Dear Dr. Aravena,

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Kind regards,

Ioannis Liampas, MD. PhD

Academic Editor

PLOS ONE

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 “The Health and Retirement Study (HRS) is supported by the National Institute on Aging (NIA U01AG009740) and the Social Security Administration funding the Health and Retirement Study. The English Longitudinal Study of Ageing (ELSA) is funded by the National Institute on Aging (Ref: R01AG017644) and by a consortium of UK government departments: Department for Health and Social Care; Department for Transport; Department for Work and Pensions, which is coordinated by the National Institute for Health Research (NIHR, Ref: 198-1074). Funding has also been provided by the Economic and Social Research Council (ESRC).

José M. Aravena was supported by a Fulbright Fellowship, a National Research and Development Agency of Chile (ANID) Fellowship, the Yale Social and Behavioral Sciences Research Fund, and grants from the Yale University Council on Latin American and Iberian Studies, and the Yale MacMillan Center for International and Area Studies. Xi Chen was supported by the National Institute on Aging grants R01AG077529 and P30AG021342. Becca R. Levy was supported by the National Institute on Aging grants R01AG067533 and U01AG032284.”

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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

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

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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

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: The manuscript is well-written and effectively outlines the interaction between environmental and genetic factors as contributors to Alzheimer’s disease (AD) risk among a diverse cohort. The methodology is clearly described and appropriately cited, and the results are presented in a structured and coherent manner. The discussion thoughtfully interprets the findings and is supported by relevant literature. The following are a few suggestions to enhance the manuscript further:

1. While Table 1 presents descriptive statistics stratified by APOE allele risk profile, it would be helpful to also include a summary of participant characteristics for the full sample, regardless of APOE status. This would provide a clearer overall picture of the study population.

2. Author should also explore whether the interaction between APOE genotype and social adversity differs by sex or racial/ethnic group.

3. Since social adversity was constructed using five domains of social determinants of health (SDH), it would be informative to identify which specific domain(s) demonstrated the strongest interaction with APOE genotype in relation to dementia risk.

4. In addition to the limitations already outlined, add the unique strengths and contributions of this study.

Reviewer #2: The authors demonstrated that while genetic factors, particularly APOE status, are central to dementia risk prediction, their impact is strongly moderated by social position. Using data from two large longitudinal cohorts (HRS and ELSA), they constructed a social adversity index based on education, economic stability, healthcare, neighborhood, and social context. Their analyses revealed that genetic risk was most evident among individuals with social advantage, whereas high social adversity elevated dementia risk across all genotypes. Notably, individuals with high genetic risk but social advantage had a lower dementia risk than those with low genetic risk but high social adversity. These findings highlight that social environments substantially shape the effect of genetic risk, emphasizing the importance of addressing social adversity to reduce dementia risk and improve equity in prevention strategies. Overall, the authors did an excellent job presenting their study. The manuscript is well written, highly readable, and demonstrates careful scientific consideration. The integration of genetic and social determinants of health is both timely and impactful, making this a strong contribution to the dementia prevention literature.

Reviewer #3: The manuscript “Unequal Expression: Social Position Modulates APOE Genotype Risk of Dementia” demonstrates that genetic risks affect mostly those with social advantage, and those with high social adversity have higher risks for dementia regardless of their genetic risks. The manuscript is well-written, the aims are clear, and it’s well-presented with acceptable flow. The idea in this manuscript is novel, and the data adds knowledge to the field. I do not have much, but the following comment for the improvement of the manuscript: The resolution for figures 1-3 is very low.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Unequal Expression: Social Position Modulates APOE Genotype Risk of Dementia.

PONE-D-25-31823R1

Dear Dr. Aravena,

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,

Ioannis Liampas, MD. PhD

Academic Editor

PLOS ONE