If there is anything more certain than the failure of experimental Alzheimer’s drugs — nearly 300, at last count — it is the immediate reaction of many diehard supporters of the amyloid hypothesis: They insist that idea, which served as the basis for most of those compounds, is still sound.
Roche pulls the plug on its anti-amyloid antibody crenezumab in January, after it has no chance of showing any benefit? Not enough to kill the amyloid hypothesis. Merck bails on verubecstat, which shut down production of toxic amyloid, in 2017? Still not enough. Eli Lilly announces in 2016 that its anti-amyloid solanezumab failed to show benefit in people with mild Alzheimer’s? Nope, not dead yet.
About the Author Reprints
I’ve been saying this for years–ever since I read Daniel Amen’s book. Dr. Amen is one of the first to point out that brain damage from dementia starts as young as age 40 and was immediately labeled a quack. It seems obvious that the plaque is a byproduct of cellular decomp. The fact that some people w no plaque at all still develop dementia should have been a clue. Dementia happens when neurons die and are not adequately replaced; we should long ago have focused our efforts on treating brain atrophy.
The fact that people still can have illustrious careers and hog all the multi million dollar grants for themselves despite all this failure is a travesty
It is known that people can accumulate ABeta but not get Alzheimer’s Disease (AD). Also can accumulate TAU and not get AD. But all who have ABeta, TAU and pTAU accumulation appear to get AD. We have a Therapeutic Vaccine inhibiting accumulation of all three protein. It has a chance of working based on these facts. Arthur Bollon PhD
CEO. VITRUVIAN BioMedical [email protected]
It was no surprise that Aducanumab as other strictly Ab-reducing drugs would fail. The reasons are predicted and well described by us and others in the papers listed below.
Detailed biochemical explanations are given why these drugs fail. In contrast to the amyloid hypothesis that is being constantly disproven, the alternative loss of function hypothesis is being repeatedly supported (at least not flasified) by these failures.
It has been known for many years that the amyloid hypothesis cannot be correct; the reason it survives is because it is appealingly simple and offers a treatment strategy that pharma can pursue easily by antibodies and inhibitors; it is easy to attack and reduce a single factor, even if you know that AD is a complex multifactor disease with age as the main risk factor.
The main evidence for the role of Abeta in AD was 1) PSEN and APP mutations causing AD relating to Abeta, 2) plaques in the brain constisting of Abeta; 3) toxicity of Abeta in cell and mouse models.
These observations can equally well, in fact better, be explained as a stress/loss of the normal function of the peptide. For example most of the muttaions cthat cause familial AD (PSEN mutations) actually lower total levels of Abeta, just like these drugs do. And already the first toxicity studies showed that Abeta has a window being beneficial at nanomolar concentrations but harmful at micromolar concentrations. In cells, it is present at nanomolar concentrations or below. The toxicitiy studies are mostly done at micromolar levels!
If you did the same to NaCl (1000-fold physiological concentration) you would also find that salt is toxic.
It is very common in diseases that a symptom reflects an underlying imbalance. The assumption that the plaques of Abeta are pathogenic themselves ignores the other possibility, that the brain tries to protect itself from an underlying cause and that the plaques reflect this.
We have reviewed the evidence in favor for gain and loss of Abeta function in 2016 and 2017 where we also explain how and why drugs like Aducanumab will fail. Its failure was self-evident to anyone except those who have invested money or scientific prestige in a paradigm that has been proven wrong more than any other theory that comes to mind. The multibillion dollar loss reflect yet another sad misplacement of investor funding in this field, and a new sad milestone in the blind emphasis on Abeta as a “bad” molecule.
https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1196/annals.1297.001
https://pubag.nal.usda.gov/pubag/downloadPDF.xhtml?id=22213&content=PDF
https://content.iospress.com/articles/journal-of-alzheimers-disease/jad160550
https://www.sciencedirect.com/science/article/pii/S0301008216300363
Kasper Kepp.
Professor MSO, DTU
Acupuncture improve the cognitive impairment of Alzheimer’s. Investigators should investigate how acupuncture works physio-neurologically, maybe they may find a drug correlation.
A piece of good news is that a couple of investigational drugs supported by NIH is vey likely to prevail.
Some drugs available on the commercial market have functions to deal with neuroinflammation in addition to interacting beta amyloid and other peptides or proteins.
Failures could be attributed to arrogance and egoism of people not drugs themselves. Many good drugs or drug candidates are out there, the question is “who cares?”.
Anyone can write an article complaining that what is currently being done is wrong but to then have not better suggestion other than “we need to try something else” is simply rediculace and none productive.
What we have seen are some stubborn, high profile scientists who have been clinging to their sacred cow for way too long, and the long cycle of pharma development (and the major investments sunk into a given compound) finally — arguably a decade late — finally playing out to its sad conclusion. It is indeed “time to do something else”.
Have you considered the effects of hyperinsulinemia on the brain and the positive cognitive effects derived from ketones, fasting, and healthy (increased) fat consumption?