for strategies. This systematic review will be the first to specifically target pre-diagnosis dementia populations, addressing a significant gap in the literature.

This review includes both trial-based and model-based EEs. It will not only focus on cost-effectiveness outcomes but also on methodology, data sources, and methods for measuring and valuing the costs and outcomes of existing EEs. Narrative synthesis guides the interpretation and reliability of estimates to inform allocation decision making. The results for incremental costs and incremental QALYs will be displayed on a cost-effectiveness plane when data permits, facilitating decision making.

Additionally, this systematic review will introduce the utilisation of a newly established framework adapted from CHEERS 2022 to assess the reporting quality of the included articles. Reporting quality assessment will be summarised using the traffic light system to visualise existing problems in reporting the quality of existing EEs.

This systematic review will summarise cost-effectiveness evidence, highlighting the strengths and limitations of the current literature. The findings will help identify research gaps, thereby improving the design and development of future research.

Data availability

Underlying data

No data are associated with this article.

Extended data

Figshare: Extended data file - Economic evaluations of strategies targeting pre-diagnosis dementia populations: Protocol for a Systematic Review, https://doi.org/10.6084/m9.figshare.28235993.v2¹³.

This project contains the following extended data:

- PRISMA-P Checklist
- Search strategies

Reporting guidelines

Figshare: PRISMA-P checklist for ‘Economic evaluations of strategies targeting pre-diagnosis dementia populations: Protocol for a Systematic Review’, https://doi.org/10.6084/m9.figshare.28235993.v2¹³.

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Author contributions

All participants participated in this systematic review. MH wrote this protocol. SS and AZ devised the search strategy. DT, SS, MH, and AZ were critically appraised and developed the protocol. All authors read and approved the final version of the protocol.

Faculty Opinions recommended

References

1. World Health Organization: Dementia. Updated 15 March 2023, 2025; Accessed 29 Jul 2025. Reference Source
2. Swaddiwudhipong N, Whiteside DJ, Hezemans FH, et al.: Pre-diagnostic cognitive and functional impairment in multiple sporadic neurodegenerative diseases. Alzheimers Dement. 2023; 19(5): 1752–63. PubMed Abstract | Publisher Full Text
3. Gjøra L, Strand BH, Bergh S, et al.: Prevalence and determinants of diagnosed dementia: a registry linkage study linking diagnosis of dementia in the population-based HUNT study to registry diagnosis of dementia in primary care and Hospitals in Norway. J Alzheimers Dis. 2024; 99(1): 363–375. PubMed Abstract | Publisher Full Text | Free Full Text
4. Gauthier SRNP, Morais J, Webster C: Journey through the diagnosis of dementia. 2021. Reference Source
5. Eaglestone G, Gkaintatzi E, Jiang H, et al.: Cost-effectiveness of non-pharmacological interventions for mild cognitive impairment and dementia: a systematic review of economic evaluations and a review of reviews. Pharmacoecon Open. 2023; 7(6): 887–914. PubMed Abstract | Publisher Full Text | Free Full Text
6. Livingston G, Kelly L, Lewis-Holmes E, et al.: A systematic review of the clinical effectiveness and cost-effectiveness of sensory, psychological and behavioural interventions for managing agitation in older adults with dementia. Health Technol Assess. 2014; 18(39): 1–226, v–vi. PubMed Abstract | Publisher Full Text | Free Full Text
7. Pimouguet C, Lavaud T, Dartigues JF, et al.: Dementia case management effectiveness on health care costs and resource utilization: a systematic review of randomized controlled trials. J Nutr Health Aging. 2010; 14(8): 669–76. PubMed Abstract | Publisher Full Text
8. Oremus M: Systematic review of economic evaluations of Alzheimer's Disease medications. Expert Rev Pharmacoecon Outcomes Res. 2008; 8(3): 273–89. PubMed Abstract | Publisher Full Text
9. Pouryamout L, Dams J, Wasem J, et al.: Economic evaluation of treatment options in patients with Alzheimer's Disease: a systematic review of cost-effectiveness analyses. Drugs. 2012; 72(6): 789–802. PubMed Abstract | Publisher Full Text
10. Nguyen KH, Comans TA, Green C, et al.: Where are we at with model-based economic evaluations of interventions for dementia? A systematic review and quality assessment. Int Psychogeriatr. 2018; 30(11): 1593–605. PubMed Abstract | Publisher Full Text
11. Hernandez L, Ozen A, Dossantos R, et al.: Systematic review of model-based economic evaluations of treatments for Alzheimer’s Disease. Pharmacoeconomics. 2016; 34(7): 681–707. PubMed Abstract | Publisher Full Text
12. Shamseer L, Moher D, Clarke M, et al.: Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015; 350: g7647. PubMed Abstract | Publisher Full Text
13. Hoang M, Zenker A, Saha S, et al.: Extended data file - Economic evaluations of strategies targeting pre-diagnosis dementia populations: protocol for a Systematic Review. http://www.doi.org/10.6084/m9.figshare.28235993.v2
14. Moher D, Liberati A, Tetzlaff J, et al.: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010; 8(5): 336–41. PubMed Abstract | Publisher Full Text
15. Drummond MF, Sculpher MJ, Claxton K, et al.: Methods for the economic evaluation of health care programmes. Fourth edition ed. Oxford University Press, 2015. Reference Source
16. Albert MS, DeKosky ST, Dickson D, et al.: The diagnosis of mild cognitive impairment due to Alzheimer's Disease: recommendations from the national institute on aging-alzheimer's association workgroups on diagnostic guidelines for Alzheimer's Disease. Alzheimers Dement. 2011; 7(3): 270–9. PubMed Abstract | Publisher Full Text | Free Full Text
17. Shemilt I, James T, Marcello M: A web-based tool for adjusting costs to a specific target currency and price year. Evidence & Policy. 2010; 6(1): 51–59. Publisher Full Text
18. Neumann PJ, Kim DD: Cost-effectiveness thresholds used by study authors, 1990–2021. JAMA. 2023; 329(15): 1312–1314. PubMed Abstract | Publisher Full Text | Free Full Text
19. Claxton K, Martin S, Soares M, et al.: Methods for the estimation of the National Institute for Health and Care Excellence cost-effectiveness threshold. Health Technol Assess. 2015; 19(14): 1–503, v-vi. PubMed Abstract | Publisher Full Text | Free Full Text
20. Higgins T, Thomas J, Chandler J, et al.: Cochrane handbook for systematic reviews of interventions version 6.5 (updated August 2024): Chapter 20: Economic evidence. 2024. Reference Source
21. Husereau D, Drummond M, Augustovski F, et al.: Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 explanation and elaboration: a report of the ISPOR CHEERS II good practices task force. Value Health. 2022; 25(1): 10–31. PubMed Abstract | Publisher Full Text

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Version 3

VERSION 3 PUBLISHED 23 Jan 2025

Author details Author details

Men Thi Hoang
Roles: Conceptualization, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing

Alina Zenker
Roles: Conceptualization, Methodology, Project Administration, Writing – Review & Editing

Sanjib Saha
Roles: Conceptualization, Investigation, Supervision, Writing – Review & Editing

Ulf-Göran Gerdtham
Roles: Supervision, Writing – Review & Editing

Dominic Trepel
Roles: Conceptualization, Funding Acquisition, Supervision, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

This study was funded by the Global Brain Health Institute, Economics of Brain Health Project (Project no. 212322).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (3)

version 3

Revised

Published: 29 Sep 2025, 8:11

https://doi.org/10.12688/hrbopenres.14064.3

version 2

Revised

Published: 03 Mar 2025, 8:11

https://doi.org/10.12688/hrbopenres.14064.2

version 1

Published: 23 Jan 2025, 8:11

https://doi.org/10.12688/hrbopenres.14064.1

© 2025 Hoang MT et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Hoang MT, Zenker A, Saha S et al. Economic evaluations of strategies targeting pre-diagnosis dementia populations: Protocol for a systematic review [version 3; peer review: 2 approved, 1 approved with reservations]. HRB Open Res 2025, 8:11 (https://doi.org/10.12688/hrbopenres.14064.3)

NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Key to Reviewer Statuses VIEW HIDE

ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions

Version 2

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PUBLISHED 03 Mar 2025

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Reviewer Report 27 Mar 2025

Amritpal Rehill, London School of Economics and Political Science, London, UK

Approved

https://doi.org/10.21956/hrbopenres.15492.r46287

The authors have done a good job in producing a well written and well considered protocol. They have convincingly justified why it is important to look at the pre-diagnosis dementia population to maximise the potential effect of intervening. The methods are described in detail, including what databases will be searched, what criteria for inclusion/exclusion will be used, what data will be extracted and how results will be presented. I would be interested in reading the resulting review. I have a few comment/suggestions, as follows:

It might be a good idea to briefly discuss how accurately we can currently predict who may or may not go on to have dementia in the future. It was mentioned that pharmacological interventions in the pre-diagnosis context were to be considered- presumably it would be preferred to go ahead with this for those we are particularly confident will go on to be diagnosed with dementia.
Is there a cut-off in terms of how old a study can be to be included in the review? Tied to this, for older studies, something that might be considered is that costs for different components of the interventions may be different now compared to in the past (especially if technology was involved, or if specific drugs are no longer under patent). It might be that cost-effectiveness of some interventions may be different if the intervention were provided today, however without being able to repeat the original study this might need to be listed as a limitation.
Tied to the above, under study details extracted, it may be useful for the year(s) in which the intervention was administered to be extracted.
On similar lines to time, place may also play a factor in determining cost-effectiveness. As an example, for a given intervention, studies from the US and UK may suggest it is cost-effective, but there might not be studies from other countries and there might be reasons so suggest cost-effectiveness might not hold true in other settings (e.g. in developing countries), where costs may differ. I was wondering if the authors were planning to evaluate/comment on the generalisability of the resulting cost-effectiveness estimates.
Alongside evaluating cost-effectiveness, I was wondering if there were any plans to discuss potential differences regarding implementation. For example, a group intervention studied in the US/UK may have been found to be cost-effective, but for those living in a different country where there is more stigma around dementia, individuals may not want to attend group sessions to receive the intervention. I appreciate that this is not the core focus of the study, but I think providing a brief description of this to speak to the generalisability of results where studies exist only in a few similar countries/settings would help to contextualise the findings.
It is fantastic to see that the focus is not only on cost-effectiveness but also on methods and methods used to calculate costs. Currently there is no consensus on how best to value hours of unpaid care (e.g. replacement cost approach or opportunity cost approach), and this decision can have a large impact on the ultimate cost-effectiveness calculation. This alongside other methodological decisions being noted/tracked/compared should prove useful.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: I am a quantitative researcher in the area of social care and have worked on numerous projects involving people with dementia. This has included multiple economic evaluations of trials for non-pharmacological interventions for people with dementia, as well as projecting costs and outcomes for both people with dementia and their carers.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Author Response 29 Sep 2025

Men Hoang, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

29 Sep 2025

Author Response

1. It might be a good idea to briefly discuss how accurately we can currently predict who may or may not go on to have dementia in the future. It ... Continue reading 1. It might be a good idea to briefly discuss how accurately we can currently predict who may or may not go on to have dementia in the future. It was mentioned that pharmacological interventions in the pre-diagnosis context were to be considered- presumably it would be preferred to go ahead with this for those we are particularly confident will go on to be diagnosed with dementia.
Response: We appreciate your review of our protocol and the insightful comments you provided. We will think about this point in our review and discuss its implications for identifying appropriate target populations.

