Dear Dr Hao,

Thank you very much for submitting your manuscript "Optimal Anti-amyloid-beta Therapy for Alzheimer’s Disease via a Personalized Mathematical Model" for consideration at PLOS Computational Biology. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please carefully respond to all reviewer comments and address concerns within the manuscript.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Adrianne Jenner

Associate Editor

PLOS Computational Biology

Virginia Pitzer

Deputy Editor-in-Chief

PLOS Computational Biology

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A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

[LINK]

Please carefully respond to all reviewer comments and address concerns within the manuscript.

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: In this paper, an ODE system consists of five equations governing the dynamics of Amyloid beta, Phosphorylated tau, nonamyloid-dependent tau, neurodegeneration, and cognitive decline is used to study Alzheimer’s disease (AD) treatment. In particular, it incorporates four AD clinical markers to determine individual parameters for the ODE system sequentially. The AD interventions are studied by adding a degradation term in the equation of Amyloid beta. The objective is to find a treatment to minimize both amyloid and cognitive impairment at the end of the treatment while keeping the cognitive impairment and side-effects over the treatment interval minimal.

The paper is well written and is easy for readers to understand and follow. The overall goals are well articulated and authors proposed methods based on ODE model, parameter fitting, and numerical optimization to find the optimal therapy. Thus I would recommend the publication after a minor revision. Here are some questions that authors may address.

Q1: Even though AD clinical markers are used to determine individual parameters, some dataset only has three longitudinal datapoints in a short range of time. The starting time is chosen as T_0 = 50. Will the fitting results vary a lot with respect to the choice of the initial time? In the paragraph, it was mentioned that some longitudinal dataset is available for up to 10 years. Does the parameter fitting work well for these kinds of dataset?

Q2: For Table 2, how can one tell whether they are for 78-week or 10-year treatments? Top versus bottom? As the numerical values ranges roughly from 10^-7 to 29, the average may not be a good indicator. Maybe use median instead. Most readers will be benefited from understanding why the decline varies widely. In what situation, the decline will be small? In Table 3 and Table 4, some values are as small as 10^-16 which is about the machine precision. This raises the concern of the accuracy of the numerical methods. Can authors address that? Are the results reliable?

Here are some minor suggestions:

Keywords: “Alzheimer's” instead of “alzheimer's”

On page 9, one of the “%” in relative errors for A_{\\beta} is misallocated.

On page 10, caption in Fig.3: “with age 84.7” instead of “with 84.7”.

On page 11, line 172: “are in average 5.9%” instead of “are 5.9%”. Is this for 78-week treatment? Also check the last sentence in this paragraph. Be specific in discussing the results that you have.

Reviewer #2: The review is uploaded as an attachment. Please address all my (minor) concerns.

Reviewer #3: The authors formulate a mathematical model which enables them to simulate personalized clinical trials of the anti-amyloid medicines Aducanumab and Donanemab. The data of the selected patients are taken from the ADNI data bank. The conclusions of the simulations seem to agree with actual clinical trials, in the sense that the amount of amyloid is reduced substantially but the effects on cognitive decline are marginal.

The basic mathematical equations are surprisingly simple (for example, spatial effects are totally neglected). Therefore the model contains very few parameters which, due to the cascade-structure of the equations, can be easily estimated from known biomarkers. The personalized character of the in silico trials is modeled through relatively simple optimization techniques. It is at least curious that such a simple mathematical set-up leads to results which confirm actual clinical trials. Without any doubt this makes the paper interesting.

To fully judge the importance and level of reliability of the model, it would be important to have information about the optimality of single personalized trials. Do the authors have any indications for the reliability of the optimization of the trial for single patients? If not, do they have any argument to convince the reader of such reliability, or, at least, can they indicate how to handle this issue in the future? This would make the paper more valuable.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No: The authors plan to make codes available upon the acceptance of the article

Reviewer #2: Yes

Reviewer #3: Yes

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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.

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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

Reviewer #3: No

Figure 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. 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 us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References:

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.

Attachments

Attachment

Submitted filename: PCOMPBIOL-D-22-00432-Report.pdf

Dear Dr Hao,

Thank you very much for submitting your manuscript "Optimal Anti-amyloid-beta Therapy for Alzheimer’s Disease via a Personalized Mathematical Model" for consideration at PLOS Computational Biology. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please make the minor changes that the reviewer suggests (below) before we accept can accept manuscript for publication. Also, please ensure that the code is published and available at this stage, as dictated by our code-sharing policy.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Adrianne Jenner

Associate Editor

PLOS Computational Biology

Virginia Pitzer

Deputy Editor-in-Chief

PLOS Computational Biology

***********************

A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

[LINK]

Can the authors please make the minor changes that the reviewer accepted before we accept their manuscript for publication.

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The authors have addressed reviewers’ suggestions. The publication is recommended after the minor revision. Here are some more minor suggestions.

On page 2, line 39: remove the space after taupathology.

On page 8, line 148: add a space after (6).

It seems that \\lambda_{\\tau A_\\beta} and \\lambda_{\\tau} refer to the same parameter. It is better to make it consistent across the manuscript.

Reviewer #2: The authors have satisfactory responded to all reviewer comments and concerns.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No: The code will be published upon the acceptance of the article.

Reviewer #2: Yes

**********

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

Figure 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. 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 us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References:

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.

Dear Dr Hao,

We are pleased to inform you that your manuscript 'Optimal Anti-amyloid-beta Therapy for Alzheimer’s Disease via a Personalized Mathematical Model' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology. 

Best regards,

Adrianne Jenner

Associate Editor

PLOS Computational Biology

Virginia Pitzer

Deputy Editor-in-Chief

PLOS Computational Biology

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