Michael Fossel Michael is President of Telocyte

October 10, 2017

Should everyone respond the same to telomerase?

A physician friend asked if a patient’s APOE status (which alleles they carry, for example APOE4, APOE3, or APOE2) would effect how well they should respond to telomerase therapy. Ideally, it may not make much difference, except that the genes you carry (including the APOE genes and the alleles for each type of APOE gene, as well as other genes linked to Alzheimer’s risk) determine how your risk goes up with age. For example, those with APOE4 alleles (especially if both are APOE4) have a modestly higher risk of Alzheimer’s disease (and at a lower age) than those with APOE2 alleles (expecially if both are APOE2).

Since telomerase doesn’t change your genes or the alleles, then while it should reset your risk of dementia to that of a younger person, your risk (partly determined by your genes) would then operate “all over again”, just as it did before. Think of it this way. If it took you 40 years to get dementia and we reset your risk using telomerase, then it might take you 40 years to get dementia again. If it took you 60 years to get dementia and we reset your risk using telomerase, then it might take you 60 years to get dementia again. It wouldn’t remove your risk of dementia, but it should reset your risk to what it was when you were younger. While the exact outcomes are still unknown, it is clear is that telomerase shouldn’t get rid of your risk, but it might be expected to reset that risk to what it was several years (or decades) before you were treated with telomerase. Your cells might act younger, but your genes are still your genes, and your risk is still (again) your risk.

The same could be said for the rate of response to telomerase therapy. How well (and how quickly) a patient should respond to telomerasse therapy should depend on how much damage has already occurred, which (again) is partially determined by your genes (including APOE genes and dozens of others). Compared to a patient with APOE2 alleles (the “good” APOE alleles), we might expect the clinical response for a patient with APOE4 alleles (the “bad” APOE alleles) to have a slightly slower respone to telomerase, a peak clinical effect that was about the same, and the time-to-retreatment to be just a big shorter. The reality should depend on how fast amyloid plaques accumulates (varying from person to person) and how fast we might be able to remove the plaque (again, probably varying from person to person). The vector (slope of the line from normal to onset of dementia) should be slightly steeper for those with two APOE4 alleles than for two APOE3 alleles, which would be slightly steeper than for two APOE2 alleles. Those with unmatched alleles (APOE4/APOE2) should vary depending upon which two alleles they carried.

To give a visual idea of what we might expect, I’ve added an image that shows the theoretical response of three different patients (a, b, and c), each of whom might respond equally well to telomerase therapy, but might then need a second treatment at different times, depending on their genes (APOE and other genes) and their environment (for example, head injuries, infections, diet, etc.). Patient c might need retreatment in a few years, while patient a might not need retreatment for twice as long.

 

August 10, 2017

Progeria and Telomerase

Recently, John Cooke at the Houston Methodist Research Institute, showed that telomerase, when expressed in cells from progeric children, caused a “substantial physiologically relevant and meaningful effect on the lifespan and function of the cells.” As many of you know, progeria is a disease in which young children appear old, with baldness and osteoarthritis, and usually die of advanced cardiovascular disease, such as heart attacks, typically around age twelve. In short, they appear to have extremely rapid aging. Cooke’s results suggested that telomerase might offer a therapy. Oddly enough, both Cooke and the media described this finding as “surprising”.

While these results are promising, they are hardly surprising. In 1996, I published a book going into this prospect in detail, then wrote the first medical papers on this the medical potential in JAMA in 1997 and 1998. This was followed up with a medical textbook which explored the entire area in 2004, and another book in 2015 that described the medical potential of telomerase. What is truly surprising is not the most recent results, but that anyone finds the results at all surprising.

While not actually surprising, they present a bitter irony, in that any number of deaths, including deaths of progeric children, might have been prevented and may still be prevented if we only understand and act upon what we have known for two decades and which Cooke’s results only highlight again.

