The Last Hurrah For The Amyloid Hypothesis Of Alzheimer's Disease?

| About: Biogen Inc. (BIIB)


Aducanumab's results are skewed due to the last observation being carried forward.

Amyloid plaques are not likely the cause of Alzheimer's disease.

Drugs that target oxidative stress are likely the key to treating Alzheimer's Disease.

It is part of the creed of many Alzheimer's researchers and scientific journalists that amyloid plaques are linked to the onset and progression of Alzheimer's disease even though no direct evidence exists to support these claims. Biogen (NASDAQ:BIIB) has capitalized upon these claims to suggest that its plaque antibody may some day be used to prevent and effectively treat Alzheimer's disease.

However, Biogen's own data indicates that its drug is ineffective or minimally effective at slowing down the progression of the disease in its early stages. At 26 weeks there was no difference between placebo and the highest dose drug group (10 mg) using a cognitive staging test for Alzheimer's disease (CDR-SB). At 54 weeks, there was a 1.44 difference between Aducanumab at 10mg and placebo using the same test. The high dose group seemed to show an incremental improvement between 26 and 54 weeks. The mini-mental state scores followed a similar pattern except at 26 weeks the 10mg group performed slightly better than the placebo group (charts in article).

These statistics are rather perplexing. An effective drug for Alzheimer's disease should produce a discernible difference at 26 weeks. And then to see such a dramatic difference between the placebo and the drug group between 26 and 54 weeks is quite unexpected. The problem, however, is that the improvement was largely a statistical sleight of hand rather than a slowing of the progression of the disease. Biogen statisticians carried the last observed results forward. Only 10 percent of the placebo group dropped out of the trial before 54 weeks whereas 31 percent of the high dose group dropped out due mainly to severe adverse effects including brain swelling. Many of these participants had the ApoE4 gene which appears to correlate with a more rapid decline early in the disease. So statisticians are comparing a placebo group most of whom made it to the end of the trial with a sizeable dropout group taking the highest dose of Aducanumab whose last observed cognitive test results were carried to the end of the study. If this had not been done, it is highly likely that there would have been little to no difference between the placebo group and the high dose group at 54 weeks just as was the case at 26 weeks (critical review).

At this point, at least, the Aducanumab trial results seem to remove two of the excuses for why amyloid antibodies have produced poor results: the drug was not given early enough and it did not remove enough of the plaque. Now Biogen is suggesting that the drug be given years before the onset of the disease to be especially effective. One can wonder how amyloid does such damage before symptoms even appear, why not all people with amyloid plaques develop Alzheimer's disease, and why some people with Alzheimer's disease have few if any plaques. The most logical answer is that amyloid is not the cause of Alzheimer's disease.

Instead the principal cause of Alzheimer's disease is likely oxidative stress. Oxidative stress contributes to the formation of the c-terminal fragment of the amyloid precursor protein, to amyloid plaques, and to nitrated and/or hyperphosphorylated tau proteins. The release of intracellular calcium leads to the formation of the intermediate amyloid oligomers. The c-terminal fragment of the amyloid precursor protein (the one produced by the beta secretase) amplifies oxidative stress more than amyloid oligomers and amyloid oligomers amplify oxidative stress more that amyloid plaques (which produce little to no oxidative stress). The supposed amyloid cascade likely works in reverse: not from the least toxic species to most toxic species but from most toxic species to the least toxic species.

For those trying to develop medicines or natural products to treat Alzheimer's disease the following is the key.

Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer's Disease: Understanding the Therapeutics Strategies

We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis. (research article).

Biogen stock skyrocketed early last year based partly on a very optimistic view of Aducanumab's chances for success. Unimpressive data since then has contributed to the stock's decline. Perhaps the release of information showing how effective the drug is at targeting amyloid plaques is meant to impress potential buyers. Biogen has several drugs in the pipeline, but if investors are expecting this drug to be a game-changer or a major breakthrough against Alzheimer's disease they should probably temper those expectations.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

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