Genetic Insights into the Impact of Complement in Alzheimer’s Disease

Round 1

Reviewer 1 Report

In this review paper, Torvell and colleagues analyze the role that complement exerts in alzheimer's disease etiology, evaluating the impact of genetic variants in complement genes.

The review is very well written and organized, and there is a clear flow that allow the reader to follow the topics illustrated by the authors troughthout the text body. The table is comprehensive and the figures are of very high quality.

Author Response

The authors thank the reviewer for their prompt review. We are pleased the reviewer found the manuscript comprehensive and well written. Thank you.

Reviewer 2 Report

This is a very nice review and covers some of the important complement components, but certainly not all.  I think a pretty strong case could be made for C9, among other complement components.  Why these were chosen over others is not clear.  Because the strongest association is still ApoE, the authors should include an opinion piece on the effect ApoE might have on the complotype.  I strongly recommend the reviewers look at the references once again.  There were a few instances where the citation did not match the content, "Clusterin mRNA is upregulated in AD tissue [64, 65]".  Poor examples.  There are a couple nice papers from Buckley's group that discuss clusterin and AD.

I would refrain from making strong/without support comments e.g. "By default, these studies only address late/end stage disease and provide no clues to how complement activation impacts the disease."  There have been many clues over the years.  The fact that GWAS studies are homogenized tissue samples, peripheral blood in the vessels will be included.  It would be wise to discuss the potential implication of peripheral blood cells in the analysis, this is particularly pertinent when discussing the complement system.  

Author Response

Please see the attachment.

Author Response File: Author Response.docx