AAIC 2023

Summary

Release of Donanemab Data & Lecanemab Recommended Use Guidance

Section BLUF:  From a mAb progression point of view, Donanemab has by far the clearest efficacy signal, easily surpassing Aducanumab and marginally skirting ahead of Lecanemab. While all three mAb hold significant safety concerns, strict use guidance, and (likely) high prices, Donanemab at least revealed acceptable evidence behind its disease-modifying designation; disease modifying defined as the "altering slope/course of the disease". Cognitive and functional activity efficacy was clear despite maintaining emphasis on "reduction in decline" instead of "improvement or reversal", for which we blame big pharma repeatedly pursuing anti-amyloid intervention pathways. Anavex has significant opportunity to deviate by demonstrating improvement in patients with a unique mechanism of action. To my memory, at no point in the TRAILBLAZER-ALZ 2 presentation did any speaker make reference to Donanemab intervention causing restoral of memory or function. Donanemab does NOT reverse cognitive loss. Blarcamesine appears to be able to create a strong response in most patients, resulting in a relative halt to disease progression in most patients or restoral of function in some patients. The question is how many patients, and in which type of patient? We believe full exome sequencing will holistically inform responders. Responder criteria is important, as is evidenced by the conservative recommended use guidance established for Lecanemab. Notably, patients with seizures (up to ~64% of Alzheimer's patients), patients with cardiovascular disease (>55% of Alzheimer's patients), and patients taking anti-coagulants (~20% of Alzheimer's patients) should be excluded from Lecanemab treatment. Additionally, it was recommended that patients should have their APOE screened and those with APOE4/4 also likely be excluded from treatment due to dramatically higher risk of ARIA. Blarcamesine is not only effective against Alzheimer's, but is likely to aid these comorbidities, having shown seizure benefit in Rett Syndrome patients and various preclinical models, as well as implications in hypertension and endothelial systems. It is unknown at this time whether APOE status will have an impact on future Blarcamesine prescription status, but it appears unlikely at this time. Anavex's Blarcamesine is likely the most effective Alzheimer's drug in development and would likely reap significant market penetration upon approval due to its inclusivity, safety, oral administration, and likely cheap price (we theorize <$13,000 annually). 

Full & Unfiltered Notes on Donanemanb/Lecanemab from the Conference Below: 

- Total number of patients screened was 8,240. Of those, only 1,736 were enrolled due to heavy exclusion criteria. I think most notably, patients with low or no Tau were not accepted (25.1% of patients not accepted) and patients with 4 micro hemorrhages (part of the 19% 'other' not accepted). This means about 80% of screen patients weren't accepted. This doesn't exactly represent a holistic portion of the population - especially when only 23.2% were excluded because they were too late in disease course (the trial was for MCI and mild AD). Anavex excluded less than 10% of patients during screening for context. Note: This was a very large trial ran in 8 countries, although most patients came from the U.S.

- The trial was running 3 groups of patients. One placebo, one low-medium tau, and one high tau. Most of the data in this presentation is for Placebo vs. Low-Medium Tau, and Placebo vs. Combined (Low-Medium + High Tau).

- Black and Hispanic significantly underrepresented, but this is common.

- Comorbidity was comparable between dosed and placebo groups (people with hypertension, mood disorders, etc.)

- Primary efficacy outcome was iADRS (a global endpoint kind of like CDR-SB).

- Secondary endpoints included CDR-SB, ADCS-ADL, ADAS-COG.

- Obviously a slew of biomarkers including amyloid were endpoints.

- For iADRS, Donanemab allowed for a 35% slowing in disease progression at week 76 in the "low-medium tau" cohort. This was comparable to their phase 2 trial which saw 32%.

- For iADRS, Donanemab allowed for a 22% slowing in disease progression at week 76 in the "combined" cohort [low-medium + high tau]

- On CDR-SB, Donanemab allowed for a 36% slowing in disease progression at week 76 in the "low-medium tau" cohort.

- On CDR-SB, Donanemab allowed for a 29% slowing in disease progression at week 76 in the "combined" cohort.

- Looking at the graphs, treatment effect widened over time which indicates slowing either continues OR placebo group got worse faster. Alzheimer's is not a linear decline, meaning there are stages where decline is considerably more rapid. But overall, widening is a positive.

- After dosed patients reduced amyloid to "negative" levels (24.1 centiloids), dosed patients were swapped to placebo without their knowing. This is important because even after swapping to placebo, amyloid negative patients continued slowing disease progression even more. Not rapidly, but more nonetheless.

- For ADCS-ADL, Donanemab created a 40% slowing in the "low-medium tau" population.

- For ADAS-COG, Donanemab created a 32% slowing in the "low-medium tau" population.

- All efficacy endpoints "reduced decline" with ADCS-ADL (activities of daily living) seeing the most improvement followed by CDR-SB and then iADRS. ADAS-COG and MMSE were last.

- All sensitivity analysis revealed positive result (the way the % was calculated). The current standard (MMRM) was a 39.6% slowing in iADRS in the "low-medium tau" population. Although the analysis they used officially was NCS2 which gave the 35% mentioned previously. All-in-all, under all different types of statistical analysis, iADRS slowed by 33-40% (rounded).

- Patients in the "low-medium tau" group lowered their risk of progressing to the next stage of disease as measured by CDR-global score by 38.6%. The "combined" group lowered risk by 37.4%.

- The absolute best patients in pre-specified subpopulation analysis slowed iADRS by a whopping 60%. These were patients in the "low-medium" tau population earliest biomarker pathology and were MCI. So the theme continues with very early patients being more desirable. For these patients, they slowed CDR-SB decline by 46%. Younger patients also saw better result.

- 10 Placebo patients died, 16 Dosed died

- 3 of the dosed deaths were considered to be as a direct cause of the medication

- Placebo ARIA-E (swelling): 1.9%

- Dosed ARIA-E: 24%

- Placebo ARIA-H (bleeding): 7.4%

- Dosed ARIA-H: 19.7%

- Placebo Infusion Reaction: 0.5%

- Dosed Infusion Reaction: 8.7%

[3.6% of patients withdrew because of irritation of administration]

- ARIA overall was noticeably higher in the dosed group but was reportedly mild-to-moderate on the whole. Nonetheless, 3 patients did die and its unclear what long-term use of the drug does in this regard. Authors pointed out that monitoring is still absolutely necessary. 

- APOE4 patients were much more likely to have ARIA-E and H. This is common in MAB. Interestingly, there was no difference in ARIA and whether a patient was taking anticoagulant or anti-platelet or not. 

- On the biomarker front, the drug rapidly reduced amyloid across the board at 24 weeks and onward. Over 66% and 76% of the "combined" dosed group were amyloid negative by week 52 and 76 respectively (meaning they were swapped to placebo).

- Interestingly, there was no change to frontal tau PET. This is different than their phase 2 trial and is the only measure they missed. Along with this, there was not a clear pattern in NFL. Charts are all over the place.

- Plasma pTAU217 was rapidly reduced and it was noticed that patients that started the trial (baseline) with low pTAU217 performed notably better on iADRS and CDR-SB.

