Cutting Edge Research on Alzheimer’s Disease
Jeffrey Bland, PhD, and Dale Bredesen, MD Interview Excerpt
Original publication date: December 2012
Dale Bredesen, MD is founding President and CEO of the Buck Institute for Research on Aging in Novato, CA. The Buck Institute is the nation’s first independent research facility focused solely on understanding the connection between aging and chronic disease. It opened its doors in September 1999 with the mission of increasing the healthy years of life. At the Buck Institute, world-class scientists work in a uniquely collaborative environment to understand how normal aging contributes to the development of conditions specifically associated with getting older such as Alzheimer’s and Parkinson’s diseases, cancer, stroke, osteoporosis, heart disease, diabetes, macular degeneration and glaucoma. Their interdisciplinary approach brings scientists from disparate fields together to develop diagnostic tests and treatments to prevent or delay these maladies.
In December 2012, Jeffrey Bland, PhD, PLMI Founder and President, interviewed Dr. Bredesen for his monthly audio series, Functional Medicine Update. The following excerpt will provide the reader with a glimpse into the cutting edge research taking place in the field of Alzheimer’s disease today, and will underscore the significance of lifestyle choices in minimizing one’s risk for developing this condition.
Dr. Dale Bredesen: Epidemiologically, there are many things that have been associated with Alzheimer’s disease, and any theory that seeks to explain Alzheimer’s must take into account all of these remarkably disparate risk factors for Alzheimer’s. So if you are a woman who had an early oophorectomy, at the age of 40 or earlier, you are at a two-fold risk for Alzheimer’s disease, for example. If you had little education, if you hit your head, if your vitamin D levels are low, if your homocysteine is high, if you ate a lot of carbohydrate, if you have a large waistline—all of these things—as you well know, men with low testosterone levels, you can go on and on and on. There are remarkably disparate biochemical associations with this problem, so whatever we come away with here must explain the relationship.
The second thing is that there are a number of paradoxes that are unexplained by the current theories. As a simple example, there is some beautiful work out of Cattaneo’s lab in Italy, in which he produced what’s called the AD11 mouse. This is a mouse that simply has a germ line insertion of an antibody fragment against nerve growth factor (against NGF), and over time it develops both plaques and tangles, and classic theories of Alzheimer’s do not explain that. And there are many other currently unexplained apparent paradoxes. What we’re arguing is that Alzheimer’s disease is no different than other chronic illnesses, such as cancer, osteoporosis, and atherosclerosis. These all have to do with chronic imbalances that are because of the physiological set up—that these unfortunately feature amplification. As a simple example, if you look at cancer, cancer can result from a rare somatic mutational event because of the amplification. Once you have the imbalance between oncogene activity and tumor suppressor gene activity (both of which are normal, of course), you have an imbalance between your proliferation and survival of cells versus your programmed cell death (your turnover of cells), either because you’ve smoked cigarettes, or because you’ve been out in the sun too much, or you’ve been exposed to chemical carcinogens, whatever—anything that puts that out of balance leads to cells that select themselves in a Darwinian fashion because they now have an advantage in terms of proliferation rate and/or survival rate, so that you can end up with a clinical disease that we call cancer.
In the case of Alzheimer’s disease, this is a molecular cancer, because the amplification process occurs not at the cellular level, as in neoplasia, but at the molecular species level. This is a prionic loop disease. And instead of focusing on cellular proliferation, the focus is on plasticity, i.e., the making and breaking of synapses, the growth and retraction of neurites, and the modulation of synaptic transmission, etc. So Alzheimer’s disease is in many ways analogous to cancer, but what’s interesting is that, instead of the amplifying process being at the cellular level, where you produce more cells, the amplifying process is now at the molecular species level, where you’re producing more of a molecular species, be it prion protein, or be it A-beta, or be it phosphorylated tau, or be it alpha synuclein. In all of these cases, what we’re suggesting is that there are biochemical feedback loops related to plasticity. As you will recall, we talked earlier about the idea of a thrombus: this is the structural result of the amplification process—in that case mediated by serine proteases—that results in a transient structural change that inhibits blood flow. So, in the case of AD, we’re talking about the same thing, with the molecules involved in a transient change in structure, which is at the synapse level now, that has effects on information flow instead of blood flow, but it’s the same idea with the same sort of amplification process. And it also tells you why it is that these different epidemiological processes all feed into this process that is involved with synapse maintenance.
