Genetic Architecture of Cognitive Resilience in Alzheimer’s Disease: Mechanisms, Pathways, and Therapeutic Implications

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors This thorough, current, and conceptually solid review effectively differentiates cognitive resilience from both resistance and reserve, with its structured framework for categorizing resilience genes serving as a significant advantage that enhances precision and insight in a swiftly progressing area. The manuscript is mostly well composed and properly referenced, with notably strong parts on APOE variants, RELN-COLBOS, and mechanisms of resilience at the synaptic/network level; however, it would improve with slight tightening to minimize repetition (particularly in subsections related to APOE), clearer distinctions between established human genetic evidence and more inferential biomarker or expression-based correlations (e.g., TFEB, NPTX2), and some cautionary wording when single-case extreme-phenotype results are used to suggest wider therapeutic approaches. The Methods section could be improved by succinctly explaining how cognitive measures were standardized across cohorts and how confounding factors like education or cognitive reserve proxies were addressed. In the Results and Discussion, certain pathway assignments (e.g., systemic metabolic effects for ATP8B1 or bile acid signaling) are compelling but would gain from a more explicit recognition of indirectness and the existing limits of evidence. In general, this is a well-crafted and perceptive synthesis that will benefit the field, needing only slight adjustments for balance, brevity, and clarity. Comments on the Quality of English Language

Minor English editing is required

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript provides an extensive review of genetic factors and biological pathways that promote cognitive resilience, defined as preserved cognition despite significant Alzheimer’s disease neuropathology. The authors need to revise the structure, tighten the narrative, and provide clearer justification for major claims.

1. Abstract is overly dense for a general‑audience review. Consider simplifying the mechanistic list to focus on the most robust pathways.
2. APOE, CLU, and lipid‑related pathways are described multiple times with redundant mechanistic explanations (e.g., lipidation, HSPG binding, astrocytic lipid handling). This redundancy undermines readability.
3. The manuscript places heavy emphasis on the Colombian PSEN1 carriers with APOE3‑Christchurch and RELN‑COLBOS. These cases are fascinating but cannot serve as the backbone for generalized mechanistic conclusions. It’s better to frame these cases explicitly as hypothesis‑generating rather than broadly representative of resilience genetics.
4. The therapeutic section presents resilience‑pathway targeting as broadly feasible but does not address the dose‑dependent toxicity of TFEB activation, immune overstimulation risks (PLCG2‑mimetic therapies), challenges of gene delivery, distribution, and timing.
5. Missing discussion of confounders such as ancestry differences, Sex‑specific effects, and Age‑related transcriptional drift affecting microglial and synaptic pathways.
6. Several genes (ATP8B1, PLA2G4A, CTSH), the mechanistic arguments do not clearly connect to measurable cognitive outcomes, only to cellular effects or biomarker changes.
7. The APOE section is overly long and repetitive. A single comparative figure summarizing key functional differences among APOE2, APOE3‑Christchurch, APOE3‑Jacksonville, and APOE4 would streamline the text and improve reader understanding.
8. Several hyphenation inconsistencies
9. Text contains scattered line breaks and PDF‑extracted spacing artifacts, likely from the transfer; these should be cleaned for final submission.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I am writing to understand regarding the revised version of your manuscript. In this revision request, my previously submitted comments and your responses to those comments are not present, and it appears that the issues I raised have not been addressed.

 

Author Response

Responses to Reviewer 2 comments

We are very grateful to Reviewer 2 for additional suggestions to improve this manuscript. Overall, we have done our best to revise the manuscript keeping in mind all the suggestions from Reviewer 2. The changes that we have made can be traced in the pdf version of the manuscript with tracking.

1. Comment 1: Reduce repetition, particularly in APOE-related sections.
2. We have reduced the content and removed most of the repetitions in both the APOE-related and other sections in this revised version.
3. Comments 2: Clarify distinctions between established human genetic evidence and inferential biomarker or expression-based correlations.
4. Yes, wherever the evidence is not strong for resilience, we have emphasized that the evidence is only empirical based on expression levels. Examples include APOE3 Christchurch, probable for APOE3-Jacksonville (V236E), APP Icelandic (A673T) variant as resistant rather than resilient factor, hypothesis driven for RELN-COLBOS (H3447R) because of its rarity, probable resilient factor for NEDD9 rs760678, probable for CTSH rs2289702 and also for SPI1/PU.1 rs1057233, as context-dependent for IL1RL1 rs1921622 and finally only experimental evidence and no genetic evidence for PLA2G4A,
5. Comments 3: Methods section should clarify cognitive standardization and confounders.
6. The methods section now explains the cognitive standardization and confounding factors.
7. Comments 4: Minor English editing is required.
8. All grammatical mistakes were corrected in this revised version.