The irony – and my exquisite personal frustration – is that I proposed this approach annually in our global meetings for progeric children, starting twenty years ago. For about a decade, beginning several years before the turn of the millennium, I had been part of the annual global reunion of progeric children. Each year, we gathered with perhaps three dozen progeric children and their families from around the world, giving them a chance to meet one another, to talk with experts, and … to feel normal among other children and families who had the same problems. In 1999, among those progeric children was a young boy, whose parents were both physicians, and who were desperate to find a cure for progeria. Although I explained the potential of using telomerase as an intervention, they founded the Progeria Research Foundation and aimed it solely at genetic markers rather than epigenetic intervention. They managed to get significant funding through the NIH, fund raising, and government contacts in order to fund a set of studies that localized the genetic error responsible for progeria. As I predicted, none of the subsequent therapies based on their approach have had any effect on the disease. Worse yet, and like all the other progeric children I have known over the years, their son died of progeria. Had we gone straight to telomere-based interventions rather than taking the detour, many progeric children – not merely their son — might have been treated more effectively.

John Cooke and his colleagues have done well to show that they can reverse the problems seen in progeric cells, yet others have gone further. Maria Blasco’s group, for example, has shown that she can not merely reset aging in cells, as Cooke’s group has, but can do the same in animals. Moreover, we are collaborating with her group to take this approach in our upcoming human clinical trials next year, initially aiming at Alzheimer’s disease.

The fact that this comes as a surprise, given what we have known about the potential of telomerase for more than 20 years is a tragic example of wasted opportunities, wasted funding, and wasted lives. Telomerase was shown to reverse aging in cells 20 years ago; telomerase showed its value in animals 5 years ago; Telocyte is ready to show the benefits of telomerase in human trials next year.

July 17, 2017

Walking Toward a Cure for Alzheimer’s

Sometimes things go wrong, sometimes they go remarkably right.

        In clinical medicine, Swiss cheese theory is a explanation of why medical disasters occur, even if the explanation has a grizzly sort of humor. Basically, Swiss cheese theory says that “all the holes need to line up” for something to get through the cheese and for things to go drastically wrong in patient care. For example, if the physician is a moron (the first hole in the cheese) and orders the wrong medication, then the knowledgeable pharmacist usually cancels the order. But if the pharmacist is also a moron (the second hole in the cheese) and sends the wrong medication to the nurse, then the experienced nurse refuses to give the medication and stops the mistake long before the patient is injured. But, of course, if the nurse is also a moron (the third hole in the cheese) and simply gives the wrong medication, then you have a problem. When all the morons line up in a row, like holes in adjoining slices of Swiss cheese, then mistakes get all the way through the cheese and you have the perfect setting for a medical disaster. Medical errors are rarely the result of a single stunning error on the part of a truly epic moron; medical errors usually take a grizzly sort of teamwork among morons, all working together like clockwork. Swiss cheese theory strikes again.
Oddly enough, the opposite can also happen. If everything lines up in a positive sense then we have innovation, progress, and (very rarely) a miracle or two. For example, to have a success in the case of a biotech company, you need a series of positive events to line up. Over the past few years, that’s exactly what has been happening to Telocyte. While there have been no truly stunning single events that have created a fleeting (if flashy) success, there have been a collection of positive events that line up exactly as they need to. In our case, all the holes are lining up to build toward a successful cure for Alzheimer’s disease.
I first proposed that telomerase could be successful as a clinical intervention in 1996, but my proposal wouldn’t have gotten anywhere if a whole collection of groups and individuals hadn’t continued to move the field along over these past twenty years. From a purely practical perspective, it was the work of CNIO in Madrid (and that of their director, Maria Blasco) that demonstrated a technique that can easily be applied to human clinical trials. Yet, while we saw the potential for human disease, it was our CEO, Peter Rayson, who moved us along in a practical direction. Two years ago, Peter arranged to meet me in Boston, and we founded Telocyte. Our COO, Mark Hodges, joined us and helped shape our program. We had additional support from volunteers, spouses, and researchers, all of whom saw the value and shared our vision. Investors, such as Rob Beers, joined us, asking little and seeing much. We were approached by large global corporations, such as SAP and Amazon Web Services, who offered us support. We partnered with the world’s preeminent biotech law firm, Cooley LLP, who saw the potential and wanted to help. Other investors have come on board, investors who saw what we could do and who agreed with our goals.
Recently, we signed agreements with a major investor and submitted our protocols for FDA review, and we continue to move ahead, steadily and confidently, as we plan for our human trial next year. None of this has been the result of one person, nor even one group. Instead, it has been the result of a continual concatenation of just the right people at the right time. Everything has gracefully, carefully, and steadily lined up, creating an historic opportunity to save lives and rescue human minds. There have been no miracles, no sudden champagne, no instant success, nor wild celebrations. We haven’t seen wonders, but we’ve seen workers. We haven’t seen miracles, but we’ve met milestones. We haven’t had champagne, but now we have a chance.
With every step, a door has opened, people have helped, another step was taken.
And each step brings us closer to curing Alzheimer’s. Walk with us.

