Michael Fossel Michael is President of Telocyte

July 20, 2015

Why Solanezumab Disappoints

Insanity is doing the same thing over and

over again and expecting different results.

                                    – Variously Attributed


[This blog was written and published on Monday July 20th, two days prior to the announcement of the results of Eli Lilly’s clinical trials of solanezumab for Alzheimer’s.]


Until now, there have been only two globally-approved drugs for Alzheimer’s disease (Aricept and Namenda), and neither of these have been shown to slow, let alone stop or reverse Alzheimer’s. Most current clinical hopes have been pinned to various attempts to use monoclonal antibodies to attack beta amyloid in the brain, and none of these have been shown to slow, let alone stop or reverse Alzheimer’s disease either.

At the current meeting of the Alzheimer’s Association (July 18-23, Washington, DC) there has been growing interest in the latest clinical trial of this disappointing approach, as Eli Lily announces (on Wednesday July 22nd) the latest results of using solanezumab (also called “Soli”), a drug which was a disappointment in its initial clinical trials. Nevertheless, and to the surprise of many, the FDA gave Eli Lilly permission to continue their phase 3 trials and expectations increased the price of the Eli Lilly stock as the upcoming announcement of the results approaches. Unfortunately (not only for the company, but for all of us), the results will be equivocal at best and certainly won’t show that we can slow, stop, or reverse Alzheimer’s.

Why not?

Why don’t any of the drugs that target beta amyloid have any effect on the underlying disease process? Why have all of the monoclonal antibody drugs — with Soli just the latest heartbreaking therapeutic (or non-therapeutic) disappointment — failed to stop the disease?

The unspoken assumption has been that beta amyloid “causes” Alzheimer’s.

Oddly enough, the assumption is false: beta amyloid doesn’t cause Alzheimer’s disease. Small wonder then when our attempts intervene in the wrong target fail every time. Mind you, beta amyloid is clearly implicated in the pathology and it clearly plays an important role, but to say that is “causes” Alzheimer’s is to confuse cause and effect. If we have a patient with an infection, a high fever, and an elevated white blood cell count, we wouldn’t blame the fever or the white cells for the infection. Likewise, it would be silly (and dangerous) to “treat” the infection by simply removing the patient’s white cells. Yet this is the same sort of logical error we routinely make with Alzheimer’s disease. We know that almost all cases of Alzheimer’s disease show amyloid deposits at autopsy (or now, using other tests, even in living patients with Alzheimer’s), and we know that amyloid deposits can damage neurons, but to automatically conclude that that’s the entire ball game is to go well beyond reality and enter the realms of wishful thinking (or insanity, if we were to believe the quote given above).

None of the clinical trials aimed at removing beta amyloid have ever shown efficacy.

The problem is that amyloid is the wrong target and monoclonal antibodies against amyloid are the wrong intervention. The current failure of solanezumab is simply one more in the list of such failures. If trying the same failed approach over-and-over is insanity, then sanity would be to try a new intervention, an intervention based on a sophisticated appreciation of the actual clinical pathology. In my new book The Telomerase Revolution, I not only discuss that more sophisticated view of the pathology, but how we plan to intervene in a more rational and effective fashion.

July 15, 2015

How Does Alzheimer’s Work?


Alzheimer’s disease steals our souls.

We lose our humanity when it destroys the neurons that make up a critical part of our brains, but why those neurons die has always remained a mystery since “senility” was first noted, thousands of years ago. Even in the past century, since it was first described clinically by Dr. Alois Alzheimer in a 1907 medical article, we not only haven’t cured the disease, we haven’t even understood it. In this blog, we will come to understand exactly how it works — and what can be done to cure it.

Part of the reason we are slow to understand diseases (and many other things, for that matter) is the tendency to engage in magical thinking. We identify an association, mistake it for a causation, and then we are mystified when our naïve interventions fail. This error may seem obvious, but we make this same mistake repeatedly in medicine and in other aspects of daily life. In the case of Alzheimer’s diseases, we repeatedly identify a protein, a gene, or another product, and we naively try to intervene, then are left clueless and shocked when our best efforts fail utterly. The classic case has been that of beta amyloid plaques, common in most cases of Alzheimer’s disease, when we try to remove or prevent their formation and then cannot understand why all of our interventions fail so spectacularly. There have been hundreds of human trials aimed at beta amyloid, for example, yet none of them have proven effective. Why not?

