Alzheimer's Disease: A History Of Drug Failures

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Includes: AZN, BIIB, LLY, MRK
by: Lane Simonian

Summary

Nitro-oxidative stress is likely the root cause of Alzheimer's disease.

Amyloid is a product of this stress and contributes to it, but so too do many other factors.

Nitro-oxidative stress also contributes to the formation of tau tangles which interfere with neurotransmissions, but this is only one feature of Alzheimer's disease.

The focus on amyloid and tau has delayed progress in finding an effective treatment for Alzheimer's disease.

Early studies and clinical trials suggest that partially reversing oxidation and nitration is the key to effectively treating Alzheimer's.

AstraZeneca (NYSE:AZN) and Eli Lilly (NYSE:LLY) recently announced that they have discontinued their trial using the BACE-1 inhibitor lanabecestat to treat Alzheimer’s disease. Before that, both Merck’s (NYSE:MRK) BACE-1 inhibitor verubecestat and Eli Lilly’s amyloid antibody solanezumab were similarly scrapped. And these are just three failures in the long, futile search to find an effective anti-amyloid drug for Alzheimer’s disease.

Pharmaceutical giants such as Eli Lilly and Merck with multiple drugs in use and in trials have not been materially affected by these setbacks at least in terms of stock prices. Biogen (NASDAQ:BIIB), which is working on an anti-amyloid antibody and an anti-tau antibody, may be more vulnerable to poor trial results in the future in part because Biogen’s stock price is quite high and a portion of its current price reflects a probably misplaced optimism that its Alzheimer’s drugs will work.

What went wrong with the amyloid approach? Those who advocate that amyloid is the cause of Alzheimer’s disease still try to rescue their hypothesis by arguing that the drugs had to be given earlier (i.e. the damage had already been done by the time the drug was given), that a particular drug did not cross the blood- brain barrier in sufficient amounts (or at all), that some antibodies did not target the more toxic amyloid oligomers (versus amyloid plaques), and that amyloid is tied to a more dangerous aspect of Alzheimer’s disease: tau tangles.

All of these arguments are misguided. Even the most perfect anti-amyloid drug would likely only slow down the early progression of Alzheimer’s disease. This is the case for two reasons. First amyloid is only one of several triggers for nitro-oxidative stress which is probably the real cause of Alzheimer’s disease. This is true even in the case of genetic mutations that result in early onset Alzheimer’s disease (EOAD and oxidative stress). Secondly, excess amounts of the amyloid precursor protein itself can cause the death of neurons without amyloid itself (APP mutations neuronal cell death).

Much of the confusion as to the causes of Alzheimer’s disease is due to the fact that many of the same pathways that lead to amyloid also lead to oxidation and nitration. The sequencing of amyloid production is as follows:

Protein kinase C activation leads to the secretion of the amyloid precursor protein.

Caspase-3 activity stabilizes the BACE-1 enzyme which produces the initial cut in the amyloid precursor protein.

Intracellular calcium release leads to gamma secretase activity resulting in a second cut in the amyloid precursor protein which is followed by the formation of amyloid oligomers.

Nitration converts amyloid oligomers into amyloid plaques.

The amyloid precursor protein and amyloid oligomers themselves further activate protein kinase C – leading to more amyloid (APP mutations protein kinase C).

But more importantly, protein kinase C activation leads to oxidative and nitrostative stress in the brain. Many other factors besides amyloid such as exposure to environmental toxins, psychological stress, and a diet high in sugar, carbohydrates, high fructose corn syrup, and salt can harm the brain. Indeed, amyloid in most cases is simply an add-on insult emanating from other sources that by themselves can lead to Alzheimer’s disease.

Peroxynitrite and caspase-3 via protein kinase C activation contribute not only to the production of amyloid, but also to the formation of tau tangles which interfere with neurotransmissions. To elaborate, caspase-3 cleaves tau and peroxynitrite nitrates tau and contributes to its hyperphosporylation by inhibiting the phosphatidylinositol 3-kinase/Akt pathway. But these compounds are also responsible for many of the other aspects of Alzheimer’s disease. Caspase-3 causes DNA damage, inflammation, mitochondrial failure, and neuronal cell death whereas peroxynitrite through the oxidation and nitration of key receptors, enzymes, and transport systems in the brain diminishes the release and synthesis of neurotransmitters needed for the retrieval of short-term memory, sleep, mood, social recognition and alertness.

The lines of evidence that nitro-oxidative damage rather than amyloid or tau are at the root of Alzheimer’s disease are both diverse and fascinating. Many children exposed to high levels of air pollution in Mexico City have both diffuse plaques and tau tangles in their brains and show subtle signs of cognitive problems but when fed cocoa - a peroxynitrite scavenger - they showed improvement (air pollution and chocolate). Middle-aged adults with Down syndrome have significant levels of amyloid and tau tangles in their brain (Down syndrome), but not all go on to develop Alzheimer’s disease because they also have significant levels of hydrogen sulfide which is a peroxynitrite scavenger. Members of families with a presenilin 1 gene mutation in Colombia develop Alzheimer’s disease on average a decade earlier than members of a family with the exact same gene mutation in Japan (presenilin 1 gene mutation). The Colombian family members are exposed to some of the highest levels of mercury in the world due to mining operations and mercury causes nitro-oxidative stress. In contrast, green tea and rice bran in the Japanese diet provide some protection against such stress.

The molecular evidence is also there. Researchers have found that amyloid does no damage unless it activates protein kinase C alpha; or in other words amyloid does no damage to the brain unless it causes nitro-oxidative stress (amyloid and protein kinase C). And peroxynitrite scavengers attenuated the neurotoxicity of the c-terminal fragment of the amyloid precursor protein (c-terminal fragment peroxynitrite scavengers).

Lastly, clinical trials using known or suspected peroxynitrite scavengers led to initial improvements in cognition in patients with mild to moderate Alzheimer’s disease that were sustained for two year. This includes Korean red ginseng, Chinese herbs in conjunction with conventional Alzheimer’s medications, and Anavex 2-73 (NASDAQ:AVXL). [Korean red ginseng, Chinese herbs plus conventional medicines, Anavex report p. 31)

I would not recommend investing in any company using either the anti-amyloid approach (as amyloid is one of many triggers for Alzheimer’s disease) or the anti-tau approach (as tau tangles are only one of the many features of Alzheimer’s disease) in the hopes that it will produce a breakthrough in Alzheimer’s disease.

The transition from targeting amyloid and tau to reducing nitro-oxidative stress and to partially reversing its damaging effects on the brain should not in theory be that difficult. But so many companies and individuals have invested so much money and so much time in one approach that it is nearly impossible for them to consider another approach. This more than anything explains why after all these years we still don’t have an effective treatment for Alzheimer’s disease.

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.