Chinnapong/iStock via Getty Images

Chinnapong/iStock via Getty Images

Whenever a theory appears to you as the only possible one, take this as a sign that you have neither understood the theory nor the problem which it was intended to solve.

Karl Popper, Philosopher of Science

Most, but not all Alzheimer’s treatments are based off of four different hypotheses for the disease: amyloid, tau, neuroinflammation, and oxidative stress. In this article, I will mainly focus on three drugs designed to reduce neuroinflammation - INmune Bio’s XPro1595, Montelukast, and Alector’s AL002 - and the limitations of the neuroinflammatory approach. I will touch upon the other three hypotheses, as well as make two key, general observations.

First, the same external stimuli acting via the same pathways can produce amyloid, misfolded tau proteins, neuroinflammation, and oxidative stress. These stimuli include environmental toxins, bacterial, viral, or fungal infections, or an unhealthy diet (such as a diet high in sugar and other carbohydrates, salt, and high fructose corn syrup). External factors play a role even when genetic mutations precipitate the early onset of Alzheimer’s disease.

For instance, individuals with a presenilin-1 gene mutation in Colombia develop Alzheimer’s disease almost a decade earlier (late 40s versus late 50s) than individuals having the exact same gene in Japan. The primary reason for the difference in age of onset is that the Colombian group is exposed to some of the highest levels of mercury in the world due to mining operation, whereas their counterparts in Japan have an antioxidant diet consisting in part of seaweed and rice bran.

Secondly, amyloid, tau, and neuroinflammation are all partially the product of oxidative stress and then can further add to that stress. Unless the original stimuli are removed early on or the nitro-oxidative consequences of those stimuli are addressed, inhibiting or removing misfolded amyloid and tau proteins makes only a slight difference in the progression of Alzheimer’s disease.

Neuroinflammation is emerging as a new competitor to the amyloid and tau hypotheses for Alzheimer’s disease in part because the anti-amyloid and anti-tau approaches have not worked well. In Alzheimer’s disease, inflammation is primarily the product of oxidative damage to various molecules, including lipids and DNA (study). This results in the activation of toll-like receptors which causes the over-activation of microglia, which produce more pro-inflammatory cytokines and more oxidants.

Leukotrienes and tumor necrosis factor-alpha are two cytokines that can play a role in Alzheimer’s disease. Montelukast as an antagonist of leukotriene receptors, and INmune Bio's (INMB) XPro1595 by preventing the binding of soluble tumor-necrosis factor-α to its receptor inhibit both oxidation and inflammation. INmune Bio's drug candidate also maintains transmembrane tumor necrosis factor-α, which helps to maintain a beneficial immune response via Akt.

However, because several other cytokines are also implicated in Alzheimer’s disease (most notably interleukin-1β), and because leukotrienes, tumor necrosis factor-α, and other cytokines are mainly secondary triggers for oxidative stress, targeting them may only modestly slow down the progression of the disease. To put this another way, if neuroinflammation were the main cause of oxidative stress and most of the damage done to the brain in Alzheimer's disease was caused directly by neuroinflammation, then it would be the perfect target for the treatment of the disease. But because oxidative stress partially precedes neuroinflammation and is directly or indirectly the cause of most of the damage to the brain in Alzheimer's disease, it is the more appropriate target.

Alector’s (ALEC) AL002 increases TREM2 activity, which spurs the removal of cellular debris, presumably including misfolded amyloid and tau proteins via the phosphatidylinositol 3-kinase/Akt pathway. The idea is to produce a beneficial immune response while preventing a negative inflammatory response (similar to XPro1595). However, this neuroprotective pathway is largely blocked in Alzheimer’s disease. It seems unlikely that Alector's somewhat unorthodox approach to Alzheimer’s will work.

I have written extensively about drug candidates such as Anavex’s (AVXL) blarcamesine, Cyclo Therapeutics' (CYTH) Trappsol Cyclo, Green Valley's GV-971 (derived from brown algae), and natural products (such as panax ginseng and other East Asian herbs) as potentially breakthrough antioxidants for the treatment of Alzheimer’s disease (article). I will recap my arguments in favor of Anavex and Cyclo Therapeutics at the end of the article for those who are not familiar with this earlier work.

For now, though, I will just link panax ginseng to the other three hypotheses for Alzheimer’s disease.

Ginsenosides decrease amyloid β-protein (Aβ) formation by inhibiting β- and γ-secretase activity or by activating the nonamyloidogenic pathway, inhibit acetylcholinesterase activity and Aβ-induced neurotoxicity, and decrease Aβ-induced production of reactive oxygen species and neuroinflammatory reactions (study one).

Our analysis revealed that KRGE (Korean Red Ginseng Extract) not only inhibited tau aggregation but also promoted the disassociation of tau aggregates (study two).

In APP [amyloid precursor protein] transgenic mice, Rd [a ginsenoside] pretreatment at 10 mg/kg significantly suppresses the NF-κB pathway activity, reducing the generation of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and S100 calcium binding protein B (S100β), which can improve learning and memory abilities (study three).

It is perhaps no wonder, then, that in an open label clinical trial, Korean red ginseng/panax ginseng led to improvements in cognition that were sustained for two years.

To summarize, inhibiting, scavenging, and partially reversing the damage done by oxidants helps prevent the development of amyloid, partially reverse the aggregation of tau, and reduces neuroinflammation and thus limits additional oxidation and nitration. On the other hand, removing or reducing the formation of misfolded amyloid and tau proteins and lessening neuroinflammation only slows down the production of oxidants without reversing the damage done by these oxidants. Thus, my semi-humble prediction (running somewhat afoul of Karl Popper’s admonition) is that antioxidant drugs and natural products will be much more successful at treating Alzheimer’s disease than anti-amyloid, anti-tau, and anti-inflammatory drugs.

From a financial perspective, most companies focusing on Alzheimer's and/or other neurodegenerative diseases have entered a down period for several reasons: they are in between results, expectations have been tempered after a period of overhype that not only affected the companies that were overhyped but their competitors as well, and in some cases doubts over mechanism of action. All of the companies mentioned in this article either have or appear to have sufficient resources to carry out their current trials, although Cyclo Therapeutics presently has considerably less cash on hand than its competitors (Alector, Anavex, INmune Bio, Cyclo Therapeutics). In the end, the specific financial numbers, while not unimportant, are less important than whether a drug candidate will actually effectively treat a disease.

For Anavex's blarcamesine, the signs of effectiveness seen at 148 weeks in a very small trial (results) will need to be replicated in a phase 2b/3 trial, which may be completed later this year. Cyclo Therapeutics is in the process of launching a phase 2 clinical trial for Alzheimer's disease based on positive results from one case study. Anavex has reported positive data for Parkinson's Disease Dementia and adult Rett syndrome, and Cyclo Therapeutics has done the same for Niemann Pick disease type 3. Anavex is also close to completing a trial for pediatric Rett syndrome. The exact timeframe in which both companies will complete all of their work is difficult to predict, but the results could be critical for the treatment of a series of untreatable or poorly treated diseases.

Anavex's blarcamesine inhibits the formation of oxidants by reducing the release of intracellular calcium and Trappsol Cyclo does the same by lowering levels of cholesterol in lipid rafts. While the proof is not all in, it appears that both drug candidates scavenge the nitro-oxidant peroxynitrite. The expectation, then, is that early signs of improvement followed by long-term near stabilization should hold up in larger trials. The antioxidant approach to Alzheimer's likely provides the best route to the effective treatment of the disease.

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Disclosure: I/we have no stock, option or similar derivative position in any of the companies mentioned, and no plans to initiate any such 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.