About 20 years ago, actually, we discovered a new kind of receptor that we called dependence receptors, and these receptors essentially sample the milieu, which includes the hormonal state of the cell, the neurotransmitter interactions, trophic factor interactions, extracellular matrix, and so forth and so on. And ultimately they integrate over that biochemical space to determine whether the cell is going to survive and is going to put out processes, maintain processes, or is going to pull back and ultimately commit suicide. This is what’s occurring in Alzheimer’s disease. The amyloid precursor protein, APP, actually turns out to be one of these dependence receptors, so ultimately it senses the trophic/anti-trophic balance. One of the interesting corollaries, here, is that the A-beta peptides themselves actually have a physiological function as anti-trophins. They interfere with, for example, insulin signaling through the insulin receptor. They interfere with neural transmission through the cholinergic system, and affect glutamatergic transmission as well as other systems. They interfere with trophic signaling through NGF and BDNF, for example. So they literally have a physiological function as anti-trophins and anti-transmitters.
Dr. Jeffrey Bland: It just strikes me so strongly, Dale, that this model that we birthed a little over 20 years ago—the functional medicine model—which has this functional medicine matrix in which you sieve antecedents, signs, and symptoms through this matrix to try to understand clinical imbalances, that that model really aligns itself so, closely, it would appear, with this emerging understanding of the etiology of Alzheimer’s disease—this construct of balance, the construct of effectors and inhibitors, the construct of environmental interrelationships with gene expression factors that create new proteins that then have differing regulatory functions on cell outcome. It seems like these models are very consistent with one another. I’m just fascinated as to the precision by which you’re developing this understanding at the Alzheimer’s disease-level and how it—I think—relates with this kind of broad brush functional medicine matrix model that we’ve been working on for 20 years.
Dr. Dale Bredesen: Absolutely. I think that these chronic illnesses are network abnormalities and relate extremely well to the functional medicine model. This, to me, has very important implications. One of the implications is in the treatment of Alzheimer’s disease—and as you know, this has been a real problem, with literally billions of dollars spent so far developing therapeutics that have virtually all failed. The currently approved drugs for Alzheimer’s disease, such as donepezil and memantine, have absolutely minimal effects on the disease. If you look at the last several years, it has been uniform failure, one drug after another, from Dimebon to Rember to Alzhemed to Semagacestat to Flurizan. You just go on and on and on, and there have been no successes. It may well be that the important point here is not what you choose to treat, but what you fail to include in your therapeutics. For example, just as it doesn’t make sense to tell someone with atherosclerotic cardiovascular disease to stop their cheeseburgers, but leave the fries and the cupcakes—this makes no biological sense—it makes no biological sense to hand a single mechanistic drug to someone with Alzheimer’s and then leave their homocysteine at 18, and their vitamin D at 17, and their cholesterol at 250, and so forth and so on. Here is another analogy: We know of over 30 molecular mechanisms underlying Alzheimer’s disease pathogenesis, many of which are interconnected, so imagine a house’s roof with over 30 holes, many of which are interconnected; now one drug company says, we’ve got a great drug that covers this hole over here very well; and another company says, we’ve got a drug that covers that hole over there very well; and everyone is arguing about which hole should be covered, but after every trial, the floor is still wet. Now, on the positive side, these “failed” drugs may ultimately turn out to be part of the optimal cocktail, but to know that, you need to get the rest of the holes covered. This requires understanding the critical thresholds for the various processes, because so many of these parameters play onto the ultimate thresholds. Just as people like Caldwell Esselstyn have shown, and Colin Campbell, and yourself and others, you have to get to a certain threshold before you are actually picking up plaques instead of laying down plaques in your vessels. The same, of course, occurs with cancer: as long as you’re driving a cell toward proliferation and metastatic survival, you’ re not going to be successful in treating cancer. We believe now that the same occurs at the synaptic level with Alzheimer’s disease. And the important point here is we don’t know yet where that threshold is. Will we have to change seventeen parameters? Two parameters? If you go back to what happened with HIV, which is likely to be a much simpler disease, in that case, you had three drugs that barely worked by themselves. Fortunately, they did work enough to have a statistically significant effect, and David Ho was able to put them together and create triple therapy, which works very well for HIV. Now, let’s imagine for the moment that Alzheimer’s is a more complicated illness, and let’s imagine that it is going to take 15, or 20, or 25 different parameters that one has to normalize to hit that threshold, where you are now forming and maintaining synapses instead of losing them. This is going to be difficult, and therefore what we want to do is create therapeutics that hit as many of those network abnormalities that feed into this ultimate decision as possible. In fact, we have our first clinical trial now coming up in just a couple of months, which will be the first trial to have a comprehensive approach, where it includes all of those different mediators that have an impact on this synaptic maintenance threshold, so things like exercise, and diet, and drugs, and a whole array of specific supplements and herbs that feed into this specific balance of synaptogenesis and synaptic maintenance.
To learn more about the Buck Institute and Dr. Dale Bredesen’s work, please use these links:
The Buck Institute for Research on Aging was featured in a CBS Morning News story about healthy aging and longevity. Watch the video here: