-->PONE-D-25-60018-->-->Association of intraindividual difference in estimated glomerular filtration rate based on cystatin C and creatinine with dementia: a cohort study of the UK Biobank-->-->PLOS One

Dear Dr. Mao,

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Academic Editor

PLOS One

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Additional Editor Comments: -->

Dear Dr. Mao,

Your manuscript “Association of intraindividual difference in estimated glomerular filtration rate based on cystatin C and creatinine with dementia: a cohort study of the UK Biobank ” has been assessed by four reviewers. They have raised a number of points which we believe would improve the manuscript and may allow a revised version to be published in PLOS ONE. Their reports, together with any other comments, are below.

If you are able to fully address these points, we would encourage you to submit a revised manuscript to PLOS ONE.

Best regards,

Prof. Donovan McGrowder

[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?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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-->5. Review Comments to the Author

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Reviewer #1:  1. Originality

Using the intraindividual difference as a potential early biomarker for dementia represents the main originality of this study. Although, up to this point, the difference between eGFR measurements has been associated with various outcomes such as frailty, sarcopenia, or metabolic complications, its association with dementia has not previously been evaluated. Additionally, as an element of novelty and originality, this study also explores the association with specific dementia subtypes.

2. Importance

Given that patients with chronic kidney disease represent a population at increased risk of developing neurological and psychiatric disorders, the evaluation of early biomarkers may provide an important advantage for improved risk assessment and the introduction of specific therapeutic measures. Considering the multiple vascular changes present in these patients, changes that favor psychiatric and neurological impairment,it becomes clear why an early biomarker could enhance clinical evaluation.

Importantly, beyond early detection, such a biomarker should also support the development of therapies capable of modifying disease progression. Why is this study important? Because it highlights an additional relationship, evaluated only minimally in prior research, between the brain and the kidney, suggesting the involvement of systemic processes such as sarcopenia, chronic inflammation, and altered metabolic status.

3. Results

The study analyzes a large population of approximately 450,000 participants, evaluating the long-term risk of dementia (up to 15 years) in association with the eGFR difference. Furthermore, the study demonstrates an L-shaped relationship, showing that the risk decreases sharply as eGFRdiff increases toward the midrange zone, with no additional benefits beyond this threshold. As a result, patients with a markedly negative eGFR difference exhibit the highest risk of developing the aforementioned conditions.

An additional and very important aspect of this study is the neuroimaging analysis, which shows that differences in eGFR are associated with structural brain changes, but without differences in hippocampal volume, suggesting the predominance of vascular mechanisms.

4. Questions

a.Are there additional biochemical or molecular data evaluated in the study that were not presented in the manuscript?

b.Is the genetic component considered in patients with pre-existing conditions?

c.What should be the optimal eGFRdiff threshold for screening?

Reviewer #2: This manuscript investigates the association between the intraindividual difference in cystatin C– and creatinine-based estimated GFR (eGFRdiff) and the risk of dementia, dementia subtypes, neuroimaging markers, and cognitive function in the UK Biobank. The study leverages a very large cohort (n≈460,000, median 13.5 years of follow-up) with comprehensive sensitivity analyses, and the findings are consistent and potentially clinically meaningful. However, the manuscript requires substantial revision before it can be considered for publication. Key issues concern the interpretation of eGFRdiff, unmeasured or residual confounding, the accuracy of dementia diagnosis, and clarity in the causal interpretation.

1. e-GFRdiff is strongly influenced by non-renal determinants. The authors should discuss this in the discussion.

2. Hospital-based dementia diagnoses have substantial misclassification, particularly under-ascertainment in early dementia.

3. Many modifiable dementia risk factors were included, important confounders remain unaccounted for: cardiovascular disease history and medication use. Given that eGFRdiff correlates with frailty, chronic inflammation, and general health status, residual confounding likely remains.

4. Brain MRI was performed years after baseline measurements for many participants. The manuscript needs clearer explanation of this.

5. Several statements in the Discussion and Conclusion suggest that eGFRdiff may be an early biomarker of dementia. Given the observational design, this is too causal.

Reviewer #3:  Dear Author/s

Greetings

There are many deficiencies in the article.

-GFR is a parameter that decreases with age and is ultimately a sign of kidney failure, so the link between dementia and CKD is unclear.

-What were the serum urea values? Did a differential diagnosis of uremic encephalopathy or uremic dementia make?

-What were the kidney imaging results?

-What were the durations of kidney failure and treatment compliance (P, Ca, PTH, Hgb values)?

Due to fundamental deficiencies, the article is not suitable for publication.

Best regards

Reviewer #4:  This manuscript presents a large-scale cohort study examining the association between the intraindividual difference in estimated glomerular filtration rate (eGFRdiff) and dementia risk using UK Biobank data. The authors analyzed 458,668 participants over a median follow-up of 13.5 years and found that negative eGFRdiff values were associated with increased dementia risk, adverse neuroimaging changes, and cognitive decline.

Major Concerns:

Mechanistic clarity: While the authors propose several mechanisms (sarcopenia pathway for AD, microvascular complications for VaD), the biological basis for why eGFRdiff predicts dementia remains speculative. The manuscript would benefit from a more coherent mechanistic framework or acknowledgment of this limitation upfront.

Population generalizability: The cohort is 94.6% white and from the UK. The significant interaction with ethnicity (particularly for VaD) raises questions about the applicability of these findings to diverse populations. This limitation needs more prominent discussion.

Clinical utility: While the authors suggest eGFRdiff could serve as an early biomarker, the manuscript lacks practical guidance on implementation. What eGFRdiff threshold would trigger clinical action? How does its predictive value compare to existing risk scores?

Dementia ascertainment: Relying solely on hospital records and death certificates likely underestimates dementia incidence, particularly for mild cases. This could bias the associations, especially if detection bias differs across eGFRdiff groups.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Yavuz Ayar

Reviewer #4: No

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<p>Association of intraindividual difference in estimated glomerular filtration rate based on cystatin C and creatinine with dementia: a cohort study of the UK Biobank

PONE-D-25-60018R1

Dear Dr. Mao,

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,

Donovan Anthony McGrowder, PhD., MA., MSc

Academic Editor

PLOS One