- GFAP was rapidly reduced as well.

- According to a statistical analysis of 'time saved for patient', iADRS results reveals a 4.4 months saving. And if calculated on CDR-SB, it is a 7.5 months saving. Now, in my opinion these numbers are very far off from each other. It should probably be determined by the community which endpoints should be used to calculate "time saved" which is a trending topic.

- Notably, 47% of dosed patients did not decline on CDR-SB at week 52. Although, 29% of placebo patients didn't either. 

[still no mention of improvement].

- An 18 month extension is currently ongoing. Those that were amyloid negative in the main study and swapped to placebo will continue on placebo without their knowing.

- Another Donanemab trial is ongoing to test asymptomatic patients to see if the drug can prevent or slow them from becoming symptomatic.

Conclusion: Strong signal. Clear slowing. Safety still a bit questionable. Unknown price. Community needs to focus on improvement, not slowing. Still excited for Anavex full data. I think they have a real opportunity to pitch improvement vs. slowing.


Drinks with Dr. Timo Grimmer

Dr. Grimmer was in good spirits. I booked us an exclusive seating at a high end cocktail lounge in downtown Amsterdam. He does not normally drink cocktails as his work keeps him too busy to enjoy himself, but he took any recommendations and enjoyed some very cool 'roaring 20's' style cocktails... and some spicy nuts!

We discussed a great manner of things. I gave him my impression of the CNS research community and their (my perception) inability to focus and delineate research tasks. It seems like a lot of groups are working on the same things and publishing separately. He agreed and acknowledged a lot of money would be saved by having a better research management portal to prevent doubling up on the same research. He also said he looks through thousands of posters every year and usually only comes across 10-15 novel ideas. This tells me two things. First, my assumptions of the community were correct. Second, Dr. Grimmer clearly believes Anavex to be a novel idea - one that is quickly progressing through late stages.

Getting to Anavex more in a little bit, first a few more interesting tidbits. I reminded him of my role at AAIC: to identify trends in research and make determinations on ideas/compounds worthy of investment - ones separate from Anavex as they did not present here this year. When I stated this he immediately brought up Alector, specifically their AL002 compound in phase 2 Alzheimer's co-developed with Abbvie. It is a TREM2 modulator, that target being of high interest at AAIC this year. He acknowledged he was only familiar with it on the surface and that I should look into it more. Note: For those interested in Biovie, I brought up their 30 week trial length. He said for a 'symptomatic' drug designation 30 weeks was good enough. For a disease modifying therapy it is not. This made sense and hadn't considered it before.

We also discussed Donanemab and Lecanemab. We discussed this for probably 15 minutes, but for brevity, the conclusion was that there are still a lot of questions regarding safety and "what's next" for Alzheimer's. For example, once you take Donanemab and get to amyloid-negative levels (~25cl) you stop taking the drug. As of right now, you're done, that was the dosing regimen, that's what we can do for you (the patient). What if we can identify disease pathology ultra early, administer MAB, and then start a 'maintenance' therapy until death. What would that maintenance therapy even look like? I speculated that Blarcamesine as a catch all medicine would be beneficial for a maintenance phase or a combined therapy for Donanemab.

Moving to Anavex. Dr. Grimmer thinks they're being approached/in-convo with big pharma for purchase/partnering which is why we have not seen data yet. He also mentioned that Anavex could be looking to partner with mid-sized pharma, something we here at SOTC think is possibly more desirable than big-pharma. This was his speculation based purely on experience working with small/mid-sized pharma in the past. I was pleased with this reply because it is what many of us have already been suspecting ourselves. He is still excited about the company and ready for 'what's next'. 


Gender & Estrogen, Cholesterol (Lipids/Sterols), Inflammation, and Proteins... Oh My!

A good portion of the conference was focused on five topics, four of which are presented in this section. Unsurprisingly, as studied for over a decade and previously mentioned by Dr. Missling and Anavex officers, estrogen has been found to be protective to cognitive health in women. It was disclosed at AAIC that early menopause, women with many children, women with APOE4 alleles, and women with cardiovascular disorders all faired worse than men cognitively in late-mid/late life. In a large study, it was found that women begin seeing significant cognitive decline on average at the age of 60, especially women with APOE3/4 or 4/4. While these metrics make outlook for women's health seem bleak, it is important to remember that we can alter aspects of our lifestyles to reduce risk of dementia. For example, it was found in mice that western diets cause abundant inflammatory response and weight gain. By altering mice diets back to healthier foods, inflammation subsided. Importantly however, the mice appeared to have persisting change in the way their bodies responded to future inflammation, indicating longstanding effects. By improving diets, increasing exercise, and living healthy lifestyles, we can reduce risk of dementia by 40%. This is especially important in women with APOE4 alleles as this demographic has the highest risk for dementia. Notably, APOE4 alleles on itself is not bad. It has been found that APOE4 is like a trigger ready to be pulled - it poses a persisting threat; however, it needs a pro-inflammatory aid to tip the finger into pulling the trigger. Particularly, chronic/sustained inflammation is what amplifies APOE effect on dementia risk and break down in the endothelial system.

There have been mixed results as to whether hormone replacement therapy may be of aid to women in later years. Some trials have shown marginal improvement to cognition (~10%) in women taking hormone replacement therapy, but other trials have shown no effect whatsoever. It is theorized that timing of the therapy may be the deciding factor and more studies are expected to confirm this theory. This is a critically underrepresented demographic, especially as 65% of dementia patients are women, 12% of the population are APOE4 women - of which are up to 50% of the Alzheimer's population. 

So what does APOE, cholesterol, and hormone synthesis have to do with Anavex and Blarcamesine? It turns out, a lot! An excellent research article from 2021 helps us understand , "Proper neuronal function requires accurate control of gene expression. MicroRNA (miRNA) are small non-coding RNA known to regulate gene expression post-transcriptionally… Lipidated APOE is the principal carrier of cholesterol to neurons via APOE receptors… in this study we identify a class of miRNA in astrocyte derived APOE particles that selectively post-transcriptionally suppress catalytic enzymes in the cholesterol biosynthesis pathway in neurons. Consequently, nuclear acetyl-conezyme A is accumulated, and histone acetylation is promoted. Deprived or reduced APOE [as found in Alzheimer’s disease] not only abolishes histone acetylation levels, but also reduces multiple proteins associated with memory consolidation, ultimately resulting in damaged transcriptional activation of these genes in response to neuronal activity. Importantly, human APOE4 reprograms the metabolic state and promotes histone-acetylation-mediated memory less efficiently than APOE3”. 

That was a lot of words, so what does it all mean? We hear the terms APOE and cholesterol and think 'bad' because of the association with Alzheimer's, but this really isn't the case. APOE mostly resides in the astrocyte, a cell which regulates blood flow, transfers mitochondria to neurons, and supplies the building blocks of neurotransmitters, which fuel neuronal metabolism. Astrocyte clear away debris and junk! The APOE funnels healthy miRNA and cholesterol from the astrocyte to the neuron. When APOE is reduced, this causes miRNA to corrupt and stifles cholesterol processing. Astrocytic APOE promotes neuronal function by facilitating acetylation of active histone marks on chromatin, which subsequently enhances transcriptional activation of genes that favor memory consolidation. This process is known as chromatin remodeling - ring a bell? So to summarize, APOE funnels the miRNA which activate histone, which remodels chromatin, which enhances global RNA transcription, thus enhancing synaptic strength and thereby aiding short and long term memory consolidation... phew! Importantly, it was found that APOE3 can carry roughly double the miRNA than APOE4.

According to the same research article, APOE3 was roughly 21-25% better at activating histone for chromatin remodeling than APOE4. Additionally, APOE3 was roughly 107-127% better at controlling cholesterol than APOE4. As part of this research, 3x memory genes were selected as assayed as well: ARC, FOS, and ERG1. APOE3 was associated with ~53% higher ARC expression over APOE4, ~120% higher FOS expression over APOE4, and ~70% higher expression levels over APOE4. 

Here is another explanation of cholesterol and other lipids, APOE, and it's relation to Sigma-1 & Blarcamesine.

It should be understood that the endoplasmic reticulum is a major hub for protein, cholesterol, and other lipid synthesis. It has been found that lipid synthesis is essential for ER-stress response, which is common in people with Alzheimer’s and other neurodegenerative disorders. Lipid dysfunction has also been noted in cardiovascular disease, diabetes, and cancers.

When discussing lipids, it’s important to know the distribution of lipids in our brains. It has been found that, “cerebral lipids account for at least 50% of dry brain weight—the most lipid-rich organ next to the adipose tissue. Lipids are the basic structural component of neuronal cell membranes. Brain lipids are comprised of 50% phospholipids, below 40% glycolipids, 10% cholesterol, cholesterol ester and traces of triglycerides. Long-chain polyunsaturated fatty acids (LC-PUFAs) account for 25–30% of the total fatty acids (FAs) in the human brain, including docosahexaenoic acid (DHA) and arachidonic acid (AA)”.

On the neurodegenerative front, Alzheimer’s and Parkinson’s disease in particular both share increased development of unusual proteins (amyloid and a-synuclein) and show dysregulation of lipid metabolism. Because of this, lipid metabolism and homeostasis of the system is suspected of playing a role in the disease pathology. This role has not been fully elucidated. 

As mentioned earlier, the endoplasmic reticulum is a major metabolic hub for the cell, creating proteins and cell lipids. Quality control of these two functions is primarily regulated by the unfolded protein response (UPR), which both senses and responds to irregularity.

UPR is made up of three separate sensors which I’ve previously discussed here. IRE-1 is of particular interest however as it has control mechanisms under the HSP70 chaperone protein. Under stressful conditions, HSP70 releases IRE-1 to splice XBP-1, which in turn prompts UPR genes (like CHOP) to activate. This activation increases protein folding, turnover, and lipid metabolism to respond to the cellular threat. All three UPR sensors perform similar roles, but IRE-1 has the most direct link to the Sigma-1 receptor.

The fact that lipid and protein dysfunction both activate UPR suggests a link between the two. It should be noted that lipids contribute to proteostasis - the clearing of faulty and dead proteins. This is a function that shows clear restoration in Blarcamesine-dosed patients with modulation of the 26S proteasome. Lipids have been shown to clear inclusion bodies itself, and transport more troublesome proteins as well. 

In 2023, it was published that, “while unfolded proteins and lipid disequilibrium are known to independently induce the UPR, our novel finding demonstrates that changes in lipid pathways could significantly impact a cell’s ability to respond to protein stress and brings to light a potential mechanism through which lipid disequilibrium might facilitate the progression of proteopathic diseases”. Thus, lipid homeostasis may be of more importance than protein homeostasis when it comes to signaling the UPR for aid.

All the way back in 2005, it was found that, “Sigma-1 receptors possess a putative sterol-binding pocket and are predominantly expressed on the endoplasmic reticulum (ER) where most lipids and their precursors are synthesized”.

Additionally noted, “recent studies demonstrated that sigma-1 receptors target the lipid-storing subcompartments of the ER and are colocalized with cholesterol and neutral lipids. Sigma-1 receptors form detergent-insoluble lipid microdomains (lipid rafts) on the ER subcompartments and can translocate on the ER when stimulated. Upregulation of sigma-1 receptors affect the levels of plasma membrane lipid rafts by changing the lipid components therein. The membrane reconstitution thus induced by sigma-1 receptors in turn affects functions of proteins residing in plasma membrane lipid rafts including tropic factor receptors and tyrosine kinases.”

Thus it was found that Sigma-1 receptors almost certainly have a role in regulating ER lipid transport and resultant plasma membrane lipid raft reconstitution.

Considering the fact that lipids as the basic component of cell membranes, it’s of no surprise that Sigma-1 plays an important role in human health as well as brain function.

So what exactly ties lipids to Alzheimer’s? Has there been direct evidence? Absolutely, there has. Alterations of fatty acids at the level of lipid rafts and cerebral lipid peroxidation were found in the early stage of AD. Additionally, genetic and environmental factors such as apolipoprotein (APOE), lipid transporter carrying status, and dietary lipid content are associated with AD.

Lipids that have direct links to Alzheimer’s related pathology are as follows:

1. Sphingolipids increase = amyloid creation 

2. Saturated and trans fats increase = BBB dysfunction 

3. Cardiolipin decrease = mitochondrial dysfunction 

4. MAG & DAG increase and SPM decrease = inflammation 

5. ISO-P increase = oxidative stress

6. KB decrease = oxidative stress and mitochondrial dysfunction 

When you combine these factors together, you get synaptic loss and memory impairment. You also get chronic stress. We therefore now have a good understanding of the vast impact lipid homeostasis has on core cellular function.


We discussed earlier that Sigma-1 receptors play importance in lipid raft creation. So what are lipid rafts? Essentially, they are enriched structures along the cell membrane comprised of clustered sphingolipids, cholesterol, and other lipids. They are important for signal transduction, cell adhesion, and lipid/protein sorting. Additionally, it has been found that many AD-associated proteins co-locate in lipid rafts, such as amyloid precursor protein, beta-secretase, y-secretase, and neprilysin. It is within these lipid raft structures that the aforementioned proteins corrupt. Amyloid reacts with APOE and tau to create amyloid oligomers and hyperphosphorylated tau. Amyloid genesis itself is directly related to lipid raft content. Lipids are the mediators that orchestrate numerous immune & inflammatory responses.

Now, the major sterol lipid in humans is cholesterol. Cholesterol in the brain is created internally, as the BBB prevents most external cholesterol from entering. As mentioned before, cholesterol is delivered to neurons, and when delivery is low, it is found that synaptic plasticity and neurotransmission decreases, while tau pathology and neurodegeneration increases. This combination ultimately ends with neuronal death.

Conversely, “elevated cholesterol is responsible for Aβ formation and was observed in early stages of AD patients. Aβ production is mainly determined by β-secretase 1 (BACE1) levels in lipid rafts, the enzyme that cleaves βAPP to generate Aβ”. 