April 12, 2017

We Already Know It Works

Oddly enough, many investors don’t realize how far we are down the road to a cure.

In fact, most people don’t understand why such studies are done and – more to the point – why Telocyte is doing one. Just to clarify: we’re not doing an animal study to prove efficacy. We already know it’s effective in animals.

The reason we do an animal study is because the FDA, quite reasonably, requires an animal safety study in order to assess risks and side effects. Most people assume that animal studies are done to show that a potential therapy works in animals, so that it might work in humans as well. In fact, however, once you have shown that a therapy works in animals, as we have already, then before you can go on to human trials, you first need to do an animal safety study.

Animal studies are done to assess safety, not to assess efficacy.

For an initial human trial, the main question for the FDA isn’t efficacy, but safety. Sensibly, the FDA requires that the safety data be done carefully and credibly, to meet their careful standards. We know telomerase gene therapy works, but we still need to prove (to the FDA’s satisfaction) that telomerase gene therapy is safe enough to justify giving our therapy to human patients. So the question isn’t “Do we have a potential intervention for Alzheimer’s?” (which we do), but rather “Do we know what the risks are once we give it?” We’re fairly certain that we know those risk, but we need to document them rigorously.

In getting our therapy to human trials, you might say that there are three stages:

  1. Animal studies that show efficacy (already done by our collaborators).
  2. Animal studies that show safety (an FDA requirement).
  3. Human trials before release for general use (an FDA requirement).

Telocyte already has good data on the first stage: we know that telomerase is remarkably effective in reversing the behavioral decline seen in aging animals and that the same result will likely occur in aging human patients. In short, we are already confident that we can prevent and at least partially reverse Alzheimer’s disease. The FDA doesn’t need us to demonstrate efficacy: we already have good data on efficacy. What the FDA wants from us is more (and more detailed) data on the probable safety, which we’re about to provide.

While we are now ready to start on the FDA animal safety trial. Doing our FDA animal study isn’t a way of showing that telomerase gene therapy works – which is already clear from animal studies – but a detailed look at side effects, preparatory to our having permission to begin human trials next year.

Telomerase therapy works.

March 21, 2017

The Frustration of (Not) Curing Alzheimer’s

I am deeply frustrated by two plangent observations: 1) we squander scant resources in useless AD trials and 2) AD can easily be cured if we applied those same resources to useful AD trials. Applying our resources with insight, we will cure Alzheimer’s within two years.

The first frustration is that most pharmaceutical firms and biotech companies continue to beat their heads against the same wall, regardless of clinical results. Whether they attack beta amyloid, tau proteins, mitocondrial function, inflammation, or any other target, the results have been, without exception, complete clinical failures. To be clear, many studies can show that you can affect beta amyloid or other biomarkers of Alzheimer’s disease, but none of these studies show any effect on the clinical outcome. In the case of amyloid, it doesn’t matter whether you target production or the plaques themselves. Despite hundreds of millions of dollars, despite tens of thousands of patients, not one of these trials has ever shown clinical efficacy. Yet these same companies continue to not only run into walls, but remained convinced that if they can only run faster and hit the wall faster, they will somehow successfully breach the wall. They succeed only in creating headaches, accompanied by lost money, lost opportunities, and lost patients. The problem is not a lack of intelligence or ability. The researchers are – almost without exception – some of the most intelligent, well-educated, technically trained, and hard-working people I know. The irony is that they are some of the best 20th century minds I know. The problem, however, is that it is no longer the 20th century. If you refuse to adapt, refuse to change your paradigm, refuse to come into the 21st century, you will continue to get 20th century results and patients will continue to die of Alzheimer’s disease. Money and intelligence continues to be dumped into the same clichéed paradigm of pathology, as we aim at the wrong targets and misunderstand how Alzheimer’s works. And the result is… tragedy.

The second frustration is that we already know the right target and we already understand how Alzheimer’s disease works. We are entirely able to cure and prevent Alzheimer’s disease now. At Telocyte, we already have the initial resources we need to move ahead, but it is surprising how difficult it is for some people — wedded to 20th century concepts — to grasp the stunning potential, both clinically and financially of what we are about to do at Telocyte. We can not only reverse Alzheimer’s disease, but we can also cut the costs of health care while creating a stunningly successful biotech company in the process. We have the right tools, the right people, the right partners, and the sheer ability to take this through FDA trials. Already, we have several lead investors committed to our success. We are asking for a handful of additional investors, those who can see what the 21st century is capable of and who can understand why Telocyte is both the best clinical investment and the best financial investment in innovative medical care.

 

November 15, 2016

Close to a Cure

We are now within two years of a cure for Alzheimer’s disease.

What a brash and disruptive claim! What hubris! Yet events are coming together, underlining a new and far more complete understanding of the disease, illuminating the cause, supporting the ability to intervene, safely and effectively. We finally see a way to intervene in the basic pathology, underlining the potential to both prevent and cure Alzheimer’s disease.

But why has it taken so long? Why was Alzheimer’s disease first defined 110 years ago, and yet remains totally beyond our ability to intervene even now? Why have all other approaches, whether those of big pharma or those of biotech, failed utterly? Why has not a single clinical trial shown any ability to change the progress of this frightening disease? Why is Alzheimer’s disease not only called “the disease that steals human souls”, but also called the “graveyard of companies”? Why has every single approach (which has at most shown only an effect on biomarkers, such as beta amyloid), still failed to show any change in the cognitive decline in patients with this disease? Why have we failed universally, until now?

Because every approach has concentrated on effects, not on causes.

Currently, most approaches target beta amyloid, many target tau proteins, and some target mitochondrial function, inflammation, free radicals, and other processes, but no one targets these problems as a single, unified, overarching process. Alzheimer’s isn’t caused by any one of these disparate processes, but by a broader, more complex process that results in every one of these individual problems. Beta amyloid isn’t a cause, but a biomarker. Equally, tau proteins, phosphodiesterase levels, APOE4, presenilins, and a host of other markers are effects, not causes. The actual cause lies upstream and constitutes the root cause of the dozens of separate effects that are the futile downstream targets of every current FDA trial aimed at Alzheimer’s disease. Understanding this, we will be targeting the “upstream” problem, rather than the dozens of processes that others target individually and without success. Our animal studies support the ability to effectively intervene in human disease: when we say that we are about to cure Alzheimer’s disease, we base claim that on a clear and consistent theoretical model, supported by equally clear and consistent data.

Within the next few months, we will begin our FDA toxicity study, preparatory to obtaining an IND that will permit us to begin our FDA human trial. Our toxicity study will take 6 months and will meet FDA requirements for human safety data. Our first human trial is planned to begin one year from now and is intended to show not only safety, but a clear efficacy. We will include a dozen human volunteers, each with (not just early, but) moderate Alzheimer’s disease and our human trial will last 6 months, including a single treatment and multiple measurements of behavior, laboratory tests, and brain scans. We expect to show unambiguous cognitive improvement within that six-month period. We are confident that we cannot merely slow, not merely stop, but reverse much of the cognitive decline in our twelve patients. We intend to demonstrate an ability to cure Alzheimer’s disease clearly and credibly.

Curing Alzheimer’s requires investments of money, time, and thought. The toxicity study costs 1 million dollars; the human trial costs 2.5 million dollars. Telocyte has half a million dollars committed to this effort and at least one group of investors with a firm interest in taking us all the way through the human trials. We are close and we grow closer each day.

After 110 years, we are about to cure Alzheimer’s.

April 26, 2016

The Tempo of Alzheimer’s

Hardly a day goes by, and never an entire week, without my seeing yet another article, often a cover article, that suggests we will soon cure Alzheimer’s disease. If articles were anything to go by, then the increasing tempo of those articles, to say nothing of the increases in both research and funding, would suggest we will soon solve the problem. But, publicity, laboratories, and money are not the same as actual clinical results. In fact, the issue is never the amount of resources, but where you aim those resources. If we wish to cure Alzheimer’s, then we need to put some honest intellectual effort into understanding Alzheimer’s. Until then, publicity, laboratories, and funding are only a reflection of wishful thinking. No one ever cured a disease by injecting money into the patient, let alone making them swallow a laboratory, or listen to publicity.

Yet oddly enough, publicity is often perceived as a goal in itself. I see biotech companies who strive to get themselves mentioned on the news, as though that would create success. But whether are on the cover of Time magazine or mentioned in this week’s edition of The Scientist, news stories are never equivalent to a cure for Alzheimer’s or anything else. In fact, I suspect there is often an inverse correlation: the more your drug or your biotech company is mentioned in the media, the less likely it is to get through FDA trials, let alone improve patient care. Just a suspicion, but founded on frequent observations over the past two decades or more.

Some of us want to find a cure, and never mind the kudos.

Other people just want the kudos.

The fact that we hear about another potential “drug that may cure Alzheimer’s disease” on an approximately weekly basis, underscores not only the frantic need for a cure, but the fact that none of the alleged cures actually work. As we say in medicine, when you have dozens of professed cures for a disease, you can be pretty sure that none of them actually do a damn thing. The more strident the claims for “the cure” the more you should suspect an absence of data. When there is a cure and when it works, it will be a single intervention and you’ll know it works because, guess what, it will actually work.

I regret that the media gets caught up in the inflated claims, but it speaks to the public’s hunger to believe. One of these days, it won’t be a claim and it won’t be inflated, it will simply be the facts. When we finally have the facts, it will be because we have shown we can cure Alzheimer’s disease and it will be Telocyte on the cover, but only after we cure Alzheimer’s.

 

April 12, 2016

Rational Behavior

We waste stunning amounts of money and effort on comprehensively ineffective trials.

As a recent article points out, in the past 15 years, there have been 123 Alzheimer drug failures and, while four medicines have been approved, none of them affect the progress of the disease. Symptomatic therapy at best, we have no medications – none – that have any effect on the disease or on its mortality. A quick look at clinicaltrials.gov lists almost 1,500 interventional trials aimed at treating Alzheimer’s disease, yet once again there is no evidence that any of these trials has resulted (or will result) in an intervention that changes the outcome of Alzheimer’s disease.

Federal funding for Alzheimer’s is estimated at almost half a billion dollars and some have estimated that Eli Lilly’s potential treatment for Alzheimer’s, solanezumab, may end up costing the company one billion dollars to achieve approval of that drug alone, even though there is no evidence that it actually prevents or cures the disease. The most optimistic interpretation of the statistical data of thousands of patients over many years, would be stretching it to suggest it might possibly delay cognitive decline and death by 2-3 months over an eight year period from diagnosis to death. Even that wishful thought is doubtful and scarcely any consolation to those enduring an extra handful of weeks in a skilled care nursing home (or having to pay for it).

No matter what the current target of choice – beta amyloid, tau proteins, inflammation, or any other target-du-jour – none of these targets have ever been shown to offer a glimmer of hope. Despite the history of repeated and consistent failure, we continue to spend (and vote to spend) money on these same drug targets. We eagerly bash our empty heads against the same solid brick wall, naively hoping that one day we fill find that the wall will be made of air (like the air in our brains, which leads to our irrational behavior). The apocryphal observation pertains: the definition of insanity is doing the same thing over and over and expecting a different result. We waste money and effort on ineffective and expensive trials aimed at targets that we know are futile.

