The Alzheimer’s Etiology Wars! $AVXL $ANVS

Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor! And I am long $AVXL FYI

A Battle in Etiology Wars!

The most prevalent hypothesis of the etiologies of Alzheimer’s disease is the A-Beta Amyloid deposits theory.  The theory has been evolving into few branches.  One of them states that there is production of A-beta in the axions of neurons in response to stress and the toxicity of A-beta works its way from axions to the whole neurons.  This evokes the problems of axonal transport with all its complexity, involving among others the A-beta deposits interference with the process of transport, autophagy and mitochondrial health.  Just to mention the most prominent ones, without talking in detail on the mechanism.  I refering here to paper titled

[1] Axonal generation of amyloid-b from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes link:

The precursor protein to production of A-beta is called APP. In the case of axion production of A-beta this compound gets palmitoylated that is another chain of a compound is attached to APP, since then it is referred as palAPP.  This is done to differentiate it from the A-beta produced from APP by the center body of the neuron, that is without being palmitoylated.  The researchers asks how they can control the production of A-beta by axions, as in their view that is what precedes axion swelling, indicating the onset of Alzheimer’s disease in vitro, and implied to be connected with axonal transport interference. Interrupting the production palAPP becomes in their eyes a therapeutic target. In a further explanation, palAPP is attached to the lipid rich outer cell membrane where the Mitochondria Associated Membrane (MAM) of Endoplasmic Reticulum comes into contact with the former.  As it can be seen in the illustration, the sheer number of MAM’s is connected with the increased occurrence of palAPP sticking from the cel membrane where the A-beta is cleaved off the palAPP chain by Beta-secretase to create the A-beta deposits in the extracellular  space.  These deposits of A-beta are blamed for toxicity which ultimately kills neurons starting with axions swelling. 

Literature provided few observations. First, that intra axonal A-beta is generated ahead of extracellular A-beta when axions are under stress. Would it mean that axions are the first under stress? The genetic degeneration which was described in the post (link: [2] [2]) starts with the lack of trascription of the protein neccesary for the axions to function and atrophy of axions sets in. Nevertheless, the quantity of palAPP is just 20% of APP total created in the model of FAD (mutation) Human Neural Progenitor Cell. FAD stands here for familial AD. In healthy neurons ~40% of A-beta comes from axions so the 20% in FAD model of Alzheimer’s disease seems like changing the nature of the ratio. In grand picture of the disease this should not stand as the most importan source of A-beta. Should we think that the placement of pal APP in the axions matters? Again, the question of axonal trasport.

 If we connect this fact with turning on the cellular stress response mechanism and so increased transcription of the SIGMAR1 gene into the protein so that MAM’s population increases with the associated increase in palAPP on the cell walls then we have an explanation tying A-Beta etiology with function of SIGMAR1. I am only speculating here, all in the light of the information from the paper. In this scenario A-beta is part of the stress copying mechanism of axons and neurons.  Also another observation is that, Amyloid deposits decrease when A-beta generation moves from axions to body of the cell, and 70% of palAPP is concentrated in MAM’s. So if you fault the axions for production of palAPP and connected it with the occurrence in axions of MAM’s then if can you control the quantity of MAM’s you can lower the production of A-beta. This reasoning is only valid if you fault A-beta alone for the damage.  Here, enter our friend SIGMAR1 protein, which is associated with the creation of MAM’s on the surface of Endoplasmic Reticulum.  The researchers silenced the production of SIGMAR1 protein and after 48 hours halved the production of SIGMAR1 protein.  But what is more interesting for us, in 72 hours of  silencing SIGMAR1 production to the level of 10% remaining cells became none-responding to viability tests, they became zombies.   Further on, researchers used agonist/antagonist pair to double or halved the number of MAM’s with resulting production of palAPP.   SIGMAR1 is not yet here, a therapeutic target per se, but rather a tool to control palAPP through MAM population. Nevertheless, agonist to SIGMAR1 increased production of axonal A-beta40 vs. none made when antagonist where used, but that was in vitro so systemwide assessment is missing. How relevant this is?  We will give a tentaive answer at thee end of this post.

