{Trying to} Elucidate the Glucose - Alzheimer's Relationship

I think I've been trying to look for a clear-cut answer when there really is none. It would be great if one group of people were definitely right. If one theory could be proven so it is an absolute truth, we would be living in a perfect world. But the reality simply is that we can't crack someone's skull open and observe Alzheimer's development in vivo. But you already knew that.

So the question then becomes, what can we do? We know our limitations, but how do we work within those boundaries? So one answer to that, could be C. elegans, or mice, or pigs, or sheep, or any organism that is as close as possible to human without actually being human. And as I think about my podcast amidst all of this, I am again and again coming back to the idea that understanding human biology is not a straightforward, one-stop shop kind of thing. Which you would think is something that I've realized long before recently but sometimes, it's easy to forget that and we take our current scientific standing for granted.

On a more general scale, it's like you've worked really hard to score well in a specific subject, but because that success has become the new normal, it's possible to forget everything before the present and of course, when you want to improve even more, it's more difficult to bring back that zealous spirit. Obviously, not everyone works like this, but I think this holds true for myself and especially when I think about my attitude towards C. elegans in the past. I used to read about clinical studies and consider their future impact on the field, but I would never think about what was done in the past to lead up to that breakthrough. It's not necessarily always something bad because dwelling for too long on the past isn't good either, but perspective is important. We must take stock of what was necessary prior, and how the current findings affect future studies without losing sight of either piece.

The other thing now, that has been occupying my mind quite intensely is this Alzheimer's-Hyperglycemia relationship that it seems I cannot even begin to understand. So I've looked a little more closely at the published studies on this and what I was surprised to find is that people have tested this connection but in an almost reversed manner. They've started with a population that has diabetes (most looked at type 2) and done a longitudinal study to see if that population was at greater risk for Alzheimer's Disease later in life. I spent some time thinking about this yesterday and I think I've concluded that I'm asking a, related, but distinctly separate question (at least concerning the glucose piece of the oxidative stress theory - not my larger research question).

My inquiry lies in whether a precursor gene such as APP or PSEN1 - assuming that they cause oxidative stress prior to plaque accumulation - also causes high blood-glucose levels as a result of Alzheimer's Disease. Because it's one thing to have diabetes before AD and another thing to develop it as a direct result of the disease. The biggest thing for me about studies that start with diabetes and test if it leads to AD is, how are subjects of the studies being controlled? How can you ensure that the diabetes did not come from a completely different genetic predisposition or environmental/habitual factor and had virtually no effect on the independent development of Alzheimer's? By doing the opposite, then, by starting with people who have AD and develop diabetes later on in their diagnoses, you aren't completely eliminating that margin of error/limitation, but minimizing it because AD is a disease that when developed, leads to whole-body effects since it changes the brain's function.

But then again, it's still really difficult for me to understand something like that. Why do cells in the brain just stop accepting glucose? Is that like negative feedback from aging? If that were the case though, would it be as easy to detect as what we consider to be the more common condition of Diabetes? Could Alzheimer's really begin in the pancreas? Because essentially, if the body is not producing enough insulin to help brain cells accept glucose, then we're talking about the pancreas. But simultaneously, you've got beta secretase for all proteins in the pancreas. Assuming that the Amyloid-beta protein is cut according to a beta structure as a result of beta cells (insulin-carrying cells in the langerhans coming from the pancreas and thus associated negatively with diabetes) does that mean all proteotoxicity arising from misfolded beta fluctuations comes from diabetes? From the pancreas? But I think that's a weird question because if the pancreas is not producing enough insulin, then it should not be producing enough beta cells either... do you see my dilemma? Or actually, does the real case lie in that beta cells are being produced but the other cells, be it in the brain or the rest of the body, are developing a resistance to glucose? The next thing that comes to mind though, is how do two mutations such as the one for type 1 diabetes and an Alzheimer's precursor gene interact with one another. Which one prevails and thus engenders the snowball of detrimental conditions?

As I'm sure you can tell, I am very very confused on this early November morning. But I must remember the same concept I was discussing earlier. Breakthroughs, the answers to these questions aren't going to come overnight and they definitely won't be clear. We've got to start small and work our way up. How did I come to understand (as little as I do at the moment) Alzheimer's? By learning the characteristics, symptoms, pathways that we know of, etc. But that doesn't mean I can assume I completely understand Diabetes. Remember, don't forget the work it took to get where you are. Maybe I should go back and study Diabetes in isolation before trying to understand the relations of pathogenesis between the two diseases. Although thinking about all of this stuff makes my own brain hurt, questions are liberating and they are guiding. I probably won't explore every single question I've raised over the past four months but the larger the question bank, the more ownership one must take. My only hope then, is to take ownership of the right questions.