PONE-D-23-05935Do pharmacological interventions targeting beta-amyloid improve cognition, physical functioning, and overt behaviour of Alzheimer’s Disease (AD) patients: A protocol for a meta-analysis of Phase 3 clinical trials both completed and terminatedPLOS ONE

Dear Dr. Stellick (Bedrejo),

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jul 06 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Kensaku Kasuga

Academic Editor

PLOS ONE

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2. Please ensure all language is factually accurate. Specifically, as many of the contentious amyloid papers are under active investigation, "fraud" cannot be definitively stated. Therefore, please modify the language used on page 4 (e.g., to "potentially fraudulent").

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Additional Editor Comments:

As a reviewer points out, the preclinical stage is not “based on A+T-N- classification, indicating the presence of Aβ deposits without the presence of tau tangles and neurodegeneration” as author described. Please carefully review the definition of preclinical AD.

As another reviewer pointed out, biomarker information is essential. Therefore, authors should include these biomarkers to outcome measures in meta-analysis.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

Reviewer #2: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript addresses a protocol for a forthcoming meta-analysis of anti-Aβ therapy for Alzheimer's disease. While the results of the meta-analysis are important, it is difficult to judge the significance of publishing the protocol because the method itself of the meta-analysis is not novel and only items are modified.

Although grouped together as anti-Aβ drugs in the protocol, the mechanisms of drugs that inhibit Aβ production and those that promote Aβ clearance are very different, and I am concerned that the scientific significance of the results may be diminished by grouping them together as "anti-Aβ drugs".

Overall, it seems that the authors' understanding of Alzheimer's disease and its drug development is somewhat lacking, and the introduction section contains incorrect information and misleading representations.

- The preclinical stage is just the clinically asymptomatic stage, which can include A+T+N- and even A+T+N+ as well as A+T-N-.

- "BETA1" is a typo for BACE1 (beta-site amyloid precursor protein cleaving enzyme 1).

- Although many have criticized the approval of Aduhelm because of the ambiguity of the decision criteria by the FDA, I guess no one has described it as "it is a step backwards".

- At the time of submission, Lecanemab was already approved in addition to Aducanumab, so that should also be listed.

methods section:

- Since phase III trials of anti-Aβ drugs were not initiated until 2007 or later, it is more likely that the 2011 NIA-AA criteria are used in the trials rather than the older NINCDS-ADRDA criteria.

- CDR-SB is a composite of cognitive function and global function (probably equal to "physical function" in the article), so for those familiar with clinical trials in Alzheimer's disease, it is uncomfortable to put it alongside ADAS-cog. Refer to the FDA guidance for industry published in 2018.

Reviewer #2: The authors carefully review the currently available evidence regarding amyloid-targeted pharmacotherapy for early AD, based on awareness of academic/social controversy about unfruitful results of the previous AD pharmacotherapy clinical trials. The reviewer raises some points to be clarified, possibly to improve the manuscript for better-understanding to the readers：

Types of outcome measures

“We are not interested in changes in biomarkers (Cerebrospinal fluid (CSF) indications of beta-amyloid 42, Tau, and

phospho-tau) therefore, changes in biomarkers are not included in our study.”

- In focusing pharmacotherapeutic potentials of AD trials, these important biological information is essential to be reviewed. Authors should include these biomarkers to the outcome measures in meta-analysis.

Study selection

“To facilitate the screening process, the team will use Covidence (see www.covidence.org), a web-based tool designed to support systematic review screening and manage references and full-text PDFs. Duplicates will be removed by the Covidence software.”

- Authors should explain more clearly what type of process will be handled by Covidence staff.

Data extraction

“Any discrepancies between the two reviewers were resolved by consensus and by consulting a third reviewer.”

- Authors should describe clearly who will be the candidate of the third reviewer.

Quantitative synthesis

“We will calculate the I2 to test for heterogeneity for each pooled result. We will pool our results based on each outcome of interest (ADAS-Cog 11, ADAS-Cog 12, ADAS-Cog 13, ADASCog 14, CDR-SB, MMSE, EQ-5D, EQ-5D (Proxy), QoL-AD, ADCS-ADL, and NPI).”

- It is known that there are some discrepancies of the scores in the versions of NPI, NPI-Q and NPI-NH. Authors should clarify what version of NPI was used in each clinical trial.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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PONE-D-23-05935R1Do beta-amyloid-targeted interventions improve cognition, physical functioning, and overt behaviour of Alzheimer’s Disease (AD) patients: A protocol for a meta-analysis of Phase 3 clinical trials both completed and terminatedPLOS ONE

Dear Dr. Stellick (Bedrejo),

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by May 31 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Kensaku Kasuga

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The author partially complied with the reviewers' comments and revised the manuscript. Let me point out only a few minor points.

1) Please include "Eisai's lecanemab" in P.4, L.9. Since lecanemab is the only drug that is fully approved and already widely used in clinical practice, it is unnatural that it is not mentioned here.

2) As another reviewer pointed out, please add "2011 NIA-AA criteria" alongside the NINCDS-ADRDA criteria to the last paragraph of P.6 and inclusion criteria in Table 2. As the author mentioned in response comments, older trials (the number should be larger) used the NINCDS-ADRDA criteria. However, the NINCDS-ADRDA criteria is getting less familiar to inexperienced researchers. This is just to make the paper and its value understandable to more researchers.

3) If it is appropriate, please mention the period during which the paper to be extracted was published. (ex. "published from xx to xx", "published by 2024 xx")

Reviewer #2: The authors responded to all the points raised by the reviewer to be clarified. The reviewer recognizes that the qualitiy of the revised manuscript has enough to be considered to be published in PLoSone.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Do beta-amyloid-targeted interventions improve cognition, physical functioning, and overt behaviour of Alzheimer’s Disease (AD) patients: A protocol for a meta-analysis of Phase 3 clinical trials both completed and terminated

PONE-D-23-05935R2

Dear Dr. Stellick (Bedrejo),

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Kensaku Kasuga

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: