The Plot Thickens

This week was a very exciting one for the Alzheimer's Research world. Two research teams, one in Japan and one in Sweden, published papers on their groundbreaking research that could unlock the key to Alzheimer's disease. The catch here? One supports the Amyloid hypothesis, furthering our knowledge on the pathway, and the other seeks to disprove it, arguing that Alzheimer's is like diabetes in the brain.

It was pretty interesting, as I read these publications, I noticed that both papers claimed to have identified a novel characteristic about Alzheimer's. I wonder though, does the fact that they explore Alzheimer's in two completely different directions take away from how groundbreaking they are? I mean, probably not because as I mentioned last time, each paper will be significant in it's audience of scientists who agree with the assumed hypothesis.

Okay, so you're probably wondering exactly what these publications discussed. The team from Japan was exploring the theory of oxidative stress being the prime causer of Alzheimer's Disease. Here, they developed a visual model to illustrate how closer study of the Alzheimer's medication (Memantine) proved that the disease is similar to a "diabetic disorder of the brain." Just like insulin helps cells to acquire energy from glucose and regulates blood-sugar levels, this team theorized that insulin plays an important role in memory acquisition through CaM kinase II activation by a membrane channel blockade (remember the red fences on the chaos tower?) Essentially, in studying the Memantine medication, researchers built upon the knowledge that the treatment uses NMDA (N- Methyl- D - Aspartate) inhibitors to prevent excessive glutamate deposits from manifesting by saying that it also inhibits activity of ATP -sensitive membrane channel mentioned earlier. This, in turn, causes dysfunction throughout the brain's insulin signaling network. When I read this, I had so many questions going through my head. A few that I ended up prioritizing were, first, what phenotypic effect does the Memantine accomplish? Is it used to improve short term recall or increase plasticity or something totally different? Because unless I understood what the medication was initially designed to target, it would be difficult to understand exactly how these researchers used it to make such a statement about Alzheimer's. The answer I found was that on a visual level, Memantine is used to treat "severe confusion" by improving people diagnosed with dementia's memory, awareness, and the ability to perform daily tasks. Okay, so the next question I had was, why on earth is the Memantine designed to target the NMDA and AMPA receptors at the Glutamergic terminal of a membrane? There has been very little evidence of Glutamate being problematic in Alzheimer's Disease. As far as this one goes, I haven't found a complete answer yet, but I'm thinking that the people used in this study likely possess some kind of pro- aggregate genetic background that makes Glutamate deposits a threat. I was also really excited while reading this article, because they discussed LTP! It means Long-term Potentiation and this was a concept I learned early last year about neuroplasticity - one of the common problem areas for both Alzheimer's and Autism. It was kind of nice to be able to understand all the receptor names and understand the process in the context of something like the Memantine medication. But that's essentially the general idea of the paper. It seems pretty groundbreaking and they present a compelling argument, but it also seems that people are rather skeptical. So I found this article on Twitter and one of the replies to the tweet was questioning whether or not throwing the amyloid-hypothesis out of the picture is right. I think this brings up an important point - time and trust. A lot of people subscribe to the Amyloid - Hypothesis because it's been around for a long time and there is quite a bit of evidence in its favor. On the other hand, I'm not convinced that the diabetic pathway theory is wrong, but I also hesitate to say that it's what Alzheimer's research has been missing all of these years. It takes time to build trust and it also takes time to convince to change their minds. If this theory truly is the real explanation, then time will tell, even if only from the evidence point of view.

The other article now, hailing from Sweden, was a little more agreeable in terms of what most people believe (I was the only one who replied to this tweet with a question). Here, they looked at the origin of Amyloid plaques, stating right from the beginning that they are assuming the Amyloid - hypothesis and do not believe that brain atrophy or hypometabolism play any sort of role in Alzheimer's pathogenesis. To be brief, this team looked at people who had pre-clinical Alzheimer's meaning they had the A-beta precursor gene. They did mention, however, that there was to some degree, possible error caused by less than 100% surety that all subjects of the study were definitely looking at Alzheimer's in the future. At times, the gene can present itself asymptomatically while at other times, it can be combined with a number of other diseases. The team found that the earliest signs (using PET scans) of dangerous Amyloid amounts could be found in Cerebrospinal Fluid and the first plaques were located in the Default Mode Network - explaining why cognition becomes severely impaired. Acknowledgement of the proteins within CSF though, does something important - it affirms the involvement of the Glymphatic system in Alzheimer's Disease and in waste drainage from the brain. My biggest question about this article, was how could they conclusively state that none of this plaque buildup could be attributed to hypometabolism when they didn't even do tests to rule out oxidative stress? Once again, we see that monopoly of the Amyloid-hypothesis over this publication and much of the neuroscience world. Because the team in Japan did not assume the theory, they presented an alternative. But the team from Sweden neglected to consider the possibility of an alternative, without a question assuming that the hypothesis holds true. It's quite fascinating really, how each theory could be it's own completely separate realm of research...

Over this weekend I was very fortunate to learn all of this new information about Alzheimer's, really, the timing could not have been better. But as the title of this journal reads, the plot is thickening and it is clear that whatever I do, I have to clearly be on one side of this theory line. There is no in-between space here.