2. Is there a cut-off in terms of how old a study can be to be included in the review?
Response: Thank you for your thoughtful comment. We include all publications from January 1, 2000, to January 14, 2025.
We added a sentence in the protocol:
“We searched for articles published between January 1, 2000, and January 14, 2025.”

Tied to this, for older studies, something that might be considered is that costs for different components of the interventions may be different now compared to in the past (especially if technology was involved, or if specific drugs are no longer under patent). It might be that cost-effectiveness of some interventions may be different if the intervention were provided today, however without being able to repeat the original study this might need to be listed as a limitation.
Response: In our review:
1) We adjust cost of intervention up to 2024 value and convert to int$
2) We will consider mentioning this limitation of simple adjustments in discussing the final paper.

3. Tied to the above, under study details extracted, it may be useful for the year(s) in which the intervention was administered to be extracted.
Response: Thank you for your comment. In our review, we extract the year of publication and price year when costs were reported (if available).

4. On similar lines to time, place may also play a factor in determining cost-effectiveness. As an example, for a given intervention, studies from the US and UK may suggest it is cost-effective, but there might not be studies from other countries and there might be reasons so suggest cost-effectiveness might not hold true in other settings (e.g. in developing countries), where costs may differ.
Response: 4. Thank you for your suggestion. Indeed, we will have a paragraph to discuss country-specific decision-making in considering the cost-effectiveness of interventions in our review manuscript based on the final extracted data.

I was wondering if the authors were planning to evaluate/comment on the generalisability of the resulting cost-effectiveness estimates
Response: Two willingness-to-pay (WTP) benchmarks were used to demonstrate the comparative cost-effectiveness of the strategies: $150,000 per QALY, indicative of the relatively unregulated market context in the United States (US) 18, and £12,936 per QALY, representing the more resource-limited system in the United Kingdom (UK)19. These values were selected to capture the range between higher and lower reference points. The cost-effectiveness plane is used solely for illustrative purposes, we will not alter the original conclusion regarding the cost-effectiveness of the included articles.

5. Alongside evaluating cost-effectiveness, I was wondering if there were any plans to discuss potential differences regarding implementation.
For example, a group intervention studied in the US/UK may have been found to be cost-effective, but for those living in a different country where there is more stigma around dementia, individuals may not want to attend group sessions to receive the intervention.
I appreciate that this is not the core focus of the study, but I think providing a brief description of this to speak to the generalisability of results where studies exist only in a few similar countries/settings would help to contextualise the findings.
Response: Thank you for your thoughtful comment. We will take your suggestion into account in the discussion section of our review. Exploration of whether included studies were actually implemented is a very good suggestion but is unfortunately beyond the scope at this time. In the final paper, we will discuss this as a recommendation from this review. The point on generalisability is well taken and, at this protocol paper stage (for the benefit of non-economists.

6. It is fantastic to see that the focus is not only on cost-effectiveness but also on methods and methods used to calculate costs. Currently there is no consensus on how best to value hours of unpaid care (e.g. replacement cost approach or opportunity cost approach), and this decision can have a large impact on the ultimate cost-effectiveness calculation. This alongside other methodological decisions being noted/tracked/compared should prove useful.
Response: Thank you for your comment. For each included article, we will summarise its details, such as: title, purpose, country, funding source, type of EE, study design, type of model (if applicable), time horizon, perspective, population, intervention, comparator, resource measurement, utility measurement, uncertainty analysis, currency and price year, discount, quality of article in terms of our newly developed framework to provide an objecty score from CHEERS checklist, economic measure in terms of total cost, total QALY, incremental cost and QALY, intervention cost.

We wholeheartedly agree with this limitation in the literature and, informed by and conducted in parallel to this review, we are conducting work to reach greater consensus (Trepel, D. (2019). Core outcome set for economic evaluation of dementia interventions. COMET Initiative. Retrieved April 7, 2025, from https://www.comet-initiative.org/Studies/Details/1737). This review, along with reviews of post diagnostic EEs (Scanlon, H., Saha, S., Trepel, D. (2024). Economic evaluations of interventions for people living with dementia and their caregivers: A systematic review and core outcome set of resource use. ResearchGate), are extracting data on varying resource use data, and this will inform a consensus exercise to ultimately produce a core outcomes set for future dementia economic evaluation. To extend this discussion, we will also extract which unit costs are applied to informal care across EEs.
1. It might be a good idea to briefly discuss how accurately we can currently predict who may or may not go on to have dementia in the future. It was mentioned that pharmacological interventions in the pre-diagnosis context were to be considered- presumably it would be preferred to go ahead with this for those we are particularly confident will go on to be diagnosed with dementia.
Response: We appreciate your review of our protocol and the insightful comments you provided. We will think about this point in our review and discuss its implications for identifying appropriate target populations.

2. Is there a cut-off in terms of how old a study can be to be included in the review?
Response: Thank you for your thoughtful comment. We include all publications from January 1, 2000, to January 14, 2025.
We added a sentence in the protocol:
“We searched for articles published between January 1, 2000, and January 14, 2025.”

Tied to this, for older studies, something that might be considered is that costs for different components of the interventions may be different now compared to in the past (especially if technology was involved, or if specific drugs are no longer under patent). It might be that cost-effectiveness of some interventions may be different if the intervention were provided today, however without being able to repeat the original study this might need to be listed as a limitation.
Response: In our review:
1) We adjust cost of intervention up to 2024 value and convert to int$
2) We will consider mentioning this limitation of simple adjustments in discussing the final paper.

3. Tied to the above, under study details extracted, it may be useful for the year(s) in which the intervention was administered to be extracted.
Response: Thank you for your comment. In our review, we extract the year of publication and price year when costs were reported (if available).

4. On similar lines to time, place may also play a factor in determining cost-effectiveness. As an example, for a given intervention, studies from the US and UK may suggest it is cost-effective, but there might not be studies from other countries and there might be reasons so suggest cost-effectiveness might not hold true in other settings (e.g. in developing countries), where costs may differ.
Response: 4. Thank you for your suggestion. Indeed, we will have a paragraph to discuss country-specific decision-making in considering the cost-effectiveness of interventions in our review manuscript based on the final extracted data.

I was wondering if the authors were planning to evaluate/comment on the generalisability of the resulting cost-effectiveness estimates
Response: Two willingness-to-pay (WTP) benchmarks were used to demonstrate the comparative cost-effectiveness of the strategies: $150,000 per QALY, indicative of the relatively unregulated market context in the United States (US) 18, and £12,936 per QALY, representing the more resource-limited system in the United Kingdom (UK)19. These values were selected to capture the range between higher and lower reference points. The cost-effectiveness plane is used solely for illustrative purposes, we will not alter the original conclusion regarding the cost-effectiveness of the included articles.

5. Alongside evaluating cost-effectiveness, I was wondering if there were any plans to discuss potential differences regarding implementation.
For example, a group intervention studied in the US/UK may have been found to be cost-effective, but for those living in a different country where there is more stigma around dementia, individuals may not want to attend group sessions to receive the intervention.
I appreciate that this is not the core focus of the study, but I think providing a brief description of this to speak to the generalisability of results where studies exist only in a few similar countries/settings would help to contextualise the findings.
Response: Thank you for your thoughtful comment. We will take your suggestion into account in the discussion section of our review. Exploration of whether included studies were actually implemented is a very good suggestion but is unfortunately beyond the scope at this time. In the final paper, we will discuss this as a recommendation from this review. The point on generalisability is well taken and, at this protocol paper stage (for the benefit of non-economists.

6. It is fantastic to see that the focus is not only on cost-effectiveness but also on methods and methods used to calculate costs. Currently there is no consensus on how best to value hours of unpaid care (e.g. replacement cost approach or opportunity cost approach), and this decision can have a large impact on the ultimate cost-effectiveness calculation. This alongside other methodological decisions being noted/tracked/compared should prove useful.
Response: Thank you for your comment. For each included article, we will summarise its details, such as: title, purpose, country, funding source, type of EE, study design, type of model (if applicable), time horizon, perspective, population, intervention, comparator, resource measurement, utility measurement, uncertainty analysis, currency and price year, discount, quality of article in terms of our newly developed framework to provide an objecty score from CHEERS checklist, economic measure in terms of total cost, total QALY, incremental cost and QALY, intervention cost.

We wholeheartedly agree with this limitation in the literature and, informed by and conducted in parallel to this review, we are conducting work to reach greater consensus (Trepel, D. (2019). Core outcome set for economic evaluation of dementia interventions. COMET Initiative. Retrieved April 7, 2025, from https://www.comet-initiative.org/Studies/Details/1737). This review, along with reviews of post diagnostic EEs (Scanlon, H., Saha, S., Trepel, D. (2024). Economic evaluations of interventions for people living with dementia and their caregivers: A systematic review and core outcome set of resource use. ResearchGate), are extracting data on varying resource use data, and this will inform a consensus exercise to ultimately produce a core outcomes set for future dementia economic evaluation. To extend this discussion, we will also extract which unit costs are applied to informal care across EEs.
Competing Interests: No competing interests were disclosed. Close
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COMMENTS ON THIS REPORT

Author Response 29 Sep 2025

Men Hoang, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

29 Sep 2025

Author Response

1. It might be a good idea to briefly discuss how accurately we can currently predict who may or may not go on to have dementia in the future. It ... Continue reading 1. It might be a good idea to briefly discuss how accurately we can currently predict who may or may not go on to have dementia in the future. It was mentioned that pharmacological interventions in the pre-diagnosis context were to be considered- presumably it would be preferred to go ahead with this for those we are particularly confident will go on to be diagnosed with dementia.
Response: We appreciate your review of our protocol and the insightful comments you provided. We will think about this point in our review and discuss its implications for identifying appropriate target populations.

2. Is there a cut-off in terms of how old a study can be to be included in the review?
Response: Thank you for your thoughtful comment. We include all publications from January 1, 2000, to January 14, 2025.
We added a sentence in the protocol:
“We searched for articles published between January 1, 2000, and January 14, 2025.”

Tied to this, for older studies, something that might be considered is that costs for different components of the interventions may be different now compared to in the past (especially if technology was involved, or if specific drugs are no longer under patent). It might be that cost-effectiveness of some interventions may be different if the intervention were provided today, however without being able to repeat the original study this might need to be listed as a limitation.
Response: In our review:
1) We adjust cost of intervention up to 2024 value and convert to int$
2) We will consider mentioning this limitation of simple adjustments in discussing the final paper.

