Michael Fossel Michael is President of Telocyte

August 25, 2015

Alzheimer’s: One Disease?

Most of us have wondered about what causes Alzheimer’s. As commonly happens, we stumble badly when we make assumptions, even in asking questions, let alone in trying to answer those questions. The question “what causes Alzheimer’s?” presupposes that there is a single such disease (Alzheimer’s) and that we can define it well enough to ask about “its” cause. Neither of these is probably an accurate assumption. The reality is that there is considerable difficulty in agreeing on the “hallmarks” (the pathognomonic characteristics that define AD) and the “boundaries” between AD and other somewhat similar diseases on the differential diagnosis. Comparing Alzheimer’s to many other age-related neurological diseases can be humbling – and it should be. Small wonder we have so much trouble understanding the cause, let alone finding a cure when we don’t really know what we’re looking at.

Rather than just reinforce our preconceptions, let’s look at reality a bit more closely.

One of the things that has become clearer over the past century – and especially so over the past two decades – is that there is a remarkable amount of overlap in the pathology found in what we have thought of as different age-related neurological problems. This has become grudgingly accepted as we compare not only Alzheimer’s and Parkinson’s disease, but a host of other clinical problems, such as microvascular infarcts, vascular dementia, frontotemporal dementia, hippocampal sclerosis, Huntington’s disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, and mixed dementia (a term that sort of sums up the problem we’re discussing). Just to restrict ourselves to the two classic diseases – AD versus PD – Alzheimer’s tends to have primarily cognitive rather than motor problems, whereas Parkinson’s tends to have primarily motor rather than cognitive problems. In reality, however, both Alzheimer’s and Parkinson’s patients tend to have some of both, particularly as their diseases progress. At the histological level, we tend to distinguish the locations of each disease, and at the neurochemical level we likewise make distinctions, yet there still remains overlap at almost any level, once we look more carefully.

Perhaps there is a single, common, underlying causative pathology that results in BOTH of these diseases. Could both AD and PD be two different manifestations of a shared problem?

This same question surfaces when we look carefully at the vascular dementias: they overlap in many ways with the classical “non-vascular” etiologies. Again: could all of these have a common underlying factor with disparate clinical presentations? We see the same problem when we look at age-related neurological dysfunction in animal models, such as laboratory-created Alzheimer’s models in mice, as well as the “normal” decline in any wild species (such as mice or rats). We go to a lot of trouble to introduce human genes into laboratory species in order to produce a “mouse model of Alzheimer’s”, yet these animals show behavioral declines even in the wild and when we introduce human genes, it’s certainly not clear that we end up with a mouse model that teaches us anything useful when we want to find a cure.

We could put all of these clinical changes together by positing that they derive from a common cellular problem, that of cell senescence. Different patients have different genes and different patterns of gene expression, so their disease expressions differ, some having AD, some having PD, some having any number of other disease phenotypes. Different animals (humans versus mice, for example) likewise have differing genetic and epigenetic settings, so their disease expressions also differ, humans showing beta amyloid and tau protein changes, mice showing a different pattern, but all showing behavioral and cognitive decline over time, whatever the individual pathway the pathology uses to express itself.

Consider our diagram of the “Common Pathological Pathways in Age-Related CNS Failure” (see figure A). The proposition illustrated in this diagram is that of a single underlying problem, with multiple possible pathways, and a shared outcome: age-related CNS failure. One cause, multiple pathways (often defined as different diseases), but one outcome. Whatever the pathway chosen, the outcome is an increasing neurological dysfunction with age.

 

Figure A08-25-15 Figure A

In the case of particular diseases (or particular species), the clinical phenotype depends on which cells are senescing fastest (e.g., glial cells in the brain, endothelial cells in the arterial tree, etc.) and which protein products (e.g., beta amyloid, tau protein, alpha synuclein, etc.) are most likely to cause problems first, depending upon the genetic landscape and the epigenetics of the individual patient or the individual species. If we now label the common diagram with specific diseases and species, we get something like the second diagram (see figure B).