Alzheimers disease cascade

The reason lies in magical thinking: knowing that some diseases (such as Sickle Cell) are clearly a genetic disease, and knowing that there are genetic correlations with Alzheimer’s disease, we conclude that Alzheimer’s is also a “genetic disease” and that if we could only find just the right gene, we would know how to cure the disease. Unfortunately, Alzheimer’s isn’t a genetic disease. Despite all of the candidate proteins, genes, and gene locations we are still investigating, these are correlations, not the cause of the pathology. Whether we look at beta amyloid (and its precursor protein in several variant forms), presenilin, APOE4, R4YH, UNC5C, SORL1, CLU, CR1, PICALM, TREM2, A2M, GST01 & 02, BAB2, CALHM1, TOMM40, CD33, ADAM10, PLD3, or any of the dozens of other candidates (the list grows longer by the day), none of these “cause” Alzheimer’s disease.

Alzheimer’s is not a genetic disease, Alzheimer’s is an epigenetic disease. All of those genes (I just saw another one published this morning) contribute to the risk, yet none of them — not a single one of the identified genes — causes Alzheimer’s. To quote a previous blog, each of them is a tree, but Alzheimer’s is a forest. When we focus on trees, we forget the broader pathology of the forest.

To use another common analogy, each of the genes identified with Alzheimer’s is like a submerged rock. As we age, the problem is not the hidden genetic rocks — such as APOE4 — but the fact that the water level is gradually falling, until the hidden rocks become exposed and cause a medical shipwreck. Treating APO-E4 will not resolve the problem. Alzheimer’s is not caused by the amyloid protein itself, which is necessary to neuronal function when present in appropriate amounts, but to the failure of amyloid clearance by aging microglia. The aging microglia becomes less and less capable of recycling and maintaining appropriate levels of not only beta amyloid, but a number of other things a well. This becomes apparent earlier in those with an APOE4 gene, but the problem is ubiquitous and not restricted to a single gene product. APOE4 wouldn’t be a problem is the microglial function was up to snuff, as it is in young adults. As the microglia age, as the water level falls, we expose the hidden rocks — the barely sufficient turnover of amyloid proteins in the case of those with two APOE4 alleles. To extend the water analogy, consider the two most well-known of those hidden rocks: APO-E4 and APO-E2. The first (the more dangerous allele) is a rock that lies just a few feet under the water, while the second (the safer allele) is a rock that lies a bit deeper down in the water. Neither of these hidden rocks are a problem when the lake water level is high (i.e., when we are young and our microglial clearance of amyloid is high). However, as the water level falls (i.e., as we age and microglial clearance begins to fall due to epigenetic shifts induced by telomere shortening), we expose first the APO-E4 rock (particularly in those with two copies of the APOE4 gene) and then, much later in life, the APO-E2 rock (in those who are lucky enough to have two copies of the APOE2 gene). Nor are these the only hidden genetic rocks. The rocks include not only the long list of “Alzheimer’s genes” given above, but literally hundreds of other risk factors, factors that become increasingly exposed as our microglia age and fail to protect us. As we age, as the water level falls, we expose risk-after-risk, rock-after-rock, gene-after-gene until we run aground and our minds go down for good.

The solution is not to find each and every genetic rock and hope to prevent disaster by filing down the rocks one-by-one, but to simply raise the water level again. Once we reset gene expression — not only theoretically, but based on animal trials — the pathology resolves. When we go after the key causal element in the pathology, when we reset gene expression in the microglial cells, the neurons are no longer at risk. If we want to cure Alzheimer’s, we need to aim at the cause of the disease, not at the genes, not at the proteins, not at the tangles, not at the microaggregates, and not at the plaques. To date, not one of these approaches has been effective.

Alzheimer’s doesn’t begin in the neurons; Alzheimer’s begins in the microglia. The key to curing Alzheimer’s is not to identify genes, but to reset gene expression and the key to resetting gene expression is to use telomerase therapy.

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