3. Tied to the above, under study details extracted, it may be useful for the year(s) in which the intervention was administered to be extracted.
Response: Thank you for your comment. In our review, we extract the year of publication and price year when costs were reported (if available).

4. On similar lines to time, place may also play a factor in determining cost-effectiveness. As an example, for a given intervention, studies from the US and UK may suggest it is cost-effective, but there might not be studies from other countries and there might be reasons so suggest cost-effectiveness might not hold true in other settings (e.g. in developing countries), where costs may differ.
Response: 4. Thank you for your suggestion. Indeed, we will have a paragraph to discuss country-specific decision-making in considering the cost-effectiveness of interventions in our review manuscript based on the final extracted data.

I was wondering if the authors were planning to evaluate/comment on the generalisability of the resulting cost-effectiveness estimates
Response: Two willingness-to-pay (WTP) benchmarks were used to demonstrate the comparative cost-effectiveness of the strategies: $150,000 per QALY, indicative of the relatively unregulated market context in the United States (US) 18, and £12,936 per QALY, representing the more resource-limited system in the United Kingdom (UK)19. These values were selected to capture the range between higher and lower reference points. The cost-effectiveness plane is used solely for illustrative purposes, we will not alter the original conclusion regarding the cost-effectiveness of the included articles.

5. Alongside evaluating cost-effectiveness, I was wondering if there were any plans to discuss potential differences regarding implementation.
For example, a group intervention studied in the US/UK may have been found to be cost-effective, but for those living in a different country where there is more stigma around dementia, individuals may not want to attend group sessions to receive the intervention.
I appreciate that this is not the core focus of the study, but I think providing a brief description of this to speak to the generalisability of results where studies exist only in a few similar countries/settings would help to contextualise the findings.
Response: Thank you for your thoughtful comment. We will take your suggestion into account in the discussion section of our review. Exploration of whether included studies were actually implemented is a very good suggestion but is unfortunately beyond the scope at this time. In the final paper, we will discuss this as a recommendation from this review. The point on generalisability is well taken and, at this protocol paper stage (for the benefit of non-economists.

6. It is fantastic to see that the focus is not only on cost-effectiveness but also on methods and methods used to calculate costs. Currently there is no consensus on how best to value hours of unpaid care (e.g. replacement cost approach or opportunity cost approach), and this decision can have a large impact on the ultimate cost-effectiveness calculation. This alongside other methodological decisions being noted/tracked/compared should prove useful.
Response: Thank you for your comment. For each included article, we will summarise its details, such as: title, purpose, country, funding source, type of EE, study design, type of model (if applicable), time horizon, perspective, population, intervention, comparator, resource measurement, utility measurement, uncertainty analysis, currency and price year, discount, quality of article in terms of our newly developed framework to provide an objecty score from CHEERS checklist, economic measure in terms of total cost, total QALY, incremental cost and QALY, intervention cost.

We wholeheartedly agree with this limitation in the literature and, informed by and conducted in parallel to this review, we are conducting work to reach greater consensus (Trepel, D. (2019). Core outcome set for economic evaluation of dementia interventions. COMET Initiative. Retrieved April 7, 2025, from https://www.comet-initiative.org/Studies/Details/1737). This review, along with reviews of post diagnostic EEs (Scanlon, H., Saha, S., Trepel, D. (2024). Economic evaluations of interventions for people living with dementia and their caregivers: A systematic review and core outcome set of resource use. ResearchGate), are extracting data on varying resource use data, and this will inform a consensus exercise to ultimately produce a core outcomes set for future dementia economic evaluation. To extend this discussion, we will also extract which unit costs are applied to informal care across EEs.
1. It might be a good idea to briefly discuss how accurately we can currently predict who may or may not go on to have dementia in the future. It was mentioned that pharmacological interventions in the pre-diagnosis context were to be considered- presumably it would be preferred to go ahead with this for those we are particularly confident will go on to be diagnosed with dementia.
Response: We appreciate your review of our protocol and the insightful comments you provided. We will think about this point in our review and discuss its implications for identifying appropriate target populations.

2. Is there a cut-off in terms of how old a study can be to be included in the review?
Response: Thank you for your thoughtful comment. We include all publications from January 1, 2000, to January 14, 2025.
We added a sentence in the protocol:
“We searched for articles published between January 1, 2000, and January 14, 2025.”

Tied to this, for older studies, something that might be considered is that costs for different components of the interventions may be different now compared to in the past (especially if technology was involved, or if specific drugs are no longer under patent). It might be that cost-effectiveness of some interventions may be different if the intervention were provided today, however without being able to repeat the original study this might need to be listed as a limitation.
Response: In our review:
1) We adjust cost of intervention up to 2024 value and convert to int$
2) We will consider mentioning this limitation of simple adjustments in discussing the final paper.

3. Tied to the above, under study details extracted, it may be useful for the year(s) in which the intervention was administered to be extracted.
Response: Thank you for your comment. In our review, we extract the year of publication and price year when costs were reported (if available).

4. On similar lines to time, place may also play a factor in determining cost-effectiveness. As an example, for a given intervention, studies from the US and UK may suggest it is cost-effective, but there might not be studies from other countries and there might be reasons so suggest cost-effectiveness might not hold true in other settings (e.g. in developing countries), where costs may differ.
Response: 4. Thank you for your suggestion. Indeed, we will have a paragraph to discuss country-specific decision-making in considering the cost-effectiveness of interventions in our review manuscript based on the final extracted data.

I was wondering if the authors were planning to evaluate/comment on the generalisability of the resulting cost-effectiveness estimates
Response: Two willingness-to-pay (WTP) benchmarks were used to demonstrate the comparative cost-effectiveness of the strategies: $150,000 per QALY, indicative of the relatively unregulated market context in the United States (US) 18, and £12,936 per QALY, representing the more resource-limited system in the United Kingdom (UK)19. These values were selected to capture the range between higher and lower reference points. The cost-effectiveness plane is used solely for illustrative purposes, we will not alter the original conclusion regarding the cost-effectiveness of the included articles.

5. Alongside evaluating cost-effectiveness, I was wondering if there were any plans to discuss potential differences regarding implementation.
For example, a group intervention studied in the US/UK may have been found to be cost-effective, but for those living in a different country where there is more stigma around dementia, individuals may not want to attend group sessions to receive the intervention.
I appreciate that this is not the core focus of the study, but I think providing a brief description of this to speak to the generalisability of results where studies exist only in a few similar countries/settings would help to contextualise the findings.
Response: Thank you for your thoughtful comment. We will take your suggestion into account in the discussion section of our review. Exploration of whether included studies were actually implemented is a very good suggestion but is unfortunately beyond the scope at this time. In the final paper, we will discuss this as a recommendation from this review. The point on generalisability is well taken and, at this protocol paper stage (for the benefit of non-economists.

6. It is fantastic to see that the focus is not only on cost-effectiveness but also on methods and methods used to calculate costs. Currently there is no consensus on how best to value hours of unpaid care (e.g. replacement cost approach or opportunity cost approach), and this decision can have a large impact on the ultimate cost-effectiveness calculation. This alongside other methodological decisions being noted/tracked/compared should prove useful.
Response: Thank you for your comment. For each included article, we will summarise its details, such as: title, purpose, country, funding source, type of EE, study design, type of model (if applicable), time horizon, perspective, population, intervention, comparator, resource measurement, utility measurement, uncertainty analysis, currency and price year, discount, quality of article in terms of our newly developed framework to provide an objecty score from CHEERS checklist, economic measure in terms of total cost, total QALY, incremental cost and QALY, intervention cost.

We wholeheartedly agree with this limitation in the literature and, informed by and conducted in parallel to this review, we are conducting work to reach greater consensus (Trepel, D. (2019). Core outcome set for economic evaluation of dementia interventions. COMET Initiative. Retrieved April 7, 2025, from https://www.comet-initiative.org/Studies/Details/1737). This review, along with reviews of post diagnostic EEs (Scanlon, H., Saha, S., Trepel, D. (2024). Economic evaluations of interventions for people living with dementia and their caregivers: A systematic review and core outcome set of resource use. ResearchGate), are extracting data on varying resource use data, and this will inform a consensus exercise to ultimately produce a core outcomes set for future dementia economic evaluation. To extend this discussion, we will also extract which unit costs are applied to informal care across EEs.
Competing Interests: No competing interests were disclosed. Close
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Reviewer Report 22 Mar 2025

Jiaer Lin, The Chinese University of Hong Kong (CUHK), Hong Kong, Hong Kong

Approved with Reservations

https://doi.org/10.21956/hrbopenres.15492.r46288

There are some points are not clear and please consider to clarify:

Introduction:
1. Is there any definition for pre-diagnosis stage in either clinical practice or research?
2. What’s the differences with MCI? If prior research have already reviewed those MCI, what value of this research will be contributed to?

Methods:
Eligibility
1. For the target population, how to identify if the articles includes individuals at any stage prior dementia diagnosis? By what definition or any tests (e.g., MMSE) used? If by tests, what results are considered to be eligible?
2. Intervention: Would it be possible that (3) non-pharmacotherapy have already included (4) management strategies at home, in the community, and in long-term care?
3. Outcomes: Please specify what perspective the authors decided to adopt when reporting the cost outcomes, will the authors include all cost items? Or only for one perspective? If for all, how about costs that published in separate articles?
4. Study design:
- Trail-based and model-based EEs are very different study types. For model-based, additional information such as modeling technique, parameters, etc.
are important and should also be considered and specified clearly.
- Will the authors consider include multiple (≥2) articles that published for the same intervention for different outcomes, say cost outcomes in one article and effectiveness such as clinical outcomes in anthter.

Data synthesis
1. There are three guidelines that provides instructions of
conducting systematic review on cost-effectiveness studies (Cochrane HandBook, CRD from York, and ISPOR), the authors should consider to follow one of each for the data synthesis process.
2. The authors stated that "Where studies report both total costs and outcomes expressed in QALYs, results will be adjusted and will be visually presented on a cost-effectiveness plane to facilitate decision-making." The authors should clarify more details for the following points;
- How to adjust the results?
- How about costs in different countries? Any standardized method will be used?
- What threshold of williness-to-pay will the authors use to present the cost-effectiveness plane?
- Will this study conclude with which strategy is cost-effective/cost-saving or not, how?
- There are others details need to consider especially for model-based EEs. The authors could reconsider whether to include model-based studies or not.

