Dear Dr. Okholm,

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 Aug 29 2025 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.

• 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 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,

Aleksandra Klisic

Academic Editor

PLOS ONE

Journal Requirements:

1. When submitting your revision, we need you to address these additional requirements.-->--> -->-->Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at -->-->https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and -->-->https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf-->--> -->-->2. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. -->--> -->-->Before we proceed with your manuscript, please address the following prompts:-->--> -->-->a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.-->--> -->-->b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.-->--> -->-->Please update your Data Availability statement in the submission form accordingly.-->--> -->-->3. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.-->--> -->-->4. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.-->?>

5. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

6. 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. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1:  Dear Dr. Dr. Aleksandra Klisic,

Thank you for the opportunity to review the manuscript titled “Type 2 diabetes and age-related cognitive decline over 40 years in Danish men – A cohort study based on the Danish Aging and Cognition (DanACo) cohort,” submitted to PLOS ONE.

This manuscript presents a well-designed and methodologically robust investigation into the long-term association between type 2 diabetes (T2D) and cognitive decline over a 40-year period, utilizing data from the Danish Aging and Cognition cohort. A notable strength of the study is the inclusion of pre-morbid cognitive ability assessed in young adulthood, which enhances the interpretability of the longitudinal findings and provides a key methodological advantage over many prior studies in the literature.

The authors report a modest yet statistically significant difference in IQ decline among men diagnosed with T2D compared to non-diabetic counterparts, alongside an increased risk of substantial cognitive decline as measured by the Reliable Change Index. The study’s methodological rigor is further supported by the use of both self-reported and registry-based diabetes diagnoses, as well as comprehensive adjustment for a range of relevant confounding variables, including depression, educational attainment, smoking status, and body mass index (BMI). These methodological strengths contribute to the overall robustness and credibility of the findings.

I find the manuscript to be a valuable and timely contribution to the expanding body of research on cognitive aging and metabolic

health. The study is methodologically sound and conceptually relevant. However, I recommend a few minor revisions aimed at enhancing the clarity of presentation and strengthening the contextual framing of the findings within the broader literature:

1. Clarify Clinical Significance: The observed IQ difference (~1.8 points) is statistically significant but may be perceived as small. While the authors note this in the discussion, a brief elaboration on the potential functional impact—or lack thereof—would help readers interpret the practical meaning of the result.

2. Depression Interaction: The rationale for excluding depression as a moderating factor could be more clearly stated. A brief explanation in the discussion about why a synergistic effect between T2D and depression was not observed (e.g., cohort characteristics) would be welcome.

3. Participation Bias: Given the relatively low participation rate (~14%), this limitation should be emphasized more clearly in both the abstract and conclusion sections to ensure appropriate interpretation of generalizability.

4. Terminological Precision: The manuscript occasionally shifts between “IQ” and “cognitive ability.” Standardizing or clarifying the usage of these terms may improve precision for interdisciplinary readers.

5. Formatting and Flow: Some minor editorial polishing would improve clarity—especially in integrating Table 4 more directly into the narrative and improving typographic consistency.

I recommend that the manuscript be accepted pending minor revisions, as outlined above. This is a thoughtfully designed and well-contextualized study that offers a meaningful contribution to our understanding of the long-term cognitive consequences associated with type 2 diabetes.

Thank you again for the opportunity to review this work.

Sincerely,

Reviewer #2:  Thank you for the opportunity to review this manuscript, which investigates the association between type 2 diabetes (T2D) and cognitive decline over 40 years in Danish men using the unique Danish Aging and Cognition (DanACo) cohort. The study leverages longitudinal cognitive data from young adulthood to late mid-life, aiming to address gaps in prior literature regarding pre-morbid cognitive assessment and long-term follow-up.

Title (Page 1, Lines 2–4)

The title specifies "Danish men" but does not clarify the male-only cohort in the introduction.

Abstract (Page 1, Lines 25–46; Page 9, Lines 24–46)

The abstract states the objective as investigating T2D’s influence on cognitive decline "over a period of more than 40 years" (Lines 26–28). However, the mean retest interval is 44 years (Page 15, Line 193), and the range (35.5–53.2 years, Page 11, Line 91) suggests significant variability.

Results misalignment: The abstract reports a 1.81-IQ-point decline (Lines 38–39) but Table 2 (Page 18) cites 1.83 points.

Outcome ambiguity: "Significant IQ decline" is defined via the Reliable Change Index (RCI) (Lines 35–36), but the abstract omits the clinical relevance of the 13.2-IQ-point cutoff.

Introduction

Background/Rationale (Page 10, Lines 49–82)

The introduction hypothesizes synergistic effects of T2D and depression (Lines 81–82) but later dismisses this (Page 15, Lines 173–178) without reconciling the initial rationale.

The manuscript positions itself as unique in assessing pre-morbid cognition (Lines 62–68) but downplays the single prior study (Reference 12) addressing this (Lines 63–66).

Objectives (Page 11, Lines 77–82)

The aim to analyze "potential synergistic effect" of T2D and depression (Line 82) is not evaluated in primary results (Table 2) or discussed robustly (Page 23, Lines 337–340).

Methods

Study Design & Participants (Page 11–12, Lines 83–98)

157 participants lost due to "technical errors" (Page 11, Line 95) are excluded without detailing the nature of errors or potential bias.