I want to quote here the paper.

The degree of dementia in AD is primarily correlated with loss of synapses. Synaptic dysfunction, preceded by reduced syn- aptic transmission and loss of dendritic spines, is largely driven by neurotoxic Ab42-oligomers (Cleary et al., 2005; Haass and Selkoe, 2007). Physiological levels of Ab42-oligomers have also been shown to suppress long-term potentiation (LTP) in hippocampal slices (Mango et al., 2019). In contrast, Ab in the picomolar range has also been shown to be required for LTP in- duction (Koppensteiner et al., 2016). 

I would like to stress here that the last sentence in this quotation bring the chickens to roost home.   Mostly in medicine, total removal of any compound can be detrimental so does the same applies to A-beta?  A-beta has its function in spite the fact that its currently blamed for the onset of the disease. It sure, is not toxic in small concentrations as the quote suggests. Well, your long term memory needs it. Besides the produced A-beta was A-beta40 not the most toxic A-beta42.  The other fact is that the interruption in axonal production of A-beta did not lower the total APP and A-Beta production in the 3D in-vitro model of Alzheimer’s disease. 

Scientific papers are not written in an objective manner.  From the onset they presuppose some approach that is tested in the papers.  In biology where the vastness of sheer number of connections overwhelms human cognition one has to go one step at a time.  There is number of competing views on Alzheimer’s and not all of them can be correct.  There, lies the root of the cause of 10 drugs out of 11 tried failing.  Papers can be convincing but the final word is with the clinical trials and the progress the patients make.  

Researchers face a dilemma, they can lower palAPP at the cost of silencing SIGMAR1 that ultimately makes cells not viable, in vitro.  If the cost of therapy is so defined as endangering the cells viability, they restore to hinting at “MAM deregulation” as a probable cause of axonal A-beta production leading to axon swelling. In the context of the paper I postulate that the as the axons become under stress they turn on their stress fighting mechanism and the increased transcription of SIGMAR1 gene leads to among others heightened production of palAPP as part of the copying mechanism.  Yet, few fold production of A-beta might interfere with axonal transport for example. This scenario makes sense in the face of few voices claiming that A-beta’s toxicity is part of infection fighting mechanism of the brain.  It  even turned out be toxic to brain tumors cells, but overproduced can be toxic to the whole brain.

From the years long results of dosing Blarcamesine, the stress fighting and neurotrophic factors released from MAM’s by the action of the agonist (see my previous post link:   ) ultimately restore neuronal health. 

Search of Drugs to Lower palAPP Production

Though the researches make a point that SIGMAR1 antagonist could be used to control palAPP and axonal A-beta other target gets their attention, and I can directly quote them.

We and others have previously shown that the loss or inhibition of the MAM-resident enzyme acyl-co-enzyme A:ACAT reduces cell surface localization of APP and Ab genera- tion (Huttunen et al., 2009; Bhattacharyya and Kovacs, 2010; Murphy et al., 2013). More recently, we showed that inhibition of ACAT reduces palAPP in lipid-rafts by ~76%, in vitro (Bhatta- charyya et al., 2013). Palmitoylation inhibitors 2-bromopalmitate and cerulenin also reduced palAPP level and Ab generation in vitro (Bhattacharyya et al., 20 .  

The inhibitors for A:ACAT  already exist and are  being involved in treating atherosclerosis  due to their connection to cholesterol theory.  From short search I think that these drugs have been tested in animal models for  a decade, and as far as I searched it did not yield a drug which phase 3 onto market in both atherosclerosis and AD.  It seems to be a dead end. 