Quality appraisal
In addition to the methodological quality of the EEs, the authors should also evaluate the publication bias of the included studies, following the Cochrane guideline. The authors can take our prior systematic review as reference for the methodology.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Yes

References

1. Huo Z, Chan JYC, Lin J, Bat BKK, et al.: Supporting Informal Caregivers of People With Dementia in Cost-Effective Ways: A Systematic Review and Meta-Analysis.Value Health. 2021; 24 (12): 1853-1862 PubMed Abstract | Publisher Full Text
2. Huo Z, Chan J, Lin J, Bat B, et al.: Cost‐effectiveness of non‐pharmacological interventions for patients with dementia: A systematic review and meta‐analysis. Alzheimer's & Dementia. 2021; 17 (S10). Publisher Full Text
3. Huo Z, Lin J, Bat BKK, Chan TK, et al.: Cost-effectiveness of pharmacological therapies for people with Alzheimer's disease and other dementias: a systematic review and meta-analysis.Cost Eff Resour Alloc. 2022; 20 (1): 19 PubMed Abstract | Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: I am a health economist and have been published work on systematic reviews related to dementia care and integrated care.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

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Author Response 29 Sep 2025

Men Hoang, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

29 Sep 2025

Author Response

Thank you for taking the time to review our protocol.
Introduction:
1. Is there any definition for pre-diagnosis stage in either clinical practice or research?
Response: Thank you for your comments.
... Continue reading Thank you for taking the time to review our protocol.
Introduction:
1. Is there any definition for pre-diagnosis stage in either clinical practice or research?
Response: Thank you for your comments.
In the literature, we found this paper defined “"Pre-diagnosis was defined as the period from the initial onset of symptoms up to the formal diagnosis”. (https://doi.org/10.1017/S1041610217000862)
In our review, we added a sentence to clarify the definition of the pre-diagnosis dementia population as “individuals who have not yet been formally diagnosed”.

“Thus, it is essential to identify and implement cost-effective strategies targeting individuals who have not yet been formally diagnosed (i.e., those in the pre-diagnosis dementia populations) to help reduce the rising impact of dementia”.
2. What’s the differences with MCI? If prior research have already reviewed those MCI, what value of this research will be contributed to?
Response: In our review, pre-diagnosis dementia populations are broader than MCI.
In the introduction, we added a sentence for clarification. “However, a comprehensive review encompassing all strategies specifically targeting pre-diagnosis dementia populations, which include the general population, at-risk groups, and individuals with MCI without detectable AD pathology, is lacking in the literature.”

Methods:
Eligibility
1. For the target population, how to identify if the articles includes individuals at any stage prior dementia diagnosis? By what definition or any tests (e.g., MMSE) used? If by tests, what results are considered to be eligible?
Response: 1. We identified the target population according to how the authors described the target populations in their economic evaluations. We added following sentence in our protocol:
“The pre-diagnosis dementia population is typically defined by authors who explicitly state that their studies start with a cohort described as having “no dementia,” or as comprising individuals with mild cognitive impairment (MCI) or at-risk population.”

2. Intervention: Would it be possible that (3) non-pharmacotherapy have already included (4) management strategies at home, in the community, and in long-term care?
Response: We revised the protocol and categorised interventions into three groups: identification, risk reduction, and others. The latter group will compass studies that do not fall into either identification or risk reduction.

3. Outcomes: Please specify what perspective the authors decided to adopt when reporting the cost outcomes, will the authors include all cost items? Or only for one perspective? If for all, how about costs that published in separate articles?
Response:  We do not adopt any perspective whilst critically appraising the literature. But rather, we "document stated perspectives" . We extracted the average total cost and intervention cost (if reported) as they may (or may not) relate to stated perspectives.

4. Study design:
- Trail-based and model-based EEs are very different study types. For model-based, additional information such as modeling technique, parameters, etc.
are important and should also be considered and specified clearly.
Response: We include articles as long as they are considered full economic evaluations according to Drummond’s classification scheme. This means we include both trial-based and model-based full economic evaluations.
- Will the authors consider include multiple (≥2) articles that published for the same intervention for different outcomes, say cost outcomes in one article and effectiveness such as clinical outcomes in anthter.
Response: The data extraction stage is a memoryless process and no attempt is made to cross reference studies to check if multiple articles were published from the same study of a single intervention. However, at analysis, where there is sufficient evidence of duplication of reporting the same findings, the study would be flagged as such.

Data synthesis
1. There are three guidelines that provides instructions of conducting systematic review on cost-effectiveness studies (Cochrane HandBook, CRD from York, and ISPOR), the authors should consider to follow one of each for the data synthesis process.
Response: Thank you for your suggestion. All systematic review processes aim to adhere to standards set out in the Cochrane Handbook and specifically Chapter 20: Economic evidence.
The results are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
The template for summarising data extracted from each individual study was based on the former template of CRD NHS EED database.

2. The authors stated that "Where studies report both total costs and outcomes expressed in QALYs, results will be adjusted and will be visually presented on a cost-effectiveness plane to facilitate decision-making." The authors should clarify more details for the following points;
- How to adjust the results?
- How about costs in different countries? Any standardized method will be used?
Response: Thanks to your comment, we identify there is an error in our statement (i.e it should be incremental cost not total cost).The cost-effectiveness plane is used solely for illustrative purposes but adjustments are required:We used CPI and PPP method, converted cost to international dollar in 2024 prices. We added in the protocol as:“the incremental cost will be converted to international dollars (value in 2024) using the purchasing power parity from the International Monetary Fund dataset ¹⁷, and visually presented on a cost-effectiveness plane to facilitate comparison.”

- What threshold of williness-to-pay will the authors use to present the cost-effectiveness plane?
Response: Two willingness-to-pay (WTP) benchmarks were used to demonstrate the comparative cost-effectiveness of the strategies: $150,000 per QALY, indicative of the relatively unregulated market context in the United States (US) 18, and £12,936 per QALY, representing the more resource-limited system in the United Kingdom (UK)19. These values were selected to capture the range between higher and lower reference points.

- Will this study conclude with which strategy is cost-effective/cost-saving or not, how?
Response: Based on the CE-plane, we can see if the intervention is in the dominant quadrant. The cost-effectiveness plane is used solely for illustrative purposes, we will not alter the original conclusion regarding the cost-effectiveness of the included articles. The intention of this review is not to determine whether any given strategy is cost effective or not (because, as the reviewer indicates, different countries will have different willingness to pay threshold). Rather, the intention is to systematically identify and critical appraisal all relevant studies. By extension, the illustration on the cost effectiveness plane provide a synthesis for comparison of the relative efficiency of each approach, however, this is not intended to endorse use in any jurisdiction but rather encourage countries to conduct their own country level appraisal (in which they may opt to adapt analyses highlighted by our review).

- There are others details need to consider especially for model-based EEs. The authors could reconsider whether to include model-based studies or not?
Response: The article is intended to provide a compendium of all EEs for non-economist audience and, as part of the wider work, we wish this to help readers understand there are two main sources of cost-effectiveness evidence.

Quality appraisal
In addition to the methodological quality of the EEs, the authors should also evaluate the publication bias of the included studies, following the Cochrane guideline. The authors can take our prior systematic review as reference for the methodology.
Response: Thank you for your advice. In EE, we do not have publication bias estimation. But in many reviews, they estimate the publication bias of the included intervention. We are not doing that in this review.

Once again, thank you very much for providing comments. We believe that your comments will help us in improving the clarification and transparency of this protocol
Thank you for taking the time to review our protocol.
Introduction:
1. Is there any definition for pre-diagnosis stage in either clinical practice or research?
Response: Thank you for your comments.
In the literature, we found this paper defined “"Pre-diagnosis was defined as the period from the initial onset of symptoms up to the formal diagnosis”. (https://doi.org/10.1017/S1041610217000862)
In our review, we added a sentence to clarify the definition of the pre-diagnosis dementia population as “individuals who have not yet been formally diagnosed”.

“Thus, it is essential to identify and implement cost-effective strategies targeting individuals who have not yet been formally diagnosed (i.e., those in the pre-diagnosis dementia populations) to help reduce the rising impact of dementia”.
2. What’s the differences with MCI? If prior research have already reviewed those MCI, what value of this research will be contributed to?
Response: In our review, pre-diagnosis dementia populations are broader than MCI.
In the introduction, we added a sentence for clarification. “However, a comprehensive review encompassing all strategies specifically targeting pre-diagnosis dementia populations, which include the general population, at-risk groups, and individuals with MCI without detectable AD pathology, is lacking in the literature.”

Methods:
Eligibility
1. For the target population, how to identify if the articles includes individuals at any stage prior dementia diagnosis? By what definition or any tests (e.g., MMSE) used? If by tests, what results are considered to be eligible?
Response: 1. We identified the target population according to how the authors described the target populations in their economic evaluations. We added following sentence in our protocol:
“The pre-diagnosis dementia population is typically defined by authors who explicitly state that their studies start with a cohort described as having “no dementia,” or as comprising individuals with mild cognitive impairment (MCI) or at-risk population.”

2. Intervention: Would it be possible that (3) non-pharmacotherapy have already included (4) management strategies at home, in the community, and in long-term care?
Response: We revised the protocol and categorised interventions into three groups: identification, risk reduction, and others. The latter group will compass studies that do not fall into either identification or risk reduction.

3. Outcomes: Please specify what perspective the authors decided to adopt when reporting the cost outcomes, will the authors include all cost items? Or only for one perspective? If for all, how about costs that published in separate articles?
Response:  We do not adopt any perspective whilst critically appraising the literature. But rather, we "document stated perspectives" . We extracted the average total cost and intervention cost (if reported) as they may (or may not) relate to stated perspectives.

4. Study design:
- Trail-based and model-based EEs are very different study types. For model-based, additional information such as modeling technique, parameters, etc.
are important and should also be considered and specified clearly.
Response: We include articles as long as they are considered full economic evaluations according to Drummond’s classification scheme. This means we include both trial-based and model-based full economic evaluations.
- Will the authors consider include multiple (≥2) articles that published for the same intervention for different outcomes, say cost outcomes in one article and effectiveness such as clinical outcomes in anthter.
Response: The data extraction stage is a memoryless process and no attempt is made to cross reference studies to check if multiple articles were published from the same study of a single intervention. However, at analysis, where there is sufficient evidence of duplication of reporting the same findings, the study would be flagged as such.

Data synthesis
1. There are three guidelines that provides instructions of conducting systematic review on cost-effectiveness studies (Cochrane HandBook, CRD from York, and ISPOR), the authors should consider to follow one of each for the data synthesis process.
Response: Thank you for your suggestion. All systematic review processes aim to adhere to standards set out in the Cochrane Handbook and specifically Chapter 20: Economic evidence.
The results are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
The template for summarising data extracted from each individual study was based on the former template of CRD NHS EED database.

2. The authors stated that "Where studies report both total costs and outcomes expressed in QALYs, results will be adjusted and will be visually presented on a cost-effectiveness plane to facilitate decision-making." The authors should clarify more details for the following points;
- How to adjust the results?
- How about costs in different countries? Any standardized method will be used?
Response: Thanks to your comment, we identify there is an error in our statement (i.e it should be incremental cost not total cost).The cost-effectiveness plane is used solely for illustrative purposes but adjustments are required:We used CPI and PPP method, converted cost to international dollar in 2024 prices. We added in the protocol as:“the incremental cost will be converted to international dollars (value in 2024) using the purchasing power parity from the International Monetary Fund dataset ¹⁷, and visually presented on a cost-effectiveness plane to facilitate comparison.”

