Forty-two steps in the right direction for Alzheimer’s research – Medical University of South Carolina

Forty-two new genes related to Alzheimers disease (AD) have been discovered, reports the European Alzheimer & Dementia Biobank consortium in a study published on April 4 in Nature Genetics. As the largest study of genetic risk for AD, its findings will be the foundation for new research ideas and treatments. It certainly has raised the interest of MUSC researchers.

There is still so much we dont know about Alzheimers disease, said Lori L. McMahon, Ph.D., vice president for Research at MUSC. As researchers, were working to find the causes of this disease, and identifying genetic risk factors is an essential discovery and could lead to improving lives of those dealing with its effects.

Several leading AD researchers in the Department of Pathology and Laboratory Medicine at MUSC were asked to offer insights into what these findings means for the future of AD research and treatment. Steven Carroll, M.D., Ph.D., chairs the department and heads up the Carroll A. Campbell Jr. Neuropathology Laboratory, a brain bank that serves as an important resource for researchers studying AD and other dementias. In his own research, Carroll has identified chemical tracers that concentrate in regions of the brain affected by AD, allowing them to be visualized by a scan. This visualization provides a potential means to detect AD early and monitor its progression.

Hongkuan Fan, Ph.D., an associate professor in the Department of Pathology and Laboratory Medicine, collaborates with Perry Halushka, M.D., Ph.D., Distinguished University Professor of Cell and Molecular Pharmacology, to study the role leaky blood vessels caused by inflammation could play in the development of AD. They have recently identified a potential therapeutic target.

Eric Hamlett, Ph.D., an assistant professor in the Department of Pathology and Laboratory Medicine, studies the aging brain and has shown in an animal model that a certain type of fat cell can help to resolve inflammation and could potentially help to prevent memory loss caused by long-term inflammation in patients with AD and Down syndrome.

Q. Before these findings, what were the limitations in AD research, and how have they addressed those limitations?

A.(Carroll) One of the big limitations has been that we didnt have a complete understanding of what causes the disease. These findings are really helping us in a couple of ways. First, it confirms the importance of key players in AD development that we had already identified such as amyloid and tau. Second, it drives home the message that other cell types, such as microglia, play a very important role in the inflammatory process that is essential for the development of the disease. Our understanding is evolving. We once thought of AD as a disease of neurons. Its now becoming clear that AD is a disease that involves complex interactions between numerous cell types in the brain and not just neurons alone.

You know, this is about 42 new genes that had not been previously implicated in causing the disease. And now this means that there are a whole host of new pathways that can be studied to treat people with AD and other dementias.

A. (Fan) Recently, people have realized that if we only target amyloid or tau, that will not be sufficient to cure AD. Therefore, a broader picture is needed to improve our understanding of the underlying mechanisms. The study identified 42 new genes involved in AD development, broadening our understanding of AD pathology. This will encourage people in this field to study these genes and understand how they are involved in AD development. This research could lead to a novel treatment for AD.

Q. How will this finding affect patient treatment?

A.(Carroll) There has been some speculation that AD may not be just one disease. There may be several different types of it. Now that we've got a much broader handle on a large number of genes involved in causing AD, we can begin looking at whether some of these genes are involved in some cases of AD and others are involved in other cases. So, if that turns out to be the case, then it means there may not be a one-size-fits-all therapeutic approach for AD. We may need to sort out whether there are subtypes of AD so that treatment can be personalized based on a patients subtype.

The authors of this paper developed a scoring method that could be used to measure how many of these potentially causative variants an individual with Alzheimers has. That raises the possibility that we might be able to identify individuals who are at higher risk and prioritize them for early treatment with some of the currently available medications.

A. (Hamlett) What we really want to do is to treat something like AD extremely early, when people are in their 50s and 60s and not yet showing symptoms because thats when treatments are most likely to be effective. This paper provides a more extensive road map into the pathways involved in the development of AD. We have to know all the factors that are in play so that we can try to find a biomarker that can predict disease onset.

Q. What does this paper teach us about the role of inflammation in the development of AD?

A.(Hamlett) I study factors that affect inflammation. I'm excited that this articles findings support our approach and provide more rationale for studying inflammatory responses. I was also excited to see that Im not currently studying some of the genes identified by the paper as important to inflammation. I need to fold these discoveries into how I look at inflammation. Im sure there are many other researchers who are thinking the same thing. Inflammation is clearly playing at least some sort of temporal role in the development of the disease.

A.(Fan) This paper highlights the immune response and inflammation in AD development. We recently discovered that a transcription factor named Fli-1 plays a critical role in AD development and that it may be a therapeutic target for AD. If we suppress Fli-1, we can dramatically suppress inflammation levels. The focus of my research will be on limiting neural inflammation and trying to develop a treatment strategy for AD.

Q. What do you think is the most important takeaway from this research?

A.(Carroll) I think the most important takeaway is that AD is a lot more complicated than we realized. However, an understanding of it is within our grasp, and these findings provide much-needed clarity as to who the players are and what the critical pathways are that are involved in this disease. This is going to give us a very strong foundation for a lot of hypothesis-driven studies moving forward that are going to clarify whats causing the disease and how we can intervene to treat it.

Q. How might the studys findings of a genetic basis for AD be misinterpreted by the public? Do you have words of caution to offer?

A. (Hamlett) If you read this paper, you may come from it and think Oh my goodness, my dad or my brother has got Alzheimers. Im going to get it now. Thats not the case. Lifestyle also matters. This study does not address your risk for AD if you're eating a good diet or you have a healthy lifestyle. Theres no way to understand accurately how each of these mutations interfaces with lifestyle, and thats the part thats missing. The discovery of genetic fingerprints can be awfully scary. But what do we do about that? We continue to maintain a good lifestyle until researchers can find drug targets using this new information to decrease our chance of getting AD.

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Forty-two steps in the right direction for Alzheimer's research - Medical University of South Carolina