Why The Anti-Amyloid Approach To Alzheimer's Disease Has Failed


A recent well-written analysis in Seeking Alpha noted that nearly all the drugs in phase three clinical trials for Alzheimer’s disease target amyloid (Seeking Alpha article). As the writer and many others have noted this strategy has not worked in the past and is not likely to work in the future. Thus investing in drug companies solely on the belief that the anti-amyloid approach will eventually work is an unwise decision.

The arguments for and against amyloid as a cause for Alzheimer’s disease seem on the surface to be compelling. Those who say that amyloid has to be the cause of Alzheimer’s disease note that certain genetic mutation which increase amyloid production all lead to the early onset of the disease. But missing here is a failure to recognize that the age of onset varies considerably due to other factors. For example, families with a presenilin 1 gene mutation in the Antioquia region of Colombia develop Alzheimer’s disease about a decade earlier than individuals with the same gene in Japan. The families in Colombia are exposed to some of the highest levels of mercury in the world due to mining operations. And here lies an important clue, amyloid is a cause of oxidative stress (in some genetic cases it may be the most important contributor), but it is only one factor. As such removing amyloid may only delay the onset of the disease and slow down its early progression.

The main argument against the amyloid hypothesis of Alzheimer’s disease is that many people have plaques in their brain but do not have Alzheimer’s disease. Indeed both children exposed to high levels of air pollution in Mexico City and elderly nuns who ate foods containing antioxidant polyphenols (such as grapefruit) have many diffuse plaques in their brain but do not have Alzheimer’s disease. These plaques are a sign of oxidative stress that has not advanced too far. On the other hand, dense-core plaques do associate closely with Alzheimer’s disease, but not because they cause the disease but because they are a reflection of the disease (i.e. tyrosine nitration which leads to the formation of plaques).

The advocates of the amyloid hypothesis now argue that other forms of amyloid (such as amyloid oligomers) and not plaques cause the disease. They are correct in postulating that some forms of amyloid are more toxic than others. Different forms of amyloid beta can trigger oxidative stress via their binding of zinc which activates some g protein-coupled receptors. Amyloid plaques entomb zinc so they do not produce the same affect. However, many other factors (environmental toxins, psychological stress, various pathogens, etc.) activate g protein-coupled receptors and lead to oxidative stress via protein kinase C and NMDA receptors. Researchers recently found that amyloid beta does no harm unless protein kinase C alpha is activated. Or in other words amyloid beta does no damage unless it triggers oxidative stress.

The acolytes of the amyloid hypothesis for Alzheimer’s disease have tried to save the hypothesis one more time by arguing that amyloid causes the formation of tau tangles which then lead to Alzheimer’s disease. But the misfolding of tau proteins can occur without amyloid. Indeed it is possible to have a disease that in some cases matches Alzheimer’s disease with no plaques at all (Primary-Age Related Tauopathy). Once again the problem is due to tyrosine nitration which amyloid can contribute to, but which can occur in the absence of amyloid.

For companies which look to the development of tau drugs as a backup plan, the future is not much brighter, though. Hyperphosphorylated tau also binds zinc, so dephosphorylating tau early on may reduce oxidative stress. As an additional benefit, restoring tau to its normal condition helps to improve neurotransmissions. But untangling tau does not by itself increase levels of acetylcholine–the neurotransmitter needed for the retrieval of short-term memory. The tau approach, then, may only be slightly more effective than the amyloid approach.

To treat Alzheimer’s disease early on one would in most cases not only have to remove amyloid oligomers and dephosphorylate tau but one would also have to minimize the other sources of oxidative stress. In conjunction with this one would have to inhibit the pathways that lead to oxidative stress (such as with polyphenols in a Mediterranean diet or spices from India). This is the basis for the Bredesen protocol which in some cases at least appears to have reversed early stage Alzheimer’s disease (Bredesen protocol).

The factors that trigger Alzheimer’s disease may become less important as the disease progresses as g protein-coupled receptors and protein kinase C become damaged by oxidation. At that point, the use of NMDA receptor antagonists and specific antioxidants (such as found in CBD oil, panax ginseng, and several essential oils via aromatherapy) become the likely key to preventing further nitro-oxidative stress and reversing part of the damage that has already occurred.

From an investment standpoint, some of the early anti-amyloid failures by Merck (MRK) and Eli Lilly (LLY) have not harmed their stock prices over the long run. Biogen (BIIB) did suffer significant losses, but one can argue that too much of the company’s high stock value hinged upon its Alzheimer’s drug development program.

Pharmaceutical heavyweights that have diverse drug pipelines may still be worth investing in regardless of their Alzheimer’s trials, but it is best to steer away from companies whose value depends too much on trying to tame the Alzheimer’s monster through either the amyloid or the tau approach.

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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