Another rainy day

https://www.science.org/content/blog-post/reversing-alzheimer-s

Many people have asked me about my opinion on this recent Alzheimer’s paper, and my opinion lands in the large zone of “interesting work that I hope is followed up on”. That may come as a disappointment, because some of the headlines about this paper have been breathless Cure-For-Alzheimer’s stuff, which is always a danger in this area, and for all I know there may be some folks out there who’d like to see me dismiss these results as yet another hopeless Alzheimer’s quest.

But that’s the hard part in working in this area (as I did once) or in writing about it as I do now: there are very few Alzheimer’s quests that are completely hopeless. Unfortunately, that phrase better describes our current ability to reverse the disease’s damage. I myself don’t think that the current antibody therapies even do a useful job of slowing it down, and no one is claiming that they can cause people to regain function that they have lost. But the title of this new paper starts off with “Pharmacologic reversal of advance Alzheimer’s disease in mice”, which is an attention-getter for sure.

The compound under study is called P7C3-A20, and here’s a 2014 paper on the neuroprotective effects of compounds in this class, along with a paper on their effects after traumatic brain injury. So this is not a sudden new development, and that’s not even the beginning of the story. The compound itself was described in a 2010 paper by the same group as the best hit out of a phenotypic screen for beneficial CNS compounds, and you’ll see references in those 2014 papers to effects on other neurological injuries or neurodegenerative disorders. These effects seemed consistent not with stimulating new neuronal growth per se, but with protecting the survival of new neurons as they are produced. The application of this compound to Alzheimer’s is not a surprise, and to be honest I’m surprised that it’s taken as long as it has given the earlier publications.

The 2014 work proposed a target for P7C3-A20, namely the nicotine adenine dinucleotide (NAD) salvage pathway. The compound appears to bind to (and enhance the activity of) the enzyme nicotinamide ribosyltransferase (NAMPT), which is the key enzyme in NAD re-synthesis. NAD itself is of course known as a very important small molecule in biochemistry, participating in a whole list of redox activities in the cell (many of which take place in mitochondria) and acting as a cofactor for a range of enzymes. Many of these reactions produce nicotinamide itself as a consequence of their mechanisms, and NAMPT is the enzyme for the rate-limiting step that produces fresh NAD from nicotinamide. (NAD can also be made de novo, but the “salvage pathway” is extremely important because not enough NAD can be produced otherwise).

Given its importance, the role of NAD levels and handling in diseases like Alzheimer’s has been investigated for a long time now. But just outright taking NAD supplements is not a slam-dunk idea, because many types of cancer cells have even higher NAD requirements than normal tissue. The worry has been that you will just be doing any incipient cancers a favor by raising your NAD levels across the board even though you might also be helping out beneficial cell lines like tumor-infiltrating T cells at the same time. Some studies have shown increased risks of some types of cancer with NAD supplementation, and overall, the recommendation has been to hold off on doing that until we understand the risk/benefit landscape better. (The paper under discussion has many links to the literature on this topic).

In this case, though, P7C3-A20 is claimed to restore NAD homeostasis without producing excess NAD per se, which would seem to be a better outcome. The new paper shows evidence for the robustness of NAD homeostasis and severity of Alzheimer’s, and this goes all the way up to humans. That’s through testing of brain sample of people who died showing signs of Alzheimer’s pathology in their tissue, while not exhibiting notable cognitive deficits.

That possible human connection is a big deal here, because the rest of the study is done in mouse models. These show some very interesting results where it does look like you can make the case that some deficits are being reversed, and that’s a rare thing to see in any neuronal-level CNS work. But I m not a good customer for rodent models of Alzheimer’s. My big problem is that rodent’s don’t actually get Alzheimer’s. Nor, to the best of my knowledge, do any other animals except humans. And that’s not just because we know human behaviors so much better or because we have all these higher brain functions to lose. No other animal shows the cellular-level brain pathology associated with Azlheimer’s disease. If you want to see something like that, you have to engineer it in.

How though, you might wonder, do we engineer Alzheimer’s mice when we’re still not certain of the fundamental causes of Alzheimer’s? Well should you ask. As the world knows, the main hypothesis for Alzheimer’s etiology over the decades has to do with the beta-amyloid protein,its overall levels and its handling in various regions of the brain. There are a lot of good reasons for that, as detailed in this post. And since I mention that, let me reiterate that no, the whole amyloid/Alzheimer’s field has not been based just on some work that has now been shown to be fraudulent (a statement that I still see being made by people not familiar with the history). That work did damage, but it was mostly by providing more confidence to many investigators to believe what they believed already.

You can see where this is going: the mouse models for Alzheimer’s are generally animals that have had mutations placed in pathways for amyloid production and handling. If you are more confident that amyloid handling really is a fundamental part of Alzheimer’s pathology, then this probably won’t bother you much. If (like me) you have come to doubt that connection more and more over the years, you may be less enthusiastic. But the glass-half-full position is that whether or not such animals are experiencing “real Alzheimer’s” or even something close to it, they most definitely are experiencing neuronal stress. And a compound that seems to alleviate it would be very much worth pursuing further.

So that’s where I land here. I think this compound (and/or this mechanism of action) seems worth pursuing in human trials after the usual preclinical checks, and my main question now is why it hasn’t been, after all these years and all these publications. I fear that part of the answer could well be the dominance that amyloid mechanisms (and to a lesser extent, tau protein mechanisms) have had over the field. This concentration looked for many years like a welcome level of targeted effort on the most promising hypothesis in the field, but as the decades have worn on, less so. Amyloidocentric ideas have advanced to the clinic over and over, and the absolute best of them have been - in my view - underwhelming and practically useless. If amyloid were really as central a player as we all used to think, this just should not have been the case.

The resulting starvation of alternate approaches might be well illustrated by the long-running story of P7C3-A20. I do wonder, though, if there are other factors at work. After all, other long-shot ideas in Alzheimer’s and neurodegeneration in general have made it into at least small trials based on what may well be less promising results than these. The potential for such drugs is so huge that you can often get people to put a little backing behind them, but I haven’t even seen that much here (from what I can see, P7C3-A20 has never made it into a human trial at all). Is there a Rest of the Story here? And where does the story we know about go at this point? I’ll be watching with interest.

https://www.science.org/content/blog-post/reversing-alzheimer-s