- What threshold of williness-to-pay will the authors use to present the cost-effectiveness plane?
Response: Two willingness-to-pay (WTP) benchmarks were used to demonstrate the comparative cost-effectiveness of the strategies: $150,000 per QALY, indicative of the relatively unregulated market context in the United States (US) 18, and £12,936 per QALY, representing the more resource-limited system in the United Kingdom (UK)19. These values were selected to capture the range between higher and lower reference points.

- Will this study conclude with which strategy is cost-effective/cost-saving or not, how?
Response: Based on the CE-plane, we can see if the intervention is in the dominant quadrant. The cost-effectiveness plane is used solely for illustrative purposes, we will not alter the original conclusion regarding the cost-effectiveness of the included articles. The intention of this review is not to determine whether any given strategy is cost effective or not (because, as the reviewer indicates, different countries will have different willingness to pay threshold). Rather, the intention is to systematically identify and critical appraisal all relevant studies. By extension, the illustration on the cost effectiveness plane provide a synthesis for comparison of the relative efficiency of each approach, however, this is not intended to endorse use in any jurisdiction but rather encourage countries to conduct their own country level appraisal (in which they may opt to adapt analyses highlighted by our review).

- There are others details need to consider especially for model-based EEs. The authors could reconsider whether to include model-based studies or not?
Response: The article is intended to provide a compendium of all EEs for non-economist audience and, as part of the wider work, we wish this to help readers understand there are two main sources of cost-effectiveness evidence.

Quality appraisal
In addition to the methodological quality of the EEs, the authors should also evaluate the publication bias of the included studies, following the Cochrane guideline. The authors can take our prior systematic review as reference for the methodology.
Response: Thank you for your advice. In EE, we do not have publication bias estimation. But in many reviews, they estimate the publication bias of the included intervention. We are not doing that in this review.

Once again, thank you very much for providing comments. We believe that your comments will help us in improving the clarification and transparency of this protocol
Competing Interests: None Close
Report a concern
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COMMENTS ON THIS REPORT

Author Response 29 Sep 2025

Men Hoang, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

29 Sep 2025

Author Response

Thank you for taking the time to review our protocol.
Introduction:
1. Is there any definition for pre-diagnosis stage in either clinical practice or research?
Response: Thank you for your comments.
... Continue reading Thank you for taking the time to review our protocol.
Introduction:
1. Is there any definition for pre-diagnosis stage in either clinical practice or research?
Response: Thank you for your comments.
In the literature, we found this paper defined “"Pre-diagnosis was defined as the period from the initial onset of symptoms up to the formal diagnosis”. (https://doi.org/10.1017/S1041610217000862)
In our review, we added a sentence to clarify the definition of the pre-diagnosis dementia population as “individuals who have not yet been formally diagnosed”.

“Thus, it is essential to identify and implement cost-effective strategies targeting individuals who have not yet been formally diagnosed (i.e., those in the pre-diagnosis dementia populations) to help reduce the rising impact of dementia”.
2. What’s the differences with MCI? If prior research have already reviewed those MCI, what value of this research will be contributed to?
Response: In our review, pre-diagnosis dementia populations are broader than MCI.
In the introduction, we added a sentence for clarification. “However, a comprehensive review encompassing all strategies specifically targeting pre-diagnosis dementia populations, which include the general population, at-risk groups, and individuals with MCI without detectable AD pathology, is lacking in the literature.”

Methods:
Eligibility
1. For the target population, how to identify if the articles includes individuals at any stage prior dementia diagnosis? By what definition or any tests (e.g., MMSE) used? If by tests, what results are considered to be eligible?
Response: 1. We identified the target population according to how the authors described the target populations in their economic evaluations. We added following sentence in our protocol:
“The pre-diagnosis dementia population is typically defined by authors who explicitly state that their studies start with a cohort described as having “no dementia,” or as comprising individuals with mild cognitive impairment (MCI) or at-risk population.”

2. Intervention: Would it be possible that (3) non-pharmacotherapy have already included (4) management strategies at home, in the community, and in long-term care?
Response: We revised the protocol and categorised interventions into three groups: identification, risk reduction, and others. The latter group will compass studies that do not fall into either identification or risk reduction.

3. Outcomes: Please specify what perspective the authors decided to adopt when reporting the cost outcomes, will the authors include all cost items? Or only for one perspective? If for all, how about costs that published in separate articles?
Response:  We do not adopt any perspective whilst critically appraising the literature. But rather, we "document stated perspectives" . We extracted the average total cost and intervention cost (if reported) as they may (or may not) relate to stated perspectives.

4. Study design:
- Trail-based and model-based EEs are very different study types. For model-based, additional information such as modeling technique, parameters, etc.
are important and should also be considered and specified clearly.
Response: We include articles as long as they are considered full economic evaluations according to Drummond’s classification scheme. This means we include both trial-based and model-based full economic evaluations.
- Will the authors consider include multiple (≥2) articles that published for the same intervention for different outcomes, say cost outcomes in one article and effectiveness such as clinical outcomes in anthter.
Response: The data extraction stage is a memoryless process and no attempt is made to cross reference studies to check if multiple articles were published from the same study of a single intervention. However, at analysis, where there is sufficient evidence of duplication of reporting the same findings, the study would be flagged as such.

Data synthesis
1. There are three guidelines that provides instructions of conducting systematic review on cost-effectiveness studies (Cochrane HandBook, CRD from York, and ISPOR), the authors should consider to follow one of each for the data synthesis process.
Response: Thank you for your suggestion. All systematic review processes aim to adhere to standards set out in the Cochrane Handbook and specifically Chapter 20: Economic evidence.
The results are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
The template for summarising data extracted from each individual study was based on the former template of CRD NHS EED database.

2. The authors stated that "Where studies report both total costs and outcomes expressed in QALYs, results will be adjusted and will be visually presented on a cost-effectiveness plane to facilitate decision-making." The authors should clarify more details for the following points;
- How to adjust the results?
- How about costs in different countries? Any standardized method will be used?
Response: Thanks to your comment, we identify there is an error in our statement (i.e it should be incremental cost not total cost).The cost-effectiveness plane is used solely for illustrative purposes but adjustments are required:We used CPI and PPP method, converted cost to international dollar in 2024 prices. We added in the protocol as:“the incremental cost will be converted to international dollars (value in 2024) using the purchasing power parity from the International Monetary Fund dataset ¹⁷, and visually presented on a cost-effectiveness plane to facilitate comparison.”

- What threshold of williness-to-pay will the authors use to present the cost-effectiveness plane?
Response: Two willingness-to-pay (WTP) benchmarks were used to demonstrate the comparative cost-effectiveness of the strategies: $150,000 per QALY, indicative of the relatively unregulated market context in the United States (US) 18, and £12,936 per QALY, representing the more resource-limited system in the United Kingdom (UK)19. These values were selected to capture the range between higher and lower reference points.

- Will this study conclude with which strategy is cost-effective/cost-saving or not, how?
Response: Based on the CE-plane, we can see if the intervention is in the dominant quadrant. The cost-effectiveness plane is used solely for illustrative purposes, we will not alter the original conclusion regarding the cost-effectiveness of the included articles. The intention of this review is not to determine whether any given strategy is cost effective or not (because, as the reviewer indicates, different countries will have different willingness to pay threshold). Rather, the intention is to systematically identify and critical appraisal all relevant studies. By extension, the illustration on the cost effectiveness plane provide a synthesis for comparison of the relative efficiency of each approach, however, this is not intended to endorse use in any jurisdiction but rather encourage countries to conduct their own country level appraisal (in which they may opt to adapt analyses highlighted by our review).

- There are others details need to consider especially for model-based EEs. The authors could reconsider whether to include model-based studies or not?
Response: The article is intended to provide a compendium of all EEs for non-economist audience and, as part of the wider work, we wish this to help readers understand there are two main sources of cost-effectiveness evidence.

Quality appraisal
In addition to the methodological quality of the EEs, the authors should also evaluate the publication bias of the included studies, following the Cochrane guideline. The authors can take our prior systematic review as reference for the methodology.
Response: Thank you for your advice. In EE, we do not have publication bias estimation. But in many reviews, they estimate the publication bias of the included intervention. We are not doing that in this review.

Once again, thank you very much for providing comments. We believe that your comments will help us in improving the clarification and transparency of this protocol
Thank you for taking the time to review our protocol.
Introduction:
1. Is there any definition for pre-diagnosis stage in either clinical practice or research?
Response: Thank you for your comments.
In the literature, we found this paper defined “"Pre-diagnosis was defined as the period from the initial onset of symptoms up to the formal diagnosis”. (https://doi.org/10.1017/S1041610217000862)
In our review, we added a sentence to clarify the definition of the pre-diagnosis dementia population as “individuals who have not yet been formally diagnosed”.

“Thus, it is essential to identify and implement cost-effective strategies targeting individuals who have not yet been formally diagnosed (i.e., those in the pre-diagnosis dementia populations) to help reduce the rising impact of dementia”.
2. What’s the differences with MCI? If prior research have already reviewed those MCI, what value of this research will be contributed to?
Response: In our review, pre-diagnosis dementia populations are broader than MCI.
In the introduction, we added a sentence for clarification. “However, a comprehensive review encompassing all strategies specifically targeting pre-diagnosis dementia populations, which include the general population, at-risk groups, and individuals with MCI without detectable AD pathology, is lacking in the literature.”

Methods:
Eligibility
1. For the target population, how to identify if the articles includes individuals at any stage prior dementia diagnosis? By what definition or any tests (e.g., MMSE) used? If by tests, what results are considered to be eligible?
Response: 1. We identified the target population according to how the authors described the target populations in their economic evaluations. We added following sentence in our protocol:
“The pre-diagnosis dementia population is typically defined by authors who explicitly state that their studies start with a cohort described as having “no dementia,” or as comprising individuals with mild cognitive impairment (MCI) or at-risk population.”

2. Intervention: Would it be possible that (3) non-pharmacotherapy have already included (4) management strategies at home, in the community, and in long-term care?
Response: We revised the protocol and categorised interventions into three groups: identification, risk reduction, and others. The latter group will compass studies that do not fall into either identification or risk reduction.

3. Outcomes: Please specify what perspective the authors decided to adopt when reporting the cost outcomes, will the authors include all cost items? Or only for one perspective? If for all, how about costs that published in separate articles?
Response:  We do not adopt any perspective whilst critically appraising the literature. But rather, we "document stated perspectives" . We extracted the average total cost and intervention cost (if reported) as they may (or may not) relate to stated perspectives.

4. Study design:
- Trail-based and model-based EEs are very different study types. For model-based, additional information such as modeling technique, parameters, etc.
are important and should also be considered and specified clearly.
Response: We include articles as long as they are considered full economic evaluations according to Drummond’s classification scheme. This means we include both trial-based and model-based full economic evaluations.
- Will the authors consider include multiple (≥2) articles that published for the same intervention for different outcomes, say cost outcomes in one article and effectiveness such as clinical outcomes in anthter.
Response: The data extraction stage is a memoryless process and no attempt is made to cross reference studies to check if multiple articles were published from the same study of a single intervention. However, at analysis, where there is sufficient evidence of duplication of reporting the same findings, the study would be flagged as such.

