-->PONE-D-26-08365-->-->Do Dopaminergic Genes Modulate Processing Speed in Cognitive Aging? A Longitudinal Candidate Gene Study-->-->PLOS One

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Reviewers' comments:

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

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: This 12-year longitudinal candidate-gene study tested 89 dopaminergic SNPs across nine genes against cognitive decline trajectories in 1,539 older adults using single-SNP, gene-based, and polygenic analyses. no associations survived multiple testing correction across single-SNP, gene-based, or polygenic analyses, with strongest nominal signals in COMT and DRD1 falling well below significance thresholds.

Overall, the study design and longitudinal framework are appropriate for the research question. However, a few issues require clarification or revision:

Principal components derived from 957 pathway-restricted SNPs rather than genome-wide markers inadequately control population stratification, evidenced by miscalibrated genomic inflation values (0.74 primary; 1.45 sensitivity). recompute principal components from a genome-wide panel or provide explicit justification that the current approach is sufficient for this cohort.

The study is only powered to detect relatively large effect sizes (~1% variance explained), which exceed typical common-variant effects for cognitive traits. The strong null conclusions therefore overreach what the data can support. temper your conclusions accordingly, explicitly acknowledging that smaller, plausible effects cannot be excluded.

Use of LD-pruned SNPs for MAGMA gene-based testing is inappropriate and reduces the ability to capture cumulative genetic effects, undermining the negative findings at the gene level. rerun MAGMA using the full quality-controlled SNP set per gene.

The manuscript states that no post-mortem associations survive correction, yet reports FDR-significant q-values. This internal contradiction suggests errors in statistical interpretation or reporting. correct all post-mortem statistical reporting for consistency.

The reduced-sample “deep phenotype” analysis shows substantial genomic inflation (λGC ≈ 1.45), indicating unreliable results. Despite this, it is presented as supportive, which is not justified. either resolve the inflation or explicitly present this analysis as unreliable rather than supportive of the primary findings.

Reviewer #2: This manuscript examines whether common variation in selected dopaminergic genes is associated with longitudinal processing-speed decline, age-70 cognitive performance, secondary cognitive domains, and exploratory neuropathological outcomes in an aging cohort. The study is clearly written, the longitudinal phenotype is valuable, and the null results are potentially informative. The main strength is the combination of a biologically coherent hypothesis, repeated cognitive measurement, and multiple analytic levels (single-variant, gene-based, pathway-score, and exploratory post-mortem analyses).

In my view, however, the manuscript requires substantial revision before it is suitable for publication.

Major comments

1. The manuscript remains framed as a candidate-gene discovery study, although the field has largely moved beyond this paradigm for complex cognitive traits. The Introduction and Discussion should be reframed more explicitly as a focused falsification test of a biologically plausible but historically weak approach, rather than as a broadly confirmatory evaluation of dopaminergic genetic effects.

2. The claim of “comprehensive synaptic coverage” is too strong. The analyzed set is limited to common SNPs captured on the platform and excludes several biologically relevant loci or variant classes. The title, abstract, and Discussion should be more precise about the true scope of inference.

3. Population-structure control needs stronger justification. If ancestry principal components were derived from the restricted candidate-SNP set rather than genome-wide markers, this is a significant limitation and should be discussed transparently, especially given the calibration concerns reported in the manuscript. A clearer account of genomic control behavior and robustness analyses is needed.

4. The null interpretation is currently too strong. The reported power appears sufficient only for relatively large common-variant effects, not for the much smaller effects typical in cognitive genetics. The manuscript should therefore conclude that no moderate-to-large effects were detected in this design, rather than suggesting absence of meaningful dopaminergic genetic influence more generally.

5. The pathway-level “polygenic risk score” is not described in a way that aligns with contemporary use of that term. As presented, this appears closer to an internally derived candidate-variant score than a standard externally weighted PRS. I strongly recommend renaming and re-explaining this construct.

6. The psychometric basis of the cognitive phenotypes is underreported. Because the central outcome is a latent longitudinal processing-speed construct, the manuscript should provide more information on factor structure, reliability, and longitudinal comparability of the measures in this analytic sample.