The irony – and the tragedy – is that we can both prevent and cure Alzheimer’s disease, both effectively and inexpensively if we understand the actual pathology and target the underlying causes. We could do, effectively and inexpensively, what big pharma has failed to do ineffectively and expensively. What big pharma can’t do for one billion dollars, Telocyte can do for 0.5% of that figure, simply by aiming at the right target.

We need rationality, insight, and just enough funding to prove it can be done.

April 6, 2016

The Rabbits of Research, The Frogs of Alzheimer’s

 

Perspective often shrinks personal problems.

Late Sunday night, I received a cry for help from a woman whose mother has Alzheimer’s disease: she asked me to meet her family and offer professional advice. Their concern was not only her medications, but the ability of her physician, the stress on the family, and the patient’s own medical and psychological problems. Not surprisingly for someone with Alzheimer’s, the patient not only had paranoia, depression, panic episodes, and confusion, but the heart-rending loss of memory and reasoning that really lie at the heart of Alzheimer’s – if Alzheimer’s can be said to have a heart, which is a stunning oxymoron for such a horrifying disease.

We each have our own problems and – such is human nature – we get wrapped up in those personal problems, losing sight of greater issues. I had been thinking about a dozen issues that play into any biotech effort: potential investors, vendor specifications for plasmids, approaching the FDA for pre-IND meetings, conference calls with our IP attorneys, details of our preclinical research, and whether or not one of our scientific advisory board members had time to define a sequence for us. Amazing how large these – and many more – issues loomed in my life, then suddenly became so much smaller and less important when I heard from someone whose loved one has Alzheimer’s. It’s true that the only lasting way that my colleagues and I can help her – and hundreds of thousands of others – is to complete the research and offer a cure, but there is much more to helping than curing. Sometimes, it’s simply a matter of small acts of compassion, such as finding a referral to someone who can help with day-to-day problems, even if they can’t cure the deeper problem itself. And sometimes, of course, it’s simply a matter of understanding how unimportant our own problems are, in perspective.

Two thousand five hundred years ago, a story teller described the panic of a group of frightened rabbits who, in turn, suddenly surprise a group of frightened frogs, whose panic sends them into the pond. Aesop was right about human life: there will always be rabbits, there will always be frogs. No matter how much the “rabbits” of research need our attention and our hard work, the “frogs” of Alzheimer’s patients must always have our care and our compassion.

And, perhaps quite soon, we will change those frogs into healthy humans, whose fear becomes a thing of the past.

October 30, 2015

Chaos, traffic, and Alzheimer’s disease

We’re going to take an odd detour into both chaos theory and traffic flow in order to understand Alzheimer’s disease, so fasten your seatbelt. The key cascade of pathology that we’re going to look at (and explain) is the presence of beta amyloid plaques in patients with Alzheimer’s, but the principle applies equally to tau tangles and several other hallmarks of pathology seen in aging human patients with cognitive decline. Chaos theory and traffic flow will serve as useful analogies and help clarify the dynamics involved in human pathology, as well as potential cures.

To start with, let’s consider a simple example of chaos theory, in which a continual, linear event results in a sudden inflection and an unexpected, non-linear outcome. Imagine that you are trying to retrieve your iPhone in the middle of the night in order to listen to, for example, an audible book. The lights are out, your spouse is asleep and you gently pull on the earphones, using them to pull the iPhone toward you. Realizing that the slower you pull it, the less noise you make (and the less likely it is that you will waken your spouse), you provide a very slow, gentle traction. Unfortunately, the iPhone is on the bedside table and once it gets to the edge, it suddenly falls and produces a terrible racket, regardless of how slowly and quietly you’ve pulled it up until you reached the edge. The point here is that regardless of how noise and speed were related until you got to the edge of the table, there will come a sudden inflection point with an unexpected and non-linear increase in noise. In short, the amount of noise correlates linearly with speed until the inflection occurs and then the relationship between speed and noise becomes suddenly non-linear. As we will see, much the same thing happens to the clearance of beta amyloid (or tau tangles) and its relationship to neuronal death. Things seem to be going fine until some inflection point is reached, after which there is a sudden, unexpected inflection and the pathology (and cognitive decline) begins.