Data synthesis
1. There are three guidelines that provides instructions of conducting systematic review on cost-effectiveness studies (Cochrane HandBook, CRD from York, and ISPOR), the authors should consider to follow one of each for the data synthesis process.
Response: Thank you for your suggestion. All systematic review processes aim to adhere to standards set out in the Cochrane Handbook and specifically Chapter 20: Economic evidence.
The results are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
The template for summarising data extracted from each individual study was based on the former template of CRD NHS EED database.

2. The authors stated that "Where studies report both total costs and outcomes expressed in QALYs, results will be adjusted and will be visually presented on a cost-effectiveness plane to facilitate decision-making." The authors should clarify more details for the following points;
- How to adjust the results?
- How about costs in different countries? Any standardized method will be used?
Response: Thanks to your comment, we identify there is an error in our statement (i.e it should be incremental cost not total cost).The cost-effectiveness plane is used solely for illustrative purposes but adjustments are required:We used CPI and PPP method, converted cost to international dollar in 2024 prices. We added in the protocol as:“the incremental cost will be converted to international dollars (value in 2024) using the purchasing power parity from the International Monetary Fund dataset ¹⁷, and visually presented on a cost-effectiveness plane to facilitate comparison.”

- What threshold of williness-to-pay will the authors use to present the cost-effectiveness plane?
Response: Two willingness-to-pay (WTP) benchmarks were used to demonstrate the comparative cost-effectiveness of the strategies: $150,000 per QALY, indicative of the relatively unregulated market context in the United States (US) 18, and £12,936 per QALY, representing the more resource-limited system in the United Kingdom (UK)19. These values were selected to capture the range between higher and lower reference points.

- Will this study conclude with which strategy is cost-effective/cost-saving or not, how?
Response: Based on the CE-plane, we can see if the intervention is in the dominant quadrant. The cost-effectiveness plane is used solely for illustrative purposes, we will not alter the original conclusion regarding the cost-effectiveness of the included articles. The intention of this review is not to determine whether any given strategy is cost effective or not (because, as the reviewer indicates, different countries will have different willingness to pay threshold). Rather, the intention is to systematically identify and critical appraisal all relevant studies. By extension, the illustration on the cost effectiveness plane provide a synthesis for comparison of the relative efficiency of each approach, however, this is not intended to endorse use in any jurisdiction but rather encourage countries to conduct their own country level appraisal (in which they may opt to adapt analyses highlighted by our review).

- There are others details need to consider especially for model-based EEs. The authors could reconsider whether to include model-based studies or not?
Response: The article is intended to provide a compendium of all EEs for non-economist audience and, as part of the wider work, we wish this to help readers understand there are two main sources of cost-effectiveness evidence.

Quality appraisal
In addition to the methodological quality of the EEs, the authors should also evaluate the publication bias of the included studies, following the Cochrane guideline. The authors can take our prior systematic review as reference for the methodology.
Response: Thank you for your advice. In EE, we do not have publication bias estimation. But in many reviews, they estimate the publication bias of the included intervention. We are not doing that in this review.

Once again, thank you very much for providing comments. We believe that your comments will help us in improving the clarification and transparency of this protocol
Competing Interests: None Close
Report a concern

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Reviewer Report 05 Mar 2025

Joseph Kane, Queen's University Belfast, Belfast, Ireland

Approved

https://doi.org/10.21956/hrbopenres.15492.r46271

I thank the authors for being so receptive to my comments. My queries have been ... Continue reading

CITE

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Author Response 29 Sep 2025

Men Hoang, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

29 Sep 2025

Author Response

Thank you, Dr. Kane, for your comments; they definitely help us enhance the clarity of our protocol.
Competing Interests: No competing interests were disclosed.
Thank you, Dr. Kane, for your comments; they definitely help us enhance the clarity of our protocol.
Thank you, Dr. Kane, for your comments; they definitely help us enhance the clarity of our protocol.
Competing Interests: No competing interests were disclosed. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 29 Sep 2025

Men Hoang, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

29 Sep 2025

Author Response

Thank you, Dr. Kane, for your comments; they definitely help us enhance the clarity of our protocol.
Competing Interests: No competing interests were disclosed.
Thank you, Dr. Kane, for your comments; they definitely help us enhance the clarity of our protocol.
Thank you, Dr. Kane, for your comments; they definitely help us enhance the clarity of our protocol.
Competing Interests: No competing interests were disclosed. Close
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Version 1

VERSION 1

PUBLISHED 23 Jan 2025

Views

Reviewer Report 10 Feb 2025

Joseph Kane, Queen's University Belfast, Belfast, Ireland

Approved with Reservations

https://doi.org/10.21956/hrbopenres.15446.r45165

Thank you for the opportunity to review this important work.

The first paragraph refers to dementia as single condition when it more accurately represents a construct by which a series of neurodegenerative processes manifest. Consider "Dementia is a group of conditions characterised …"

The second paragraph includes a sentence suggesting that "screening tests that enable individuals to maintain independent living" doesn't quite make - it seems like an intervention rather than a test is more likely to maintain independence.

I do follow the pragmatic approach to excluding populations with MMSE <24 but I would dispute that such populations are commonly predefined this way, certainly not clinically or in clinical trials.

I don't quite follow the exclusion of those with MCI-AD and feel this should be better and more explicitly justified.

This protocol would otherwise appear well constructed and justifiable.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Partly
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: I am a dementia clinician and researcher. I have limited knowledge of economic methodologies but do have experience in systematic review.

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Report a concern

Author Response 03 Mar 2025

Men Hoang, Trinity College Dublin, Trinity College Institute of Neuroscience, Dublin, Ireland

03 Mar 2025

Author Response

Thank you, Dr. Kane, for reviewing our protocol and providing us with valuable comments.

Reviewer's comment 1: "The first paragraph refers to dementia as single condition when it more ... Continue reading Thank you, Dr. Kane, for reviewing our protocol and providing us with valuable comments.

Reviewer's comment 1: "The first paragraph refers to dementia as single condition when it more accurately represents a construct by which a series of neurodegenerative processes manifest. Consider "Dementia is a group of conditions characterised …"
Response: Thank you for pointing it out. We revised the first sentence accordingly.
"Dementia is a group of conditions characterised by deterioration of multiple cognitive domains that significantly affects daily functioning”.

Reviewer's comment 2: The second paragraph includes a sentence suggesting that "screening tests that enable individuals to maintain independent living" doesn't quite make - it seems like an intervention rather than a test is more likely to maintain independence.
Response: Thanks for your comment. We revised as following:
“Additionally, given the significant costs associated with dementia, early interventions, such as identification strategies, may enable timely diagnosis and treatment, helping to mitigate complications, support independent living, and give family members more time to prepare.”

Reviewer's comment 3: I do follow the pragmatic approach to excluding populations with MMSE <24 but I would dispute that such populations are commonly predefined this way, certainly not clinically or in clinical trials.
Response: Thank you for your comment. Initially, we used MMSE scores to predefine the included populations. However, after the screening process, we realised that defining the pre-diagnosis population based on MMSE scores is not a common approach. The population is now defined as follows:
“Population: The target population includes individuals at any stage prior to having a formal diagnosis of dementia, such as the general population, people at risk of dementia, those with mild cognitive impairment (MCI), caregivers, and patient-caregiver dyads.”

Reviewer's comment 4: I don't quite follow the exclusion of those with MCI-AD and feel this should be better and more explicitly justified.
Response: To confirm that MCI is due to AD, biomarkers reflecting amyloid and tau pathology (core features of Alzheimer’s) are assessed. Thus, we consider MCI due to AD is post-diagnosis population.
We added:
“This is because the criteria for MCI due to AD must be confirmed by biomarkers to determine the likelihood that the syndrome results from the underlying pathophysiology of AD ¹⁶.

Reviewer's comment 5: This protocol would otherwise appear well constructed and justifiable.
Response: Thank you.
Thank you, Dr. Kane, for reviewing our protocol and providing us with valuable comments.

Reviewer's comment 1: "The first paragraph refers to dementia as single condition when it more accurately represents a construct by which a series of neurodegenerative processes manifest. Consider "Dementia is a group of conditions characterised …"
Response: Thank you for pointing it out. We revised the first sentence accordingly.
"Dementia is a group of conditions characterised by deterioration of multiple cognitive domains that significantly affects daily functioning”.

Reviewer's comment 2: The second paragraph includes a sentence suggesting that "screening tests that enable individuals to maintain independent living" doesn't quite make - it seems like an intervention rather than a test is more likely to maintain independence.
Response: Thanks for your comment. We revised as following:
“Additionally, given the significant costs associated with dementia, early interventions, such as identification strategies, may enable timely diagnosis and treatment, helping to mitigate complications, support independent living, and give family members more time to prepare.”

Reviewer's comment 3: I do follow the pragmatic approach to excluding populations with MMSE <24 but I would dispute that such populations are commonly predefined this way, certainly not clinically or in clinical trials.
Response: Thank you for your comment. Initially, we used MMSE scores to predefine the included populations. However, after the screening process, we realised that defining the pre-diagnosis population based on MMSE scores is not a common approach. The population is now defined as follows:
“Population: The target population includes individuals at any stage prior to having a formal diagnosis of dementia, such as the general population, people at risk of dementia, those with mild cognitive impairment (MCI), caregivers, and patient-caregiver dyads.”

Reviewer's comment 4: I don't quite follow the exclusion of those with MCI-AD and feel this should be better and more explicitly justified.
Response: To confirm that MCI is due to AD, biomarkers reflecting amyloid and tau pathology (core features of Alzheimer’s) are assessed. Thus, we consider MCI due to AD is post-diagnosis population.
We added:
“This is because the criteria for MCI due to AD must be confirmed by biomarkers to determine the likelihood that the syndrome results from the underlying pathophysiology of AD ¹⁶.

Reviewer's comment 5: This protocol would otherwise appear well constructed and justifiable.
Response: Thank you.
Competing Interests: No competing interests were disclosed. Close
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Respond or Comment

COMMENTS ON THIS REPORT

Author Response 03 Mar 2025

Men Hoang, Trinity College Dublin, Trinity College Institute of Neuroscience, Dublin, Ireland

03 Mar 2025

Author Response

Thank you, Dr. Kane, for reviewing our protocol and providing us with valuable comments.

Reviewer's comment 1: "The first paragraph refers to dementia as single condition when it more ... Continue reading Thank you, Dr. Kane, for reviewing our protocol and providing us with valuable comments.

Reviewer's comment 1: "The first paragraph refers to dementia as single condition when it more accurately represents a construct by which a series of neurodegenerative processes manifest. Consider "Dementia is a group of conditions characterised …"
Response: Thank you for pointing it out. We revised the first sentence accordingly.
"Dementia is a group of conditions characterised by deterioration of multiple cognitive domains that significantly affects daily functioning”.