So while at homeostasis, cholesterol regulates amyloid metabolism, fibrillation, transportation, degradation, and clearance. Seems pretty important. Almost seems like you’d want an intervention that modulates cholesterol, sterols, and other lipids. Well…

According to a STRING and KEGG analysis we ran earlier this year, Blarcamesine and its binding affinities likely influence 148 unique pathways. Of those pathways, 55 (37%) likely have interwoven ties with cholesterol and other lipids. Notice in the photo carousel how researchers at AAIC found cholesterol, sterol, lipids, and steroids to be significantly downgraded. The Sigma-1 binding affinity for Blarcamesine in particular addresses quite a bit of this. Of course, this is a somewhat hypothetical analysis based on high-confidence gene interactions (70%+ confidence) and certainly isn't a definitive listing. Below you will find the full list of pathways Blarcamesine likely influences with cholesterol/lipid ties, they are in order from highest gene interactions to lowest gene interactions with the most interesting bolded:

Dopamine 

Glutamate

Cholinergic

Serotonin 

Endocannabinoid 

Actin cytoskeleton 

Neuroactive ligand receptor interaction 

RAS signaling 

Sphingolipid signaling pathway 

GnRH secretion 

Phospholipase D signaling 

PI3K-Akt signaling 

Rap1 signaling 

Adrenergic signaling 

Growth hormone 

Cortisol synthesis 

TRP channels 

GnRH 

Parathyroid 

Insulin secretion 

Aldosterone 

Alzheimer’s 

Oxytocin 

Estrogen 

cAMP 

AGE-RAGE 

ErbB signaling 

Glucagon 

Steroid biosynthesis 

VEGF 

Cellular Senescence 

Axon guidance 

Parkinson’s disease 

Wnt signaling 

Endocrine resistance 

Prion disease  

ALS 

Inositol phosphate 

MAPK signaling

Phosphatidylinositol signaling 

CHOLESTEROL METABOLISM 

Lipolysis 

Apoptosis 

Neurotrophin 

Insulin signaling 

Hippo signaling 

Adherens Junction 

Synaptic vesicle cycle 

Tight junction 

B cell receptor signaling 

FoxO signaling 

Autophagy 

MTOR 

Metabolic pathways 

Cytokine-cytokine interaction 


So how does APOE tie into cholesterol? Why does APOE matter? APOE is the main component of lipoproteins which facilitate the transport of cholesterol in the brain. APOE4 binds to very-low-density lipoproteins, while APOE3 and APOE2 (associated with reduced dementia risk) bind to high-density lipoproteins. Very low density proteins are large, while high-density proteins are small. APOE2 decreases levels of total cholesterol while APOE3 is neutral and APOE4 increases total cholesterol. One APOE4 allele is associated with a 300% increased risk for Alzheimer’s, while homozygous APOE4 alleles are associated with 1,200% increase.

How can we tie all of these concepts together?

Summary: Sigma-1 resides in the MAM, an endoplasmic reticulum-based structure filled with compensatory mechanisms activated for cellular homeostasis. The MAM does this primarily be tethering modulating proteins and calcium between the endoplasmic reticulum and the mitochondria. The silencing (antagonistic) of Sigma-1 is correlated with at least a 200% decrease in MAM quantity compared to control. Beyond a vast slew of other issues, reduction of Sigma-1 and MAMs create lipid raft alterations. Lipid rafts are located on the cell membrane, and have primary roles in signal transduction, and lipid homeostasis (UPR response). They are also a hub for cholesterol, APOE, and Alzheimer’s-related proteins like amyloid, where they corrupt and create oligomers. It is likely that Sigma-1 is integral to saving the cell, by ensuring lipid homeostasis, policing raft function (thus decreasing Alzheimer’s pathology) AND impacting cholesterol levels. Considering the fact that APOE type influences cholesterol interaction, and APOE type has tremendous weight on dementia risk, it is easy to see why Blarcamesine’s connection to lipids and cholesterol is so important. This is of course on top of (or related to) other therapeutic benefits garnered by the compound: reductions in neuroinflammation, expression of neurotransmitters, protein clearing, oxidative maintenance, restorative autophagy, calcium homeostasis, hormone influences, and mRNA transcription. All of these factors as a combined front likely prompt cascading beneficial effects. 

As if this wasn’t enough, muscarinic receptors, particularly M1 and M2 also play a role in this system, but won’t be discussed at this time.

Brief Summary of Some Interesting Competitors Which May Warrant Investment

Cognition Therapeutics (CGTX) [CT1812]

Alector (ALEC) & Abbvie (ABBV) [AL002]

Denali (DNLI) & Takeda (TAK) [DNL919]

As always, I am not an investment advisor. These companies are attractive to me due to their science and potential in market but I do not advise anyone to purchase these companies on my writings alone. Please do your DD, especially as company financial position plays no part in my rankings.


AAIC Summary and Looking Foward

Overall, AAIC was a very enjoyable scientific conference and I appreciated the opportunity. I want to thank the 65 private investors that funded this trip. You will find my full notes below which cover a few more topics like lifestyle intervention, longitudinal studies, and protein/gene analysis. To touch on this topic, after scouring clinicaltrials.gov, it is my belief that Anavex's 2b/3 Alzheimer's trial is the first major Alzheimer's trial to include full Whole Exome Sequencing DNA data and full mRNA exome expression collection. This dedication to genome sequencing should provide extremely comprehensive analysis when comparing individual results for Blarcamesine-dosed patients. Alzheimer's patients normally differ quite dramatically between phenotypes and pathologies. Perhaps a patient has amyloid and low tau, or perhaps amyloid and lewy bodies but no tau. Perhaps a patient has PSEN1 mutations. All of these factors could change how a patient responds to treatment. It could also change when a patient should be treated. An interesting discovery at AAIC was the timing of gene sequencing. It was found that depending on the stage of disease course, genes could be completely upregulated, or completely downregulated, or somewhere in-between. This is emerging science. 

I think going forward, I am looking most to this gene data and how they correlate it with ADAS-COG and ADCS-ADL results. Which patients improved on Blarcamesine treatment? Big pharma is not improving patients with currently approved and imminently emerging drugs. Anavex has a real opportuniuty to shift this narrative. Their criteria for responders on both cognitive and functional endpoints already prove that a strong cohort of patients improved over baseline. This is truly exciting and will send ripples throughout the scientific community if presented well. Additionally, I think we could be in for a real treat soon. For those following timelines, all Alzheimer's OLE patients completed their first 48 weeks on the 96 week extension. While unknown if Anavex will do so, it could represent an excellent opportunity to release full main trial results (primary outcome data broken out by dose), biomarker data, gene data, and preliminary OLE data simultaneously for a more complete picture on lengthy dosing regimens. According to my calculations, we have entered the window where the company has already collected all of this data (or nearly completed data collection). In conclusion: While some of the specific compounds I mentioned here seem extremely promising, it should be noted that Blarcamesine already has a role in nearly all pathways targeted by these other drugs. Of course, it is likely that some of these specially targeted compounds hit their respective pathway with greater strength - as they are specially designed to do so. Anavex's Blarcamesine still appears to have the best shot of providing multi-factorial, multi-phenotype therapeutics to 'most' patients. I'm very bullish on S1R/M science and really looking forward to the full Alzheimer's 2b/3 presentation.