For the next analogy, consider traffic flow and construction slowdowns. Commuting to work each day, you (and the traffic generally) are moving along at a steady 55 mph as you approach an area of construction. In this area, the traffic slows to a speed averaging 10 mph, as a result of a traffic light at which the speed is 20 mph half the time (green light) and zero half the time (red light). However, you notice that despite this construction slowdown (which has been going on for several weeks), the traffic congestion always becomes noticeable at about the same spot and it never actually backs up indefinitely (as it might if the road was completely closed while traffic continued to arrive). As you think about it, you realize that the actual speed (55 mph versus 10 mph) isn’t the key here. The key question is the number of cars passing per unit time as they approach and as they go through the congested area. If the 55 mph cars are approaching at a rate of (say) 30 cars per minute (with a good distance between them) and the 10 mph cars are getting through the construction and the traffic light at the exact same rate of 30 cars per minute (although they are almost bumper-to-bumper), then the line of slow moving cars will only grow to a certain length before it achieves an equilibrium. We might find, for example, that despite the traffic congestion and as long as the number of cars passing each point per unit time remains equal (e.g., 30 cars per minute, regardless of how close the cars are to one another), then the line will only grow so far and no further.

But this is only true to a point.

It might be, for example, that (as long as the number of cars per minute is equal both coming into and leaving the traffic congestion) the line will be a half-mile long if the construction zone has an average speed of 15 miles an hour twice as long at 10 miles an hour, but there comes a point – perhaps at 9 miles per hour, when the line suddenly has an inflection point and begins to grow wildly (and non-linearly) because the number of cars leaving per minute has no fallen below the number of cars arriving per minute. The relationship between speed (going through construction) and the length of the traffic line was linear until some critical point, at which the relationship took an inflection, the traffic backs up, and all hell breaks loose. Not merely an example of chaos theory, but chaos in action as traffic gridlock ensues.

Much the same is occurring in the brain as it ages. Microglial cells are perfectly adept at clearing beta amyloid as it is produced. Even as these cells senesce and their rate of clearance falls, the backup of beta amyloid “traffic” is not bad enough to cause pathology and it does not trigger neuronal death – or clinical Alzheimer’s disease. There comes a point, however, when chaos theory enters the picture, a sudden inflection occurs, neuronal death ensues, and inexorable cognitive decline becomes obvious.

Think of it this way. The key questions (with beta amyloid as an example) are these: 1) how fast is beta amyloid being produced (how many cars are coming down the highway per minute), 2) how likely are the beta amyloid molecules to be abnormal perhaps because of APOE4 genes (how fast are the cars moving), and 3) how well are the senescing microglia able to clear the beta amyloid molecules (how many cars can they get through the construction area per minute)?

These same questions play a role in understanding why current interventions (e.g., monoclonal antibodies) fail and why we might want to intervene directly in cell senescence. Most current experimental approaches, such a monoclonal antibodies, only serve to “tow away some of the backed-up cars in the traffic line”, while the critical variable is our ability to move cars through the area of congestion. In short, the problem is not a static one (can we remove cars), but a dynamic one (can we keep the cars moving). Once we get a problem with traffic flow (a non-linear accumulation of beta amyloid plaques), the key intervention is not “towing away cars”, but increasing the flow of traffic through the congested area. We should be treating microglia, not beta amyloid.

Curing Alzheimer’s requires that we understand the pathology and not in a naïve, static fashion. If we want to cure Alzheimer’s, we need to improve the traffic, not the cars. The most effective point of intervention is not beta-amyloid but microglia.

Which is how we plan to cure Alzheimer’s.

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