Reviewer's comment 2: The second paragraph includes a sentence suggesting that "screening tests that enable individuals to maintain independent living" doesn't quite make - it seems like an intervention rather than a test is more likely to maintain independence.
Response: Thanks for your comment. We revised as following:
“Additionally, given the significant costs associated with dementia, early interventions, such as identification strategies, may enable timely diagnosis and treatment, helping to mitigate complications, support independent living, and give family members more time to prepare.”

Reviewer's comment 3: I do follow the pragmatic approach to excluding populations with MMSE <24 but I would dispute that such populations are commonly predefined this way, certainly not clinically or in clinical trials.
Response: Thank you for your comment. Initially, we used MMSE scores to predefine the included populations. However, after the screening process, we realised that defining the pre-diagnosis population based on MMSE scores is not a common approach. The population is now defined as follows:
“Population: The target population includes individuals at any stage prior to having a formal diagnosis of dementia, such as the general population, people at risk of dementia, those with mild cognitive impairment (MCI), caregivers, and patient-caregiver dyads.”

Reviewer's comment 4: I don't quite follow the exclusion of those with MCI-AD and feel this should be better and more explicitly justified.
Response: To confirm that MCI is due to AD, biomarkers reflecting amyloid and tau pathology (core features of Alzheimer’s) are assessed. Thus, we consider MCI due to AD is post-diagnosis population.
We added:
“This is because the criteria for MCI due to AD must be confirmed by biomarkers to determine the likelihood that the syndrome results from the underlying pathophysiology of AD ¹⁶.

Reviewer's comment 5: This protocol would otherwise appear well constructed and justifiable.
Response: Thank you.
Thank you, Dr. Kane, for reviewing our protocol and providing us with valuable comments.

Reviewer's comment 1: "The first paragraph refers to dementia as single condition when it more accurately represents a construct by which a series of neurodegenerative processes manifest. Consider "Dementia is a group of conditions characterised …"
Response: Thank you for pointing it out. We revised the first sentence accordingly.
"Dementia is a group of conditions characterised by deterioration of multiple cognitive domains that significantly affects daily functioning”.

Reviewer's comment 2: The second paragraph includes a sentence suggesting that "screening tests that enable individuals to maintain independent living" doesn't quite make - it seems like an intervention rather than a test is more likely to maintain independence.
Response: Thanks for your comment. We revised as following:
“Additionally, given the significant costs associated with dementia, early interventions, such as identification strategies, may enable timely diagnosis and treatment, helping to mitigate complications, support independent living, and give family members more time to prepare.”

Reviewer's comment 3: I do follow the pragmatic approach to excluding populations with MMSE <24 but I would dispute that such populations are commonly predefined this way, certainly not clinically or in clinical trials.
Response: Thank you for your comment. Initially, we used MMSE scores to predefine the included populations. However, after the screening process, we realised that defining the pre-diagnosis population based on MMSE scores is not a common approach. The population is now defined as follows:
“Population: The target population includes individuals at any stage prior to having a formal diagnosis of dementia, such as the general population, people at risk of dementia, those with mild cognitive impairment (MCI), caregivers, and patient-caregiver dyads.”

Reviewer's comment 4: I don't quite follow the exclusion of those with MCI-AD and feel this should be better and more explicitly justified.
Response: To confirm that MCI is due to AD, biomarkers reflecting amyloid and tau pathology (core features of Alzheimer’s) are assessed. Thus, we consider MCI due to AD is post-diagnosis population.
We added:
“This is because the criteria for MCI due to AD must be confirmed by biomarkers to determine the likelihood that the syndrome results from the underlying pathophysiology of AD ¹⁶.

Reviewer's comment 5: This protocol would otherwise appear well constructed and justifiable.
Response: Thank you.
Competing Interests: No competing interests were disclosed. Close
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Version 3

VERSION 3 PUBLISHED 23 Jan 2025

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Version 3 (revision) 29 Sep 25
Version 2 (revision) 03 Mar 25	read	read	read
Version 1 23 Jan 25	read

Joseph Kane, Queen's University Belfast, Belfast, Ireland
Jiaer Lin, The Chinese University of Hong Kong (CUHK), Hong Kong, Hong Kong
Amritpal Rehill, London School of Economics and Political Science, London, UK

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12 Views

27 Mar 2025 | for Version 2

Amritpal Rehill, London School of Economics and Political Science, London, UK

12 Views Cite this report Responses(1)

Approved

It might be a good idea to briefly discuss how accurately we can currently predict who may or may not go on to have dementia in the future. It was mentioned that pharmacological interventions in the pre-diagnosis context were to be considered- presumably it would be preferred to go ahead with this for those we are particularly confident will go on to be diagnosed with dementia.
Is there a cut-off in terms of how old a study can be to be included in the review? Tied to this, for older studies, something that might be considered is that costs for different components of the interventions may be different now compared to in the past (especially if technology was involved, or if specific drugs are no longer under patent). It might be that cost-effectiveness of some interventions may be different if the intervention were provided today, however without being able to repeat the original study this might need to be listed as a limitation.
Tied to the above, under study details extracted, it may be useful for the year(s) in which the intervention was administered to be extracted.
On similar lines to time, place may also play a factor in determining cost-effectiveness. As an example, for a given intervention, studies from the US and UK may suggest it is cost-effective, but there might not be studies from other countries and there might be reasons so suggest cost-effectiveness might not hold true in other settings (e.g. in developing countries), where costs may differ. I was wondering if the authors were planning to evaluate/comment on the generalisability of the resulting cost-effectiveness estimates.
Alongside evaluating cost-effectiveness, I was wondering if there were any plans to discuss potential differences regarding implementation. For example, a group intervention studied in the US/UK may have been found to be cost-effective, but for those living in a different country where there is more stigma around dementia, individuals may not want to attend group sessions to receive the intervention. I appreciate that this is not the core focus of the study, but I think providing a brief description of this to speak to the generalisability of results where studies exist only in a few similar countries/settings would help to contextualise the findings.
It is fantastic to see that the focus is not only on cost-effectiveness but also on methods and methods used to calculate costs. Currently there is no consensus on how best to value hours of unpaid care (e.g. replacement cost approach or opportunity cost approach), and this decision can have a large impact on the ultimate cost-effectiveness calculation. This alongside other methodological decisions being noted/tracked/compared should prove useful.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

I am a quantitative researcher in the area of social care and have worked on numerous projects involving people with dementia. This has included multiple economic evaluations of trials for non-pharmacological interventions for people with dementia, as well as projecting costs and outcomes for both people with dementia and their carers.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Author Response

29 Sep 2025

Men Hoang, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

1. It might be a good idea to briefly discuss how accurately we can currently predict who may or may not go on to have dementia in the future. It was mentioned that pharmacological interventions in the pre-diagnosis context were to be considered- presumably it would be preferred to go ahead with this for those we are particularly confident will go on to be diagnosed with dementia.
Response: We appreciate your review of our protocol and the insightful comments you provided. We will think about this point in our review and discuss its implications for identifying appropriate target populations.

2. Is there a cut-off in terms of how old a study can be to be included in the review?
Response: Thank you for your thoughtful comment. We include all publications from January 1, 2000, to January 14, 2025.
We added a sentence in the protocol:
“We searched for articles published between January 1, 2000, and January 14, 2025.”

Tied to this, for older studies, something that might be considered is that costs for different components of the interventions may be different now compared to in the past (especially if technology was involved, or if specific drugs are no longer under patent). It might be that cost-effectiveness of some interventions may be different if the intervention were provided today, however without being able to repeat the original study this might need to be listed as a limitation.
Response: In our review:
1) We adjust cost of intervention up to 2024 value and convert to int$
2) We will consider mentioning this limitation of simple adjustments in discussing the final paper.

3. Tied to the above, under study details extracted, it may be useful for the year(s) in which the intervention was administered to be extracted.
Response: Thank you for your comment. In our review, we extract the year of publication and price year when costs were reported (if available).

4. On similar lines to time, place may also play a factor in determining cost-effectiveness. As an example, for a given intervention, studies from the US and UK may suggest it is cost-effective, but there might not be studies from other countries and there might be reasons so suggest cost-effectiveness might not hold true in other settings (e.g. in developing countries), where costs may differ.
Response: 4. Thank you for your suggestion. Indeed, we will have a paragraph to discuss country-specific decision-making in considering the cost-effectiveness of interventions in our review manuscript based on the final extracted data.

I was wondering if the authors were planning to evaluate/comment on the generalisability of the resulting cost-effectiveness estimates
Response: Two willingness-to-pay (WTP) benchmarks were used to demonstrate the comparative cost-effectiveness of the strategies: $150,000 per QALY, indicative of the relatively unregulated market context in the United States (US) 18, and £12,936 per QALY, representing the more resource-limited system in the United Kingdom (UK)19. These values were selected to capture the range between higher and lower reference points. The cost-effectiveness plane is used solely for illustrative purposes, we will not alter the original conclusion regarding the cost-effectiveness of the included articles.

5. Alongside evaluating cost-effectiveness, I was wondering if there were any plans to discuss potential differences regarding implementation.
For example, a group intervention studied in the US/UK may have been found to be cost-effective, but for those living in a different country where there is more stigma around dementia, individuals may not want to attend group sessions to receive the intervention.
I appreciate that this is not the core focus of the study, but I think providing a brief description of this to speak to the generalisability of results where studies exist only in a few similar countries/settings would help to contextualise the findings.
Response: Thank you for your thoughtful comment. We will take your suggestion into account in the discussion section of our review. Exploration of whether included studies were actually implemented is a very good suggestion but is unfortunately beyond the scope at this time. In the final paper, we will discuss this as a recommendation from this review. The point on generalisability is well taken and, at this protocol paper stage (for the benefit of non-economists.

6. It is fantastic to see that the focus is not only on cost-effectiveness but also on methods and methods used to calculate costs. Currently there is no consensus on how best to value hours of unpaid care (e.g. replacement cost approach or opportunity cost approach), and this decision can have a large impact on the ultimate cost-effectiveness calculation. This alongside other methodological decisions being noted/tracked/compared should prove useful.
Response: Thank you for your comment. For each included article, we will summarise its details, such as: title, purpose, country, funding source, type of EE, study design, type of model (if applicable), time horizon, perspective, population, intervention, comparator, resource measurement, utility measurement, uncertainty analysis, currency and price year, discount, quality of article in terms of our newly developed framework to provide an objecty score from CHEERS checklist, economic measure in terms of total cost, total QALY, incremental cost and QALY, intervention cost.

We wholeheartedly agree with this limitation in the literature and, informed by and conducted in parallel to this review, we are conducting work to reach greater consensus (Trepel, D. (2019). Core outcome set for economic evaluation of dementia interventions. COMET Initiative. Retrieved April 7, 2025, from https://www.comet-initiative.org/Studies/Details/1737). This review, along with reviews of post diagnostic EEs (Scanlon, H., Saha, S., Trepel, D. (2024). Economic evaluations of interventions for people living with dementia and their caregivers: A systematic review and core outcome set of resource use. ResearchGate), are extracting data on varying resource use data, and this will inform a consensus exercise to ultimately produce a core outcomes set for future dementia economic evaluation. To extend this discussion, we will also extract which unit costs are applied to informal care across EEs.