 

Figure B08-25-15 Figure B

If we really want to understand, and cure, Alzheimer’s, then we need to start by understanding (and curing) our own preconceptions. It is only when we look at not only the clinical data, but a wide panoply of species that we can truly understand any of the diseases that we see day-to-day.

One cause, multiple pathways, and a single shared outcome: CNS failure.

Curing Alzheimer’s becomes – as it has been for a century – a fool’s errand if all we target are the specific genes and proteins that we (naively) think of as the hallmarks of the disease. If we truly want cure Alzheimer’s, then it’s time we understand the disease and it’s high time we target the actual causes of not only Alzheimer’s disease, but the entire spectrum of age-related neurological diseases that should be labelled under a common rubric, diseases of cell senescence.

It’s time we understand Alzheimer’s and time we cure it.

August 18, 2015

Alzheimer’s: Why Learn to Live With Failure?

We are too often satisfied with failure. Not believing we can succeed, we eschew further thinking, and we call it quits. In the case of Alzheimer’s therapy, we define statistical flukes as “hope”, declare victory, and retire into platitudes and misconception. Rather than cure disease or improve human lives, we content ourselves with pessimistic delusions and hype the importance of “living with Alzheimer’s”. Simple-minded mottos and political cant, can’t hide reality. We’re not living with Alzheimer’s, we’re dying with Alzheimer’s.

A dozen years ago, when I was the Executive Director of the American Aging Association, we wondered whether or not vitamin E (tocopherols) could delay Alzheimer’s by a few months. The results were minimal and subsequent studies undermined any of the initial optimism. Similar claims came and went over the years, at best suggesting we might delay the disease by a few months, if even that much. Years have passed and hopes have faded. Even the Alzheimer’s Association slowly acquired an emphasis on futility, with a focus not on curing AD, but on living with it (as if we could). Yet even with our latest approaches, even with monoclonal antibodies and huge FDA studies, success escapes us. In July 2015, the results of a large solanezumab study came out and were hyped as having a “distinct impact on Alzheimer’s disease”, and it was claimed that the results “may well illustrate the disease-modifying effect” of the drug.

08-18-15 Figure A

Figure A

 

How big an impact? How modified was the disease? Not much.

At best, the statistics suggest that solanezumab might delay the symptoms by three months (see figure A, above). Given that average course of the disease — often 7-8 years from diagnosis to death — the 3 month statistical claim s is not much of a reprieve. And what does it give us? A longer sentence to the nursing home? Prolonged financial and human costs? Does it offer anything more than an illusion of hope?

08-18-15 Figure B

Figure B

 

If we look at the published results, the most obvious fact is that the vectors — control versus treated patients — are parallel as they decline toward death (see figure B, above). How can we claim to treat Alzheimer’s when the direction of the disease process has the same slope whether you are treated or not? If we fall off a cliff regardless of treatment, does it matter if we hit the bottom now or a few moments from now? Either way, it’s the same cliff, the same fall, the same outcome. Either way, the same fact remains: we’re not living with Alzheimer’s, we’re dying with Alzheimer’s. If there is any “distinct impact”, then it’s not the questionable impact on Alzheimer’s disease, it’s the unquestionable impact as the patient hits the ground.

We are too easily satisfied with failure. We work hard and we invest millions of dollars in research, but we don’t think hard enough and we don’t invest in the right trials. We use a faulty disease model and achieve disappointing results, then resign ourselves to fate and claim that we have succeeded by redefining failure as, oddly enough, a clinical success. A lack of meaningful success becomes a “distinct impact” and a failure is touted as “success”. Where is the success in being unable to alter the vector of a disease?

