How Can Insulin Resistance Cause Alzheimer’s Disease?

Round 1

Reviewer 1 Report

Ji Hye Yoon et al. presented a literature review "How Can Insulin Resistance Cause Alzheimer's Disease". The authors review the pathophysiology of Alzheimer's disease (AD) and the association of AD to diabetes, with an emphasis on insulin resistance as an important factor in the AD development. The authors discuss how insulin resistance can be associated with dementia and the cause of AD. In addition, the insulin resistance and hypometabolism in AD is discussed as a possible reason for failing to show therapeutic effects in the treatment of AD.

Overall, this is an interesting review article that will be useful to specialists studying both AD and diabetes.

  Major

It should be noted that the relationship between Alzheimer's disease and diabetes has been demonstrated in a large number of works, while the relationship of these diseases is considered primarily through the heterologous interaction between Aβ peptide and IAPP (islet amyloid polypeptide). Many studies have revealed colocalization and possible interaction of Ab and IAPP in blood vessels and brains of mice and humans, as well as the pancreas. Misfolded IAPP has been shown to accelerate Aβ aggregation in vitro and inoculation of misfolded IAPP into mouse brain results in more severe AD pathology and significantly greater memory impairments than in untreated animals (Claudio Soto’s Lab). In this regard, I would like the authors to comment on these data and at least briefly discuss them in their review.

 

Minor

- Dementia is not a disease, but a neuropsychiatric syndrome (that is, a whole complex of symptoms related to the specific condition of the patient) (see lines 33, 53).

- In some cases, there are no references to sources of information (for example, see lines 39-40; 58-59; 83-89; 172-183, etc.).

- There is no reference to figure 1 in the text.

- The left panel of the figure 6 is hard to read, the font size should be increased.

- The data presented in chapter 2 (see lines 70-80) duplicate the information presented in section 3-3.

- Fix microtubles to microtubules (line 271).

- Fix exicitotoxicity to excitotoxicity (lines 747-748).

- Subsection titles should be in italics. Also, in the numbering of subsections, the hyphen should be replaced with a dot (for example, instead of 3-1. it should be 3.1. etc.).

- The authors should carefully review all references and arrange them in accordance with the requirements of IJMS, while removing unnecessary and adding missing information.

Author Response

Ji Hye Yoon et al. presented a literature review "How Can Insulin Resistance Cause Alzheimer's Disease". The authors review the pathophysiology of Alzheimer's disease (AD) and the association of AD to diabetes, with an emphasis on insulin resistance as an important factor in the AD development. The authors discuss how insulin resistance can be associated with dementia and the cause of AD. In addition, the insulin resistance and hypometabolism in AD is discussed as a possible reason for failing to show therapeutic effects in the treatment of AD.

Overall, this is an interesting review article that will be useful to specialists studying both AD and diabetes.

  Major

It should be noted that the relationship between Alzheimer's disease and diabetes has been demonstrated in a large number of works, while the relationship of these diseases is considered primarily through the heterologous interaction between Aβ peptide and IAPP (islet amyloid polypeptide). Many studies have revealed colocalization and possible interaction of Ab and IAPP in blood vessels and brains of mice and humans, as well as the pancreas. Misfolded IAPP has been shown to accelerate Aβ aggregation in vitro and inoculation of misfolded IAPP into mouse brain results in more severe AD pathology and significantly greater memory impairments than in untreated animals (Claudio Soto’s Lab). In this regard, I would like the authors to comment on these data and at least briefly discuss them in their review.

• Thank you for the insight about the interaction of Ab and IAPP. We have commented about these finding.

 

Minor

- Dementia is not a disease, but a neuropsychiatric syndrome (that is, a whole complex of symptoms related to the specific condition of the patient) (see lines 33, 53).

--> we have modified accordingly

- In some cases, there are no references to sources of information (for example, see lines 39-40; 58-59; 83-89; 172-183, etc.).

--> we have included some references supporting the arguments.

- There is no reference to figure 1 in the text.

 --> we have referred figure1 in the text

- The left panel of the figure 6 is hard to read, the font size should be increased.

--> we have increased the font size

- The data presented in chapter 2 (see lines 70-80) duplicate the information presented in section 3-3.

--> the contend of chapter 2 is changed simply.

- Fix microtubles to microtubules (line 271).

 --> typo was fixed

- Fix exicitotoxicity to excitotoxicity (lines 747-748).

--> fixed

- Subsection titles should be in italics. Also, in the numbering of subsections, the hyphen should be replaced with a dot (for example, instead of 3-1. it should be 3.1. etc.).

--> fixed

- The authors should carefully review all references and arrange them in accordance with the requirements of IJMS, while removing unnecessary and adding missing information.

