PONE-D-19-21691

Hippocampal subfield volumes and pre-clinical Alzheimer’s disease in 408 cognitively normal adults born in 1946

PLOS ONE

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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: I Don't Know

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Reviewer #1: Yes

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 is a very useful study that evaluated hippocampal subfields among putatively cognitively normal individuals with and without high and low amyloid low. The importance of this. Study lies in the delineation of hippocampal subfields that may be important in understanding early AD pathophysiology. Compared to β-amyloid negative participants (n=334), β-amyloid positive participants (n=74) had lower volume of the presubiculum (3.4% smaller, p=0.012).

This finding with the presubiculum and the fact that this region was not subjected to age effects. like other hippocampal subfields is intriguing.

Minor comments: A better description of specific white matter or other regions for SUVR normalization would be helpful.

Ruling out a formal diagnosis of MCI by clinical evaluation and psychometric tests allows many persons into the study who presumably had neuropsychological impairment without subjective complaints and visa-versa. As such, it not clear whether these participants were actually “cognitively normal” and a number of studies have shown that persons diagnosed with PreMCI, not MC/I not cognitively normal (NACC) or even subjective cognitive complaints may have biological underpinnings. This should. be acknowledged and the authors may even want to run some correlation between the subiculum and other diagnostic tests. The face-name association test might be one such candidate since it was not used in diagnostic formulation.

While I am personally convinced that these are genuine and important findings, multiple tests of statistical significance were run without any reference for the potential of family-wise alpha error or false discovery rate.

Overall, I really liked this paper and thought that it was well argued and well written.

Reviewer #2: The study provided evidence of differential associations in cognitively normal older adults between hippocampal subfield volumes and β-amyloid deposition and, increasing age at time of scan. The relatively selective effect of lower presubiculum volume in the β-amyloid positive group potentially suggest that the presubiculum may be an area of early and relatively specific volume loss in the pathophysiological continuum of Alzheimer’s disease.

Although I do not have any practical knowledge of the performed PET imaging analysis, I believe that the authors did not provide a well-structured, detailed and comprehensive description of the conducted analyses.

Also in the introduction and the discussion, the authors did not provided a comprensive overview of the most relevant literature to the presented work.

Also, it is not clear to me QC of the T1 scans and segmentation

I might have missed this, but were these any figures for results?

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Reviewer #1: No

Reviewer #2: No

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Hippocampal subfield volumes and pre-clinical Alzheimer’s disease in 408 cognitively normal adults born in 1946

PONE-D-19-21691R1

Dear Dr. Schott,

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

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With kind regards,

Yuankai Huo, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

All concerns have been addressed

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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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: I Don't Know

**********

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

**********

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: (No Response)

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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 #2: Yes: Guihu Zhao