7. The growth-curve modeling strategy requires fuller reporting. The manuscript should better justify the use of individual slope/intercept estimates as downstream phenotypes, clarify the degree of shrinkage involved, and discuss whether uncertainty in those estimates may attenuate association signals.

8. The sensitivity analysis is not easily interpretable because the sample is sharply reduced after adding clinical covariates. This should be presented more cautiously as a restricted complete-case robustness check rather than a parallel confirmatory analysis.

9. The inferential hierarchy is not sufficiently clear. The manuscript includes single-SNP tests, gene-based tests, pathway-level analysis, secondary cognitive outcomes, and exploratory neuropathology analyses, but the distinction between confirmatory and exploratory families is not clearly defined. This should be made explicit.

10. The post-mortem analyses are seriously underpowered and should be repositioned as exploratory pilot work only. At present, they receive more interpretive weight than the sample sizes justify.

11. The biological discussion occasionally overreaches. Strong neuroimaging and pharmacological evidence for dopamine involvement in cognition does not imply that common inherited SNP variation in the selected loci will produce detectable longitudinal effects. The manuscript should separate these levels of inference more carefully.

12. The paper needs a dedicated Limitations subsection. For a null-result genetic study, this is essential. At minimum, it should cover the candidate-gene design, incomplete locus coverage, exclusion of non-SNP variation, limited power for small effects, ancestry/generalizability constraints, and the exploratory nature of the neuropathology component.

13. Reporting transparency should be improved. The manuscript would benefit from fuller detail on QC, model diagnostics, coding decisions, and availability of full summary association results and analysis code.

14. The reference list needs careful technical revision. Several references appear real but are imperfectly formatted, and some may need updating from preprint to final journal versions. The bibliography should be thoroughly cleaned and standardized in APA style.

Minor comments

15. The title slightly overstates the scope; it would be more accurate to refer to common candidate variants or candidate SNPs rather than “dopaminergic genes” broadly.

16. In the abstract, the final inference should be softened to reflect limited power for very small effects.

17. The abstract should clarify that the pathway score is not a conventional externally derived PRS.

18. The description of processing speed as a “modifiable predictor” of dementia should be cited very carefully or rephrased more conservatively.

19. The section on oxidative stress and protein aggregation is interesting but somewhat speculative relative to the actual genetic design; I suggest shortening or clearly labeling it as exploratory rationale.

20. The hypothesis that cumulative effects should exceed single-variant effects is too strong as written and should be reformulated more cautiously.

21. Recruitment by newspaper and radio advertisement should be acknowledged more explicitly as a possible source of selection bias and restricted variance.

22. A participant flow diagram would improve clarity regarding the transition from the full cohort to the genotyped and analyzed samples.

23. Please clarify whether clinical covariates were baseline-only or longitudinally updated.

24. The LD-pruning threshold and minor-allele-frequency thresholds should be justified more explicitly.

25. The manuscript should present nominal findings more cautiously to avoid overemphasis after corrected null results.

26. For the neuropathology models, please report event counts and any checks for model instability.

27. The Discussion should moderate claims that the study “fundamentally challenges” candidate-gene research; one well-conducted null study is informative, but broader field-level conclusions should be framed more carefully.

28. The data availability statement would be more useful if it specified a concrete access pathway and whether code can be shared independently of raw data.

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Reviewer #1: Yes:  Amin Tajerian

Reviewer #2: No

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Do Common Dopaminergic Variants Modulate Processing Speed in Cognitive Aging? A Longitudinal Candidate Gene Study

PONE-D-26-08365R1

Dear Dr. Rose,

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.

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Kind regards,

Kenji Tanigaki, Ph.D., M.D.

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #2: All comments have been addressed

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #2: Yes

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

Reviewer #2: Yes

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

The PLOS Data policy requires authors to make all data 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 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 #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 #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. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #2: The authors have mainly addressed the reviewers comments and improved the manuscript significantly.

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Reviewer #2: No

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