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Competing Interests

No competing interests were disclosed.

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Reviewer Report

23 Views

22 Mar 2025 | for Version 2

Jiaer Lin, The Chinese University of Hong Kong (CUHK), Hong Kong, Hong Kong

23 Views Cite this report Responses(1)

Approved With Reservations

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Yes

References

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

I am a health economist and have been published work on systematic reviews related to dementia care and integrated care.

Respond to this report

Responses (1)

Author Response

29 Sep 2025

Men Hoang, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

Thank you for taking the time to review our protocol.
Introduction:
1. Is there any definition for pre-diagnosis stage in either clinical practice or research?
Response: Thank you for your comments.
In the literature, we found this paper defined “"Pre-diagnosis was defined as the period from the initial onset of symptoms up to the formal diagnosis”. (https://doi.org/10.1017/S1041610217000862)
In our review, we added a sentence to clarify the definition of the pre-diagnosis dementia population as “individuals who have not yet been formally diagnosed”.

“Thus, it is essential to identify and implement cost-effective strategies targeting individuals who have not yet been formally diagnosed (i.e., those in the pre-diagnosis dementia populations) to help reduce the rising impact of dementia”.
2. What’s the differences with MCI? If prior research have already reviewed those MCI, what value of this research will be contributed to?
Response: In our review, pre-diagnosis dementia populations are broader than MCI.
In the introduction, we added a sentence for clarification. “However, a comprehensive review encompassing all strategies specifically targeting pre-diagnosis dementia populations, which include the general population, at-risk groups, and individuals with MCI without detectable AD pathology, is lacking in the literature.”

Methods:
Eligibility
1. For the target population, how to identify if the articles includes individuals at any stage prior dementia diagnosis? By what definition or any tests (e.g., MMSE) used? If by tests, what results are considered to be eligible?
Response: 1. We identified the target population according to how the authors described the target populations in their economic evaluations. We added following sentence in our protocol:
“The pre-diagnosis dementia population is typically defined by authors who explicitly state that their studies start with a cohort described as having “no dementia,” or as comprising individuals with mild cognitive impairment (MCI) or at-risk population.”

2. Intervention: Would it be possible that (3) non-pharmacotherapy have already included (4) management strategies at home, in the community, and in long-term care?
Response: We revised the protocol and categorised interventions into three groups: identification, risk reduction, and others. The latter group will compass studies that do not fall into either identification or risk reduction.

3. Outcomes: Please specify what perspective the authors decided to adopt when reporting the cost outcomes, will the authors include all cost items? Or only for one perspective? If for all, how about costs that published in separate articles?
Response:  We do not adopt any perspective whilst critically appraising the literature. But rather, we "document stated perspectives" . We extracted the average total cost and intervention cost (if reported) as they may (or may not) relate to stated perspectives.

4. Study design:
- Trail-based and model-based EEs are very different study types. For model-based, additional information such as modeling technique, parameters, etc.
are important and should also be considered and specified clearly.
Response: We include articles as long as they are considered full economic evaluations according to Drummond’s classification scheme. This means we include both trial-based and model-based full economic evaluations.
- Will the authors consider include multiple (≥2) articles that published for the same intervention for different outcomes, say cost outcomes in one article and effectiveness such as clinical outcomes in anthter.
Response: The data extraction stage is a memoryless process and no attempt is made to cross reference studies to check if multiple articles were published from the same study of a single intervention. However, at analysis, where there is sufficient evidence of duplication of reporting the same findings, the study would be flagged as such.

Data synthesis
1. There are three guidelines that provides instructions of conducting systematic review on cost-effectiveness studies (Cochrane HandBook, CRD from York, and ISPOR), the authors should consider to follow one of each for the data synthesis process.
Response: Thank you for your suggestion. All systematic review processes aim to adhere to standards set out in the Cochrane Handbook and specifically Chapter 20: Economic evidence.
The results are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
The template for summarising data extracted from each individual study was based on the former template of CRD NHS EED database.

2. The authors stated that "Where studies report both total costs and outcomes expressed in QALYs, results will be adjusted and will be visually presented on a cost-effectiveness plane to facilitate decision-making." The authors should clarify more details for the following points;
- How to adjust the results?
- How about costs in different countries? Any standardized method will be used?
Response: Thanks to your comment, we identify there is an error in our statement (i.e it should be incremental cost not total cost).The cost-effectiveness plane is used solely for illustrative purposes but adjustments are required:We used CPI and PPP method, converted cost to international dollar in 2024 prices. We added in the protocol as:“the incremental cost will be converted to international dollars (value in 2024) using the purchasing power parity from the International Monetary Fund dataset ¹⁷, and visually presented on a cost-effectiveness plane to facilitate comparison.”

- What threshold of williness-to-pay will the authors use to present the cost-effectiveness plane?
Response: Two willingness-to-pay (WTP) benchmarks were used to demonstrate the comparative cost-effectiveness of the strategies: $150,000 per QALY, indicative of the relatively unregulated market context in the United States (US) 18, and £12,936 per QALY, representing the more resource-limited system in the United Kingdom (UK)19. These values were selected to capture the range between higher and lower reference points.

- Will this study conclude with which strategy is cost-effective/cost-saving or not, how?
Response: Based on the CE-plane, we can see if the intervention is in the dominant quadrant. The cost-effectiveness plane is used solely for illustrative purposes, we will not alter the original conclusion regarding the cost-effectiveness of the included articles. The intention of this review is not to determine whether any given strategy is cost effective or not (because, as the reviewer indicates, different countries will have different willingness to pay threshold). Rather, the intention is to systematically identify and critical appraisal all relevant studies. By extension, the illustration on the cost effectiveness plane provide a synthesis for comparison of the relative efficiency of each approach, however, this is not intended to endorse use in any jurisdiction but rather encourage countries to conduct their own country level appraisal (in which they may opt to adapt analyses highlighted by our review).

- There are others details need to consider especially for model-based EEs. The authors could reconsider whether to include model-based studies or not?
Response: The article is intended to provide a compendium of all EEs for non-economist audience and, as part of the wider work, we wish this to help readers understand there are two main sources of cost-effectiveness evidence.

Quality appraisal
In addition to the methodological quality of the EEs, the authors should also evaluate the publication bias of the included studies, following the Cochrane guideline. The authors can take our prior systematic review as reference for the methodology.
Response: Thank you for your advice. In EE, we do not have publication bias estimation. But in many reviews, they estimate the publication bias of the included intervention. We are not doing that in this review.

Once again, thank you very much for providing comments. We believe that your comments will help us in improving the clarification and transparency of this protocol

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Competing Interests

None

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Reviewer Report

15 Views

05 Mar 2025 | for Version 2

Joseph Kane, Queen's University Belfast, Belfast, Ireland

15 Views Cite this report Responses(1)

Approved

I thank the authors for being so receptive to my comments. My queries have been addressed in this revised manuscript. I look forward to seeing the results of this study.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

I am a dementia clinician and researcher. I have limited knowledge of economic methodologies but do have experience in systematic review.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

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Reviewer Report

26 Views

10 Feb 2025 | for Version 1

Joseph Kane, Queen's University Belfast, Belfast, Ireland

26 Views Cite this report Responses(1)

Approved With Reservations

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Partly
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

I am a dementia clinician and researcher. I have limited knowledge of economic methodologies but do have experience in systematic review.

Respond to this report

Responses (1)

Author Response

03 Mar 2025

Men Hoang, Trinity College Dublin, Trinity College Institute of Neuroscience, Dublin, Ireland

Thank you, Dr. Kane, for reviewing our protocol and providing us with valuable comments.

Reviewer's comment 1: "The first paragraph refers to dementia as single condition when it more accurately represents a construct by which a series of neurodegenerative processes manifest. Consider "Dementia is a group of conditions characterised …"
Response: Thank you for pointing it out. We revised the first sentence accordingly.
"Dementia is a group of conditions characterised by deterioration of multiple cognitive domains that significantly affects daily functioning”.

Reviewer's comment 2: The second paragraph includes a sentence suggesting that "screening tests that enable individuals to maintain independent living" doesn't quite make - it seems like an intervention rather than a test is more likely to maintain independence.
Response: Thanks for your comment. We revised as following:
“Additionally, given the significant costs associated with dementia, early interventions, such as identification strategies, may enable timely diagnosis and treatment, helping to mitigate complications, support independent living, and give family members more time to prepare.”

Reviewer's comment 3: I do follow the pragmatic approach to excluding populations with MMSE <24 but I would dispute that such populations are commonly predefined this way, certainly not clinically or in clinical trials.
Response: Thank you for your comment. Initially, we used MMSE scores to predefine the included populations. However, after the screening process, we realised that defining the pre-diagnosis population based on MMSE scores is not a common approach. The population is now defined as follows:
“Population: The target population includes individuals at any stage prior to having a formal diagnosis of dementia, such as the general population, people at risk of dementia, those with mild cognitive impairment (MCI), caregivers, and patient-caregiver dyads.”

Reviewer's comment 4: I don't quite follow the exclusion of those with MCI-AD and feel this should be better and more explicitly justified.
Response: To confirm that MCI is due to AD, biomarkers reflecting amyloid and tau pathology (core features of Alzheimer’s) are assessed. Thus, we consider MCI due to AD is post-diagnosis population.
We added:
“This is because the criteria for MCI due to AD must be confirmed by biomarkers to determine the likelihood that the syndrome results from the underlying pathophysiology of AD ¹⁶.

Reviewer's comment 5: This protocol would otherwise appear well constructed and justifiable.
Response: Thank you.

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Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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Economic evaluations of strategies targeting pre-diagnosis dementia populations: Protocol for a systematic review

Abstract

Introduction

Method and analysis

Conclusion

Ethics and dissemination

Systematic review registration

Keywords

Revised Amendments from Version 2

Introduction

Method

Registration

Eligibility criteria

Exclusion criteria

Search strategy

Study selection

Data extraction

Data synthesis

Quality appraisal

Discussion

Data availability

Underlying data

Extended data

Reporting guidelines

Author contributions

References

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Are you a HRB-funded researcher?

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Economic evaluations of strategies targeting pre-diagnosis dementia populations: Protocol for a systematic review

Abstract

Introduction

Method and analysis

Conclusion

Ethics and dissemination

Systematic review registration

Keywords

Revised Amendments from Version 2

Introduction

Method

Registration

Eligibility criteria

Exclusion criteria

Search strategy

Study selection

Data extraction

Data synthesis

Quality appraisal

Discussion

Data availability

Underlying data

Extended data

Reporting guidelines

Author contributions

References

Comments on this article Comments (0)

Open Peer Review

Comments on this article Comments (0)

Open Peer Review

Reviewer Status

Reviewer Reports

Comments on this article

Competing Interests Policy

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Are you a HRB-funded researcher?

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