Possible Scenarios Implied by Paper [1]

  • In response to cellular stress SIGMAR1 gene is transcribed in larger amounts
  • The increased SIGMAR1 protein leads to more MAM microdomains
  • This leads to increased production palAPP in axions and larger amounts of A-beta is created
  • A-beta toxicity affects axonal transport affecting viability of neurons, and or lead to axonal swelling
  • Enter Blarcamesine: a SIGMAR1 agonists releases stored in MAM neurotrophic and cellular health compound
  • The consequenses of A-beta toxicity are reversed by these compounds
  • Patients score higher on congnition test and maintain their scores

Possible Scenarios Implied by Papers [1] and [2]

  • Epigenetic change deprives axions of the neccesery protein to build viable synapses and stresses them
  • SIGMAR1 transcription increases in stressed axons especially increasing production of palAPP
  • Overproduction of A-beta beccomes toxic to neurons in synergy with epigenetic degeneration
  • Enter Blarcamesine: a SIGMAR1 agonist releasing stored in MAM neurotropic and cellular health compounds
  • The consequenses of A-beta toxicity are reversed by these compounds
  • Patients score higher on congnition test and maintain their scores

Possible Synergy with ANNOVIS $ANVS Pophisen ANVS401?

Not much is known about the Mechanism of Action of the ANVS401. The only metric released was that 60% of production of APP total is taken out of the line, so to speak. The drug does not affect the RNA for synthesis but somewhere breaks the chain of events leading to the fully folded APP. The narrative touted by ANNOVIS is improved axonal transport. Alzheimer’s disease has number of scenarios where some aspect of cellular physiology can be visibly disrupted. Reseachers “marry” certain faults and spend years pursuing them in hopes of finding the underlying cause of the disease. Hat tip to their tedious and arduous work. Nevertheless, for investors what carrier the water is a good narrative limiting the scope of the disease to single fault being fixed with particular drug.

The link to the press release is here.

The information on # NCT04524351

First let us consider the average MMSE and ADAS-Cog11 of the 14 early Alzheimer’s and Parkinson’s patients. 30% improvement with delta=-4.4 ADAS-Cog11 and 22% improvement with delta=-3.3 ADAS-Cog11 gives consistent reading of 15 ADAS-Cog11 points average starting score. On more familiar MMSE scale, that is equivalent of 25 points. All that is inspite the eligibility criteria of MMSE 18-28 points on

I have noticed that very consequently new trials in AD and PD sphere are enrolling subjects with earlier disease as it is easier to get a response from them. And no wonder, since hundreds of trials produced unremerkable results when the inclusion criteria are really MMSE 18-25. The down side of this trend will be visible in just few lines of text.

Patients improving -4.4 points on ADAS-Cog11 scale when compared to initial positions are achieving p-values p=.04. So measured against itself there is 4% chance that the data is result of statistical event and not workings of the drug in just 25 days. Isn’t p=.04 asking for some measure of randomness when measured against itself?

But when we compare these results to the placebo arm then this chance becomes 13%. The explanation of this discrepancy lies in the fact that dispersions about the average for the placebo and the dosed are a bit more indistinguishable. So versus placebo, there is the loss of the “statistically significant”.

Though the MMSE scores were collected, as well as ADAS-Cog11, by their nature they are less sensitive in this range and the company might be less prone to release them. Don’t get me wrong. Many companies recently have been releasing data from early phase2’s with just a handful of patients and after 30 days of dosing produces impressive numbers in some less known measure. I am being a bit facetious. ANVS401 is the first drug following A-beta deposit etiology and scoring high improvement rates in a short period of time.

I have been writing that the etiology of A-beta deposits is transitioning to inflammation narrative. The same etiology here lives under the narrative of axonal transportation. Would that be the more appropriate narrative for A-beta etiology?

I have also written that 30% patients diseased with Alzheimer’s diagnosis have no deposits of A-beta plaque (amyloid). Would Alzhimer’s be a syndrome, not a disease? We live in exiting times….

Writing is hard work, reward it with a beer…

Yet, for those who believe, could you just put a short parayer for me…….


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