P.S. I have a few more articles I will probably write in the next 30 - 60 days on topics I just couldn't make in to this report.

Developing Topics from 16 July, Morning

- it was found in a longitudinal midlife study (40-60yo) featuring over 14k participants that greater social engagement reduced risk incidence of dementia by ~25% after crossing over into old age (60+)

- slope of dementia incidence was extremely evident between all groups (those with low social engagement, moderate social engagement, and high social engagement) indicating clear, defined results - good study 

- it was noted that males responded noticeably worse than female participants. While female participants in the moderate and high engagement groups did well, that was not the case for males in the moderate engagement group. Males in the high engagement group were the only ones to have real impact.

- note: it was stated a few times that a persons PERCEPTION of social engagement was perhaps more important than reality.

- will go back and rewatch a presentation on sleep. The bottomline here is that high intraday variability (people that are super busy and then slow down and then are super busy again) had a relation to higher Amyloid. Patients with stable intraday variability (maintain low or moderate levels of activity) had lesser relation to Amyloid.

- it surprises no one, but yes, sleep issues are correlated to dementia. Notably, researchers in this study conclude it is “more likely” that sleep problems are a RISK factor for dementia, NOT a consequence of dementia or early pathogenesis for dementia.

- a study with MANY limitations and excessive need to re-crunch data found little evidence for air pollution and dementia. In my opinion, this study should be re-ran with more considerations, wider population, and overall better analysis.

- interestingly, there have been higher levels of platinum and palladium particulates found in cities in recent decade. Likely due to catalytic converter wear (found in cars).

- an 18 month Japanese intervention study (an extension of FINGERS I discussed in my CTAD22 review) found NO significant change in the full cohort between participants receiving exercise & diet help and those that did not. HOWEVER, there was a big difference in a sub-analysis of those with APOE4 alleles. APOE4 carriers performed significantly better under ideal exercise/diet programs. This result was also found in the original FINGERS trial. 

Meaningfulness of Clinical Trial Outcomes

This section was 1:15 hour long so I’m going to do my best to summarize. As a generalization of the block, there are a lot of ways to model data. Some ways have been identified as better than others. It’s likely that CDR-SB minimum clinically important difference [the level of improvement or slowing needed in an outcome for a patient/caregiver and clinician to agree there is a benefit] is inflated at its current established measure which ‘perhaps’ indicates Lecanemab (Leqembi) CDR change was more meaningful than previously thought - although this is not definitively the case.

- disease modifying therapies are thought to change the biology of the patient and alter the slope of disease progression

- Leqembi represents a “stepping stone”. One of the first stepping stones with many more, better stones needed.

- “time” may be the best clinical outcome to model. Time saved from later disease stages

- co-pathologies complicate analysis (like if a patient had diabetes and Alzheimer’s, etc)

- we must consider which benefit-burden thresholds are acceptable. What is acceptable to the patient/caregiver, or regulators, or payers.

- what is cared about ‘the most’ by ‘the most’ (see picture)

- CDR-SB is an 18 point scale measured in 0.5 point increments. A half point could determine if a patient is independent or dependent on someone else. It is MY opinion that CDR-SB being measured in half point increments leaves a lot of “in between”.

- an extremely intelligent gentlemen with a very nice mustache spoke about types of modeling. A lot of data is currently modeled using mixed model for repeated measures (MMRM), which is percentage reduction in decline. He explained that there are 3 other models as well and he came to the conclusion that progression model for repeated measures (PMRM) is the best because it was easiest to power [good for trials with less patients and less time] PLUS the data is more meaningful. 

- related to the above statement, COX modeling was super hard to power, as was WEIBUL. MMRM (used by many) has decent power but is less meaningful and less powered than PMRM.

- language matters, saying “drug slowed Alzheimer’s 20%” is almost never the correct way to characterize these models. 

- CDR-SB correlates decently with ADAS-COG11/13

- currently established CDR-SB MCID is 0.98 for MCI-AD and 1.63 for early-AD. These are currently almost impossible to obtain. You’d need to slow CDR-SB decline by 67% to reach current MCID so the established score is probably inflated. There are certainly some patients on Lecanemab that would claim the drug is proving them meaningful improvement. It’s about finding these responders that is important is is currently missing… more to discuss later

- according to Swiss study, mild patients regress to moderate at 2.4% monthly on average. Moderate to severe at 0.8% monthly on average.

- we must consider a therapies potential effect on mortality. There ‘could’ be a direct effect of therapy on mortality. More likely there is an indirect effect as time spent in more severe stages is lessened.

- The guy explaining some charts with blue and green lines was clearly color blind and continually mischaracterized all lines as green.

- paraphrased “it’s hard to say for the MABs what a new patient will gain on therapy individually. Their doctor can’t say ‘we think you’ll get XX’”. This was interesting to me that it was characterized this way. By Anavex revealing odds ratio so early, we can say in the clinic your odds of improving/slowing decline by XX dependent on your genes, etc. this is huge value in the clinic and seems to be missing from MAB data. It could be beneficial for Anavex to display 509 different cognitive/function charts. One for each individual patient, and then put them in a ‘responder’ or ‘non-responder group. Assess then based on genes/lifestyle, “why are you a responder, why are you not”. Leader in individualized treatment/precision medicine.

Final Notes From 17 July:

Starting off with the best first. I accidently came across Dr. George Perry today. That's right, Dean and Professor at the University of Texas at San Antonio and Editor-in-Chief of the Journal of Alzheimer's Disease (JAD).

He was helping someone out by presenting their poster on retinal health. I came in and said “I follow this company on Sigma-1 technology and it seems like there is emerging science with Sigma-1 protective properties and the retina”.

He said “hmm.. you mean Anavex?”

He then told me he normally doesn’t do consulting for free, but he likes the company and their direction so he does when asked.

REDACTED COMMENTS

He then discussed other controversies in the Alzheimer’s space.

He then noticed my name is Portuguese and told me his last name is not original, it was changed from its Portuguese origin. We are both from the Azores ancestrally. Additionally, he grew up in Lompoc which is where I was living prior to moving to Germany. Very interesting guy. The man can TALK. I wanted to bring the convo back to Anavex a couple times but it was impossible because of his rapid fire discussion. In any case, he had to go back to a special lunch. But I did think the conversation was notable. He likes Anavex, consults for free uncharacteristically because he likes it. REDACTED COMMENTS

OH! And I forgot to mention, he went out of his way to tell me he was the editor-in-chief for JAD. Which, I already knew. It seemed a little out of place. But I'm now wondering if he was foreshadowing. Anavex has been looking to get published. Total speculation.