We could do much better: we can actually succeed. We can cure Alzheimer’s disease. What it takes is not more effort and money invested in failed models, but more insight and a deeper appreciation of how the Alzheimer’s disease actually works. We must come to see it in a broader context of the age-related CNS pathology that underlies not only Alzheimer’s (and not merely beta amyloid or tau protein changes), but Parkinson’s disease, microvascular dementia, and even animal models of age-related cognitive decline. We become so lost in the genetic and protein changes specific to Alzheimer’s that we lose track of the parallel changes (with different genes and different proteins) in Parkinson’s disease. We become so lost in the neuronal changes specific to the histology of these two diseases that we lose track of the overlapping changes that occur in the vascular pathology. And, finally, we become so lost in the pathologies specific to our human patients that we lose track of how much we can learn from the typical age-related CNS dysfunction that occurs in other animals, such as mice.

08-18-15 Figure C

Figure C

 

The pathology may differ, the pathways may differ, yet each of these age-related changes still share an underlying process, one that we can take advantage of, allowing us to intervene effectively. Once we grasp the broader process that underlies the specifics of these CNS pathologies, we can finally cure them. Rather than merely claim we have achieved a minimal displacement of the same downhill vector, we can alter the vector (see figure C, above) and achieve what so many have hoped for and so few have come to believe in: a successful cure of Alzheimer’s.

Ignore the hypocrisy of “living with Alzheimer’s”.

Let’s succeed at living WITHOUT Alzheimer’s.

August 11, 2015

Can Diet Prevent Alzheimer’s Disease?

Filed under: Uncategorized — admin @ 11:17 am

No. Then why do I even bring this up? Yesterday, a patient asked me if Alzheimer’s disease could be prevented (or made less likely) if you ate the “right” diet. It’s a question that strikes not to the core of the pathology, but to the depth of our fears.

Historical precedents offer useful parallels and one of the most poignant of these is the polio epidemic that drew to a close with the advent of the Salk polio vaccine in 1954. In the 21st century, few of us understand how terrifying polio was then. Polio is easy to prevent now, but in 1950, polio was a nightmare: rampant, frightening, and enigmatic. How could you keep your children from dying, from ending up on an iron lung, or from being permanently crippled by a sudden, unexpected fever, quickly followed by disaster?

Just as with Alzheimer’s disease now, we groped for straws then, trying anything we could think of to avoid our horror. Then it was children, now it is parents and ourselves, but the tragedy is equally ubiquitous and equally terrifying. Polio scared us then, Alzheimer’s scares us now. Ironically, many of the same remedies were hawked then as are hawked now, although we have gussied up the terms a bit. Then it was nursing care, muscle therapy, oxygen, and diet; now it is nursing care, music therapy, monoclonal antibodies, and … diet.

In 1951, a book, Diet Prevents Polio, argued that the right diet could prevent polio or minimize its consequences. People took it seriously then because there was nothing else that anyone could do to protect their children from death and disability.

In 2015, people wonder if the right diet could prevent Alzheimer’s or delay its consequences. Some people take it seriously because there is nothing else that anyone can do to protect themselves or their loved ones from death and disability.

Asking if diet can help is like asking if you can make your car last longer by having the right fuel. It’s true that having the wrong fuel can shorten the life of your car markedly, but the difference between normal unleaded and a more expensive version isn’t going to make much difference. The life of your care depends on whether the car is poorly made or the used car is a “lemon”, you never check your oil, you ignore the engine warning light, you have bald tires and never replace them, or you drive like a fool. Almost without exception, the car’s lifespan is determined by how it’s made and how you drive it, not by the fuel you use.

Medically speaking, there are bad diets (all sugar and no protein, for example) that will lead to medical disaster, including obesity, diabetes, heart disease, and any number of other problems, but no diet could prevent polio in 1951 nor prevent Alzheimer’s disease now.

If you wanted to prevent polio, we needed a vaccine.

If you want to prevent Alzheimer’s, we need a cure.

 

 

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