--> we have modified the references and removed or added some information accordingly.

Reviewer 2 Report

Ji Hye Yoon et al presented a comprehensive review on the contribution of insulin resistance to the development of sporadic Alzheimer's disease (AD). In my opinion, the depth of the analysis of the problem carried out by the authors will make this review a notable event in the sea of literature already available. Indeed, if you enter the keywords AD and diabetes into PubMed, you will see that in 2022 alone, 938 articles have been published on this topic and a third of them are reviews. At the same time, about 10 thousand reviews on the pathogenesis of the disease have been published over the past three years. In this regard, it seems unjustified that the authors paid so much attention to general issues, and did not make links to other quality reviews. Figures 1-4 seem redundant and insufficiently informative. If we are to cite well-known facts, we should make appropriate explanatory captions for the figures.

It should be noted that In the first half of the review the authors  focused on the analysis of the exclusively amyloid hypothesis of the pathogenesis of AD. The amyloid cascade hypothesis is now losing its dominance. An increasingly growing body of evidence has demonstrated that AD is a heterogeneous disease caused by various pathophysiologic mechanisms beyond the typical dogma. Only one among them is insulin resistance, the contribution of which to the pathogenesis of AD is obvious, but the mechanisms remain not completely clear.

          When discussing the heterogeneity of the mechanisms of AD development, I consider it necessary to refer to a unique study Resently Ryan A. Neff et al. (Sci Adv. 2021;7(2):eabb5398)  in which  three major molecular subtypes of AD corresponding to different combinations of multiple dysregulated pathways  were identified.These subtypes are independent of age and disease severity. Importently, that  only about one-third of the AD cases carry consistent hallmarks  of a “typical” AD presentation, while the rest show opposite molecular gene regulation and other complex changes across multiple pathways and cell types.

Author Response

Ji Hye Yoon et al presented a comprehensive review on the contribution of insulin resistance to the development of sporadic Alzheimer's disease (AD). In my opinion, the depth of the analysis of the problem carried out by the authors will make this review a notable event in the sea of literature already available. Indeed, if you enter the keywords AD and diabetes into PubMed, you will see that in 2022 alone, 938 articles have been published on this topic and a third of them are reviews. At the same time, about 10 thousand reviews on the pathogenesis of the disease have been published over the past three years. In this regard, it seems unjustified that the authors paid so much attention to general issues, and did not make links to other quality reviews. Figures 1-4 seem redundant and insufficiently informative. If we are to cite well-known facts, we should make appropriate explanatory captions for the figures.

 

• Thank you for your valuable comments. We agree that it would have been better to go into depth about insulin resistance and dementia rather than starting with the general concepts of dementia and AD. However, here, we tried to summarize and present the information on the pathophysiology of AD and make a link with the pathology of insulin resistance. As a result, a lot of redundant content was included, especially figure 1-4. However, on that point, we thought the redundant content may help the readers understand the whole picture about the relationship between insulin resistance and dementia.
• We also added a explanatory caption for the figures

 

It should be noted that In the first half of the review the authors  focused on the analysis of the exclusively amyloid hypothesis of the pathogenesis of AD. The amyloid cascade hypothesis is now losing its dominance. An increasingly growing body of evidence has demonstrated that AD is a heterogeneous disease caused by various pathophysiologic mechanisms beyond the typical dogma. Only one among them is insulin resistance, the contribution of which to the pathogenesis of AD is obvious, but the mechanisms remain not completely clear.

 

• In this text, we explained the amyloid hypothesis, which was previously believed to be the main pathological mechanism, and the related effects of insulin resistance were discussed. However, as the reviewer commented, we stated that insulin resistance is only one of several pathogenic factors.

 

          When discussing the heterogeneity of the mechanisms of AD development, I consider it necessary to refer to a unique study Resently Ryan A. Neff et al. (Sci Adv. 2021;7(2):eabb5398)  in which  three major molecular subtypes of AD corresponding to different combinations of multiple dysregulated pathways  were identified.These subtypes are independent of age and disease severity. Importently, that  only about one-third of the AD cases carry consistent hallmarks  of a “typical” AD presentation, while the rest show opposite molecular gene regulation and other complex changes across multiple pathways and cell types.

 

• Since our purpose was to examine the process about how insulin resistance induces dementia, we focused more to explain on this topic. Therefore, the content of the above paper was not explained in detail, but we stated that AD has heterogenous mechanism and various disease progression and the above paper was presented as an example.

Round 2

Reviewer 1 Report

In the revised submission, the authors have addressed my comments and concerns raised on their original submission. Therefore, I hereby recommend the revised version of the manuscript for publication in International Journal of Molecular Science.