Now moving along to poster data:

- One of the authors was of particular interest. As elucidated by her poster, she had tested an already available drug called PBA to modulate HSPA5 (a chaperone like S1R). Her results were incredible. She really sold me on this. She went on to explain how difficult it was to get her research reviewed. We both speculated it’s because the drug (PBA) is already available, it would make no one any money by pursuing it further in clinical trials for Alzheimer’s disease. I asked her straight up “are you trying to sell me a product”. She has none, her interest is purely for the benefit of people and for science. We discussed corruption and corporate greed.

- What’s really interesting here though is that this relates directly to us…. HSPA5 is one of the closest proteins to SIGMAR1, and has high confidence interactions. 

- Another poster discussed muscarinic receptors and the areas of the brain that they are most abundant. It was found that in early AD patients, the areas where muscarinic receptors flourish was largely destroyed. In MCI patients however the area was still functional. It was also noted that dopaminergic, serotonergic, and adrenal areas were all functioning to some degree in early AD and MCI patients. These results could partially explain why Blarcamesine works better in earlier patients. Save the muscarinic regions before they are destroyed and no longer usable.

- According to a high quality poster I read, some genes are negatively altered by antidepressants, which is partially what is responsible for brain fog or 'pseudo dementia' experienced by depressive patients. Some of the genes altered include BACE1, ADAM10, and notable, CDK5 (gene modulated by Blarcamesine). In a separate depression-theme poster, it was found that late-life depression exacerbates amyloid buildup faster than younger depressed patients. Treating depression effectively in older demented patients is very important.

- More evidence in other posters of the role of WNT pathway in Alzheimer's disease and its protective properties in the mitochondria. More fuel for Cognition Therapeutics as a potential investment. 

- Going back to the 40hz light therapy described yesterday. A separate poster showed results in a small human trial for 6 months. Results were impressive and seemed to indicate extreme slowing of disease progression or relative halting of the disease. White matter atrophy and demyelination were statistically significantly reduced in the left hemisphere and trended towards reduction in the right hemisphere. 

Posters, Cognition Therapeutics (CGTX), Additional Lessons From the Failed GRADUATE Trials, Dr. Cummings Comment, and APOE

The posters were really enjoyable to go through today. My first poster was actually Cognition Theraputics’ (CGTX). They sport a S2R (sigma-2) antagonist as their primary candidate. I was interested because they finished a phase 2 and are actively engaged in a phase 3. But what really intrigued me was the way they’re going about their analysis. Looking at their poster, they’re really going the Anavex route by identifying genes and clusters, and then tying those to key Alzheimer’s pathways. I noticed that two of the pathways they had high scores in (WNT and RAS) are two pathways that Blarcamesine only has light play in. This had me thinking that the two compounds would be good compliments to each other. I asked the author if she had heard of Anavex and considered a combo therapy. She laughed and said that it has been considered. Very interesting. She then went on to say that because S1 and S2 are so close to each other, any direct agonism or antagonism on one would likely modulate the other to some extent. Ultimately, I need to look through the rest of their data, but their pipeline and the conversation I had with the author had me really piqued. I cannot/do not want to recommend individual stocks to anyone. I however will be initiating a small position Monday - especially as they look to disclose full phase 2 data at CTAD23.

From the failed GRADUATE studies on Gantenerumab, there were some interesting scientific post-hoc conclusions brought to light. First, the drug worked better in males, both on primary endpoints and biomarkers. It was also noted that the drug (subcutaneous MAB) worked better in earlier patients, although there was some inconsistency here. Most notably, when excluding all patients with less than 90% treatment compliance, those high compliant patients improved on CDR-SB (relative to placebo) by 16%. This is double what their overall patient population was capable of. It was also noted that the 90% compliant group was mostly eastern Asian, so it wasn’t clear if the bump in efficacy was because of their Asian genetics or because of the compliance, or both.

Right before the GRADUATE presentation I heard Dr. Jeffrey Cummings speak to a single unidentified individual saying “yes they couldn’t make it. They wanted to be here, but couldn’t get through all the data yet, there is so much of it. Of course, I’ve seen the initial stuff and that…” but then he had to run on stage. I have no idea which company he was referring to. He is a member of the Anavex SAB, but he is also widespread through the Alzheimer’s community so he could have been talking about anyone or anything. Still, I thought I should relay it.

There was a decent presentation on APOE which lasted about an hour and a half. Here are the more interesting parts:

- APOE is key to cholesterol. It increases cholesterol accumulation and reduces cholesterol efflux. As we know from my latest video, S1R plays a surprisingly heavy role in estrogen, calcium, hormones, and CHOLESTEROL/lipids.

- homozygous APOE4 alleles increase chances of Alzheimer’s by 237x over APOE2 allele people

- APOE4 likely does both “exert gain of toxic function” AND “loss of positive function”, a double whammy. HOWEVER, it appears possible that APOE4 on its own is but a trigger. It’s primed, and ready to go, but a stream of constant neuroinflammation (by either pro-inflammatory genes, co-pathology, or something else) is needed to pull the trigger. This is why some APOE4 patients do not have dementia.

- research in mice is being done right now to edit APOE4 alleles and turn them into APOE2. In fact, their team has done this, even in mice 6-8 weeks old, and they are 90% effective in doing so. By swapping astrocyte APOE4 genes out specifically, the mice have improvements in memory. Next step is to find out therapeutic windows (best time to conduct the edit) and test on humans. Based on other announcements today, there appears to be a trend towards this, gene editing.

- APOE4 females make up the ‘majority’ of the Alzheimer’s population.

- Menopause effects EPA and DHA

- there is mixed literature regarding whether or not hormone replacement therapy (HRT)  would be beneficial to offset menopause as it seems to cause brain fog and dementia 

- one large study saw HRT improve APOE4 ONLY by 10% cognitively. Another large study saw no effect.

- overall conclusion there was that women need higher DHA, especially those with APOE4, and it’s unclear if HRT will help.

- separately, it was found that older APOE4 carriers are less likely to respond to healthy diet, as they appear to metabolize omega3 from healthy fats differently 

- I was sold that a cPLA2 inhibitor (antagonist) would be a good approach HOWEVER the presenter stated that their university was the only one currently developing such a drug - which they would eventually place in clinical trials. Still, something to watch out for. Testing of the basic compound (cPLA2) restored the blood brain barrier, improved DHA, restored omega3 homeostasis, and reversed neuroinflammation.

I WILL need to go back through and look at some of these posters again. I also didn’t get around to seeing them all today and some authors won’t be arriving until tomorrow. Here are some of the findings:

- epileptiform [seizure] activity occurs in ~64% of AD patients. Seizures were found to exacerbate the spread of tau in mice models. Imagine your brain having all these creases, and then the seizure being like an earthquake. It’s transferring the tau all about - even during silent seizures you can have while totally lucid.

- TREM2 continued trending throughout the posters. Will need to investigate this further.

- amyloid pathology changes astrocyte calcium signaling. As we know, I believe calcium to be the lynchpin behind much of the damage caused in Alzheimer’s patients.