The 14.3% participation rate (Page 24, Line 368) and healthier profile of participants (Page 24, Lines 369–373) are noted but not quantitatively evaluated for impact on effect estimates.

Variables (Page 12–14, Lines 99–157)

Self-reported T2D classification uses inconsistent criteria between LiKO-15 and DiaKO-19 (Page 12, Lines 103–107). This heterogeneity is not addressed in sensitivity analyses.

The BPP test switched from paper-and-pencil to computerized format between baseline and follow-up (Page 13, Line 130). Equivalence of these formats is asserted but not empirically validated.

The RCI formula uses a baseline SD of 9.5 and reliability (omega) of 0.82 (Page 13, Lines 140–142), but the source of these values is unreferenced.

Physical activity, diet, and cardiovascular comorbidities—established confounders in T2D-cognition pathways—are not adjusted for.

Statistical Methods (Page 14–15, Lines 164–190)

The marginally significant T2D-depression interaction (p=0.046, Page 15, Line 177) is dismissed without sensitivity analysis.

Post hoc analyses reveal confounding patterns (Supplementary Table S3, Page 17, Lines 216–218), but the final model (Model 2) does not include retest interval, a key covariate.

Results

Participants & Descriptive Data (Page 15–16, Lines 192–208; Table 1)

Baseline BMI categories (Page 16, Lines 198–199) include "<18.5" (underweight), but this group’s relevance to T2D is unclear. No rationale for cutoff choices is provided.

Baseline BMI has 322 missing values (Page 16, Line 207), but analyses including BMI (Model 3) do not discuss implications of reduced sample size.

Outcome Data & Main Results (Page 17–20; Tables 2–4)

The 1.81-IQ-point decline (Table 2) is termed "modest" (Page 20, Line 277), but the 26.7% vs. 20.5% rate of "significant decline" (Page 16, Line 197) is clinically meaningful yet underemphasized.

For T2D duration ≥20 years (n=107, Page 19, Table 3), nonsignificant trends (p>0.05) are reported despite point estimates suggesting clinically relevant decline (e.g., OR=1.52 for significant decline).

Results for depression as an effect modifier (Page 15, Lines 170–178) are not quantified in tables.

Discussion

Key Findings & Interpretation (Page 20–23, Lines 275–348)

Mechanisms linking T2D to cognitive decline (Page 22, Lines 316–320) are discussed without direct evidence from the study.

Generalizability to women (Page 25, Lines 383–384) is claimed despite male-only data and acknowledged sex differences in T2D-depression comorbidity (Page 23, Line 339).

Limitations & Generalizability (Page 24–25, Lines 367–384)

The assertion that baseline characteristics were "similar" between participants and non-participants with T2D (Page 20, Lines 378–380) is unsupported by data (Supplementary Table S4 not shown).

The healthier, more educated cohort (Page 24, Lines 373–374) may attenuate observed effects, but the magnitude of this bias is not estimated.

**********

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

Type 2 diabetes and age-related cognitive decline over 40 years in Danish men - A cohort study based on the Danish Aging and Cognition (DanACo) cohort

PONE-D-25-26526R1

Dear Dr. Okholm,

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

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

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support .

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,

Aleksandra Klisic

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

Reviewer #1: Thank you for the thorough and constructive revision. The manuscript has improved substantially, particularly regarding (i) clearer framing of clinical relevance, (ii) explicit presentation of the T2D×depression analyses (now in Table 2), and (iii) the additional inverse-probability weighting analysis addressing potential selection bias. Overall, I believe the manuscript is suitable for publication pending minor editorial clarifications.

I have only a few remaining minor points:

1. IPW description (please clarify the weighting formula and implementation): In the revised text, the IPW computation is described in a way that is not fully standard/transparent (e.g., wording around “1 minus the log-odds …”). Please state explicitly: the participation model used, the exact weight formula, and whether any trimming/stabilization was applied. This will improve reproducibility and reader confidence.

2. Table 2 title/text consistency: Please check the labeling and wording around Table 2. The table content reflects analyses stratified by depression status, but the table title/caption appears to reference study origin. Also, one sentence in the Results appears to contain a minor wording inconsistency regarding the “smaller group …” (please verify and correct).

3. Abstract phrasing on generalizability: Given the male-only cohort and low participation rate, please keep language on generalizability appropriately cautious (even with the IPW robustness check).

With these minor edits, I would support acceptance.

Sincerely.

Reviewer #3: The revised manuscript entitled “Type 2 diabetes and age-related cognitive decline over 40 years in Danish men” has addressed the reviewers’ prior concerns in a thorough, transparent, and methodologically sound manner.

however, I have observed some minor areas for improvement.

Minor editorial issues remain, including small typographical errors and occasional inconsistencies in table headings and labeling, which would benefit from a final careful proofread.

Description of inverse probability weighting could be clarified using more standard methodological phrasing to improve transparency for readers.

Causal language in a few parts of the discussion should be further moderated to consistently reflect the observational nature of the study.

Generalizability beyond men could be framed more cautiously, emphasizing the need for sex-specific confirmation in future studies.

**********

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 #3: Yes:  Uzair Abbas

**********