We know that your genes play a big part in your risk for various diseases, but up until the ’90s it was believed that only one percent of Alzheimer’s cases were caused by inherited genes. Since the discovery of the ApoE4 gene in 1993, which increases the risk of Alzheimer’s as much as tenfold, scientists have been searching for more genetic risk factors that could unlock new treatments for the disease. Being Patient talked to Dr. Bruce Lamb, Ph.D., Director of the Stark Neurosciences Research Institute at Indiana University, on his search to discover new genes that might play a part in the disease by changing the DNA of mice to see what happens in with the disease’s progression.
- ApoE4 is not the only gene related to Alzheimer’s
- The immune system gene TREM-2, when mutated, increases chance of Alzheimer’s by four times
- Activating the immune system in cases of traumatic brain injury can create a lasting inflammatory response in the brain
Being Patient: Your research focusses on trying to understand the basic science behind what’s causing the degeneration of neurons in Alzheimer’s and you’ve found some surprising results about the genetics of the disease. Can you tell us about them?
Dr. Bruce Lamb: A lot of our work is revealing brand new biology, and that’s why I think genetics is so exciting. Recent discoveries have shown that some of the genes [implicated in Alzheimer’s] are immune system genes – genes that are not normally expressed in neurons. That suggests there are some connections here that we really don’t understand. We’ve been doing a lot of work studying a particular gene, TREM-2, and how we think it’s involved. It’s only expressed in these myeloid (immune) cells. There’s a known, fairly rare mutation in that gene that increases the risk [of developing Alzheimer’s] by about fourfold. So we’ve been generating [mouse] models to figure out, how is that working? What is that molecule doing and when it’s mutated, how does that change its function?
Being Patient: Have you been able to identify what role it plays?
Dr. Bruce Lamb: So for TREM-2, one of the things that’s well known [is that] when amyloid deposits in the brain, you do get a set of immune cells, called macrophages that surround it. That’s been known since the time of Alois Alzheimer. But we always wondered, is that cause or consequence [of the disease]? If you remove TREM-2 completely – it’s called a ‘gene knockout’ – where we just remove it from the mouse – these cells disappear. Those macrophages that normally surround the plaques are gone. And that ultimately leads to an increase in amyloid pathology and a worsening of overall phenotypes we see in animals. So we think, potentially those macrophages wall off amyloid, as a protective function.
Being Patient: A lot of research has linked traumatic brain injury and the development of Alzheimer’s or dementia. What has your research into immune cells shown you about the link between traumatic brain injury and dementia?
Dr. Bruce Lamb: We know very well in traumatic brain injury, one of the first and most prominent features of the disease is robust activation of the immune system in response to the injury. We’ve now shown that right after injury this TREM-2 protein is [involved in] an acute injury response. We think, initially, that’s probably a very good thing and is a normal protective response but then, it has a chronic consequence.
Being Patient: Have you been able to measure the long-term consequences of this inflammatory response on the brain?
Dr. Bruce Lamb: There is evidence now that there’s often a sustained neuro-inflammatory response in professional people who have repeated brain injuries. There’s new imaging technology that’s being developed to map inflammation in the brain, and it’s clear from that research that you can have changes in that neuro-inflammatory for decades, potentially. That brings up a whole set of questions, and again, we don’t really know. The inflammatory response is probably really good, and very important, in terms of your normal response to injury, but I think that most of our data suggests that this chronic situation is really not beneficial both for neurodegeneration or Alzheimer’s disease. But again, what is the mechanism exactly? What is it exactly about those immune cells that does that? That’s something that we don’t know.
Being Patient: We’ve seen studies with conflicting findings on the link between brain injury and neurodegeneration, with some saying it is associated with dementia and some contradicting that. Can you say, from your research, which is correct?
Dr. Bruce Lamb: There is data, strong data actually, in both directions. I think it’s fairly clear that, as you go up in severity of brain injury, there are definitely associations with a variety of different neurodegenerative diseases. Especially [in the case of] repeated concussions in football players who, at least a proportion of them, seem to go on to develop chronic traumatic encephalopathy. And so, the question for the field right now is, how common is that? Both within professional sports, but, more generally, in the overall general population. There have been a couple of general population-based studies, and it doesn’t seem like this is something incredibly common. So, the question becomes ‘What percentage of the athletes?’ but there’s been no good longitudinal study. I think it’s clear that not every professional athlete develops this, who even gets repeated concussions.