- endothelial genes in particular appear very important to frontotemporal dementia patients

- nearly ALL Down syndrome people display Alzheimer’s symptoms in later life. Sleep disturbances in Down syndrome people are very common, especially apnea. The posters conclusion: tau accumulation is linked to breathing issues during non-REM sleep. This was backed up by their animals showcasing extremely low blood oxygen. 

- had a very cool conversation with a knowledgeable student. There are tests ongoing on animals and people (hers was on animals) for 40 hertz (hz) sound and light to improve memory. I was totally sold that it worked. The problem is that you can’t use this kind of technology/method on patients with seizures. As mentioned earlier, many Alzheimer’s patients have seizures, even if silent. Additionally, it needs to be refined in humans.

I’ll fill in more on posters later, but this is what I have for now. Thanks! 

17 July, Morning: Donanemab, Longitudinal Decline, Time, Muscarinic-4, and More…

Started the morning with a presentation comparing Donanemab phase 2 data (upcoming MAB) and Aducanumab. Specifically, a comparison on amyloid reduction and safety.

- patients started with comparable tau levels

- at 12 months: 70.2% amyloid lowering for Donanemab and only 21.9% for Aducanumab 

- safety is comparable (which, safety for Aducanumab is nothing to write home about so this isn’t exactly a positive.

— AE Donanemab: 78.9%

— AE Aducanumab: 82.6%

—- ARIA: Donanemab: 29.6% [better here]

—- ARIA: Aducanumab: 40.6%


A presentation on modeling time saved from reducing decline:

- author says time should be spent on ‘whole disease’ not individual symptoms like the community is currently doing

- figured out a way to combine CDR-SB, ADAS-COG, and ADCS-ADL improvements and combine them into a single “global time component test” - basically a single score to assess time saved in someone’s life by being administered a medication:

- can use the aforementioned method on whole cohorts in trials, and also on a single individual. I really like this because you can sit down with the patient and tell them exactly what they can expect to gain from a medication based on their reaction to it.

- the method was tested in 5 drugs (I am not familiar yet with the last two but will investigate at some point) 

— Donanemab: saved 5.5 months in 18 mo dosing cycle

— Lecanemab: saved 5.1 months in the same

— Aducanumab: saved 2.6 months in the same

— AD04: saved 8.9 months in the same (small study) 

— Souvenaid: saved 6.3 months in the same


Next presentation was on subcutaneous injection of Lecanemab - expected to lower amyloid similarly to the IV variant but have better safety via lower ARIA.


Then was a presentation on the interim results for phase 1, part A of ALN-APP RNAi therapy, a first in class.

- genetic modifications to APP cause AD

- the drug forcefully cleaves APP

- drug is currently being administered in 25, 50, and 75mg doses.

- super safe in the phase 1

- 75mg dosing reduced soluble APPalpha by 56% in 6mo

- 75mg dosing reduced soluble APPbeta by 82% in 2 mo 

—- I am unsure to how meaningful this is on a patient’s cognition/ADL yet. The safety seems very promising though, I’m interested to see if these results manifest in improvement.


The muscarinic-4 receptor agonist study was interesting. It was in mice to assess sleep. The bottomline is that the drug improved non-REM sleep. However, it reduced REM and slowed arousal when waking up. I’m not sure I have too much to gain from this presentation. Each muscarinic receptor (1 through 5) appear to have different roles in sleep. I’m not sure a study on an individual one is too meaningful, as it seems like that they work in concert to ensure normal sleep behavior. Though, I suppose if a patient had non-REM problems, a sole M4 receptor may be of some assistance. 


POSSIBLY one of the most notable things so far from a pure science perspective. (I’m honestly not sure how this is only now emerging):

- amyloid is associated with faster executive decline but NOT memory (high confidence)

- tau is associated with faster memory decline but NOT executive function (mod-high confidence) 


Little tidbits:

- episodic memory testing may be the earliest measure for decline 

- amyloid positive ONLY patients should probably be tested on episodic memory 

- amyloid AND tau positive patients may see more meaningful testing in executive function and attention


And lastly for the morning:

- a cool online platform is being built to administer Alzheimer’s/dementia assays from your home, it’s called mobile toolbox (mobile toolbox.org).

- an interesting note here. The developers tried to get multi-thousand patients to join the toolkit to try it out. They wanted a diverse patient-base and went out of their way multiple times to garner black patients. Even with their deliberate efforts, their meager goal (~5% black patients) was not met, and almost all of the black population they did enroll were old.


I’ll update with poster information and the rest of the days presentations later.

July 18 Notes

- I listened to the largest study ever conducted on APOE4 demographics (68.7k patients). 

-- Women with APOE 3/4 or 4/4 had large increased in dementia starting around age 60. The spike was quite noticeable along the age continuum. 

-- APOE4 had increased effect on Alzheimer's odds in European but not African ancestry. 

-- APOE2 which has been correlated to protection has no protective qualities in East Asian population. 


- Immune Modulatory Therapeutics

-- Immune response plays a big role in Alzheimer's. If we tune immune activity incorrectly it could do more harm than good.

-- TREM2 AD variants are thought to be loss of immune function, especially in microglia.

-- Immune response nomrally result in rapid activation phase followed by rapid resolution of illness. So what happens when you modulate it as part of a drug response over a long period of time? Will this be good for us? Hard to say yet.

--  ADAM10 appears to have a direct role over TREM2 [ADAM10 is modulated by chaperone proteins like HSPA5 and S1R].

-- Soluble TREM2 increases 21 years advanced of disease in mutation carriers.

-- Higher non-mutant TREM2 levels are associated with slower cognitive decline

-- Beyond Alector mentioned earlier, Denali is also developing a TREM2 modulator known as ATV-TREM2 (DNL 919). They had an impressive presentation on the 'ATV' which was a modification to the drug to make the compound pass the blood brain barrier easier. The ATV is extremely effective in this manner. I will be looking into this compound as well.

-- The DNL 919 compound modulates mitochondria function (like Anavex) and metabolism pathways.


- There was then a presentation on hyper viral response with a lot of emphasis on NF-kB pathways and experiments on removing cGAS and the MEF2C protein. The takeaway for this presentation is that cGAS inhibitors may be beneficial. 


- I then listened to a suite of presentations on cardiovascular issues in Alzheimer's patients and other dementias. It kind of left me with more questions that answers. What was clear is that cerebral blood flow (CBF) has an impact on tissue integrity. Good CBF is needed to move metabolic byproducts and remove toxins - like Iron. According to various posters through the conference, exercise was one of the most definitive ways to alter your odds of contracting Alzheimer's disease in your lifetime, many correlating BDNF, neurogenesis, and lowering risk of cardiovascular disease.


- Listened to a presentation on Souvenaid, a food aid, which appears to be HIGHLY efficacious and has been added to the worldwide FINGERS trial on prevention/lifestyle. They conducted a three year trial which garnered 45% reduction of decline on CDR-SB, 33% less hippocampus loss. N=331. The product is made of three primary ingredients, Omega-3 (DHA), choline, and uridine.


- The final presentation of the day was "Recommendation use for Lecanemab" which featured a taskforce known as AUR and a representative of the FDA.

-- Goal: How do we pick the right patient and how do we administer the drug safely?

-- Unsurprisingly the taskforce recommends clinicians are cautious when administering the drug. Notably, patients with seizure history should be excluded from treatment (MANY Alzheimer's patients have silent seizure activity). Additionally, patients SHOULD be screened for APOE allele type and those with APOE4/4 should be excluded with extreme caution with heterozygous APOE4 as well. And finally of note, patients with cardiovascular disorders should be excluded - anticoagulant use is prohibited. 

-- FDA recommends 3 imaging events to confirm ARIA/no ARIA. The Task Force recommends 4 events.

-- General health of a patient appears to correlate to sensitivity of ARIA. Those with significant number of co-morbidities and long list of other drug use seem to trend worse.

-- Data is recommended to be tracked in a new database called ALZ NET which is endorsed by the Alzheimer's association. It will be useful for MAB development and future therapies as we can track patients longitudinally across the Alzheimer's community.

-- Still a lot of questions on how Lecanemab/Donanemab will effect patient outcomes long term. It's also concerning that Gantenerumab and Solanezumab failed in phase 3 trials.

--- Bottomeline: It was refreshing to see the Alzheimer's Association & the FDA take a very cautious and conservative approach for use on Lecanemab (and by estimates these criteria will almost all certainty align for Donanemab use in the future - except maybe anticoagulant use). Their goal: have ALL information available to the patient and caregiver to ensure they understand risks, to understand what their APOE type means for risk, and that the treatment may be able to save them 5.1 months in an 18 month treatment window.

19 & 20 July Notes 

July 19

- Multiple air pollution trials were ran and expanded upon at AAIC. It is safe to say based on these results that air quality plays a role in dementia risk, but it is unclear to what extent. Some would say its still "up in the air" OH! But really, its hard to get a definitive conclusion here and I don't think researchers ever truly will. Air quality changes so much on the day to day depending on weather. I just don't think one could find a way to meaningfully run a trial with mostly controlled variables here.


- "Nature exposure" (getting outside in any capacity) was coorelated with higher gray and white matter in the brain over 17k patients. Men appeared to benefit more than women, especially with gray matter. Even with these benefits in brain volume, cognitive improvement was very, very minor. Because most of these patients were between 40-70 years old, it was theorized that women in this sample performed worse than men because of their menopause/perimenopause. 


- 17 beta-estradiol is the most potent form of estrogen, and the 2x primary estrogen signaling pathways are ER-alpha/ER-beta and G-protein couples estrogen receptors (GPER).

- ER-beta is mostly found in areas of the brain associated with cognition, neuronal plasticity, BDNF, and promotes learning/memory. Overall, as with many studies, it was noted that longer exposure to estrogen (NOT having early menopause for example) correlated to lower risk of dementia, especially in NON APOE4 women. Note: Men also produce estrogen, I would be interested to see an estrogen-correlation study in men to see if men with abnormal estrogen levels have differing cognitive risk.


- Blood brain barrier dysfunction and small vessel disease is noted in >50% of ALL dementia patients.


- BACE1 INHIBITORS

-- NOTE: This was a big topic at AAIC. While data is overall positive when it comes to enhancing cognition, there are a lot of negative safety concerns associated with it as well. Researchers are theorizing ways of administering BACE1 inhibitors more safely. Also, 5 of 6 BACE1 trials resulted in FASTER cognitive decline in early stages of administration. Ultimately, the area seems like an interesting topic and may be beneficial, but as far as myself personally, I am not interested in investing in this approach at this time.

- BACE1 is required for amyloid build up

- To mediate BACE1 inhibitor caused faster decline, it is theorized that the inhibitor needs to be at 30% strength.

- BACE1 is located at the synapse, and has negative consequences on synaptic spine density and thus plasticity.

- Cognitive drop and safety aside, multiple presentations now show that BAC1 inhibition removes virtually all plaque.


- Amyloid imaging is now available/possible on the RETINA - the only part of the CNS not hidden by bone.

- Procedure is super safe and has excellent sensitivity. 

- Note: In my opinion an additional benefit of this approach is the ability to use ophthalmologists and optometrists to reduce specialist burden on imaging amyloid.


- Leqembi will be up for approval in EU in 2024.


- FDA acknowledges that while they prefer 2x primary endpoints (cognition and functional) with a global endpoint (CDR-SB or iADRS), they would feasibly accept a trial where only cognition showed dramatic improvement.

- FDA acknowledges the 'time gained' metric talked about so much at AAIC is an interesting notion. It is not currently accepted as an endpoint but the FDA may be open to it in the future. Note: it probably helps garner approval as part of a package whether formally accepted or not.

- FDA feels like they are "not hearing a lot from patients themselves on what they think is meaningful".

- Dr. Jeffry Cummings feels as though MCID may be overemphasized and that time saved is a better metric. He also mentions that ODDS RATIO is helpful to see who is responding and by how much. He also stated that with enough time, a disease modifying therapy would likely eventually meet MCID. This is why he says MCID is kind of arbitrary.


July 20:

- Caloric restriction = autophagy 

-- Caloric restriction regardless of weight of the patient (fat or thin) decreases amyloid load in Alzheimer's patients.

-- Autophagy is impaired in Alzheimer's patients but promoted after caloric restriction.

-- MTOR and AMPK pathways are primarily involved in autophagy 

-- Autophagy improves metabolism, organelle quality, and maintenance of proteostasis (protein build up removal).

--- Ultimately leading to anti aging and delayed onset of age related diseases.


- Early menopause is associated not only with lower cognition, but also higher vascular risk.

- When comparing women whom started menopause at 45, 50, and 55, the 45 year olds were associated with vastly lower cognition and higher vascular risk. Women at 50 performed worse as well, but better than 45. Women at 55 performed "ok" and only marginally declined over the trial period.


- In Americans over 50:

-- 40% have peripheral insulin resistance

-- 35% of AD patients have insulin resistance

-- 90% of AD patients have brain insulin resistance

-- 35% of AD patients have both peripheral insulin resistance and brain insulin resistance


- Insulin transport across the Blood Brain Barrier can occur by insulin receptor OR independently 


- Women in menopause are less insulin sensitive (bad)

- Improving insulin sensitivity reduces one's subjective hungriness feeling while fasting [interesting]


- Overweight women more strongly associated with insulin resistance than overweight men


Key takeaway: More women are insulin resistant than men; thus, overweight women in menopause (especially those who started early) and APOE4 carriers are the most at-risk patient type for Dementia.


- Midlife obesity increases Alzheimer's risk by 380%

- 60% of men and 50% of women are expected to be obese by the year 2050

-- Note: I took a picture of an excellent graphic showing mice fed a typical western diet vs. mice given healthy diets. Their inflammatory genes were measured. The western diet absolutely wrecked the mice compared to controls. It was noted that within 4 weeks of swapping western diet mice back to healthy diets, most of the damage was reversed; HOWEVER, the previously western-diet mice had permanently changed immune response going forward.


- Familial AD (<5% of all AD cases) is primarily caused by mutations to three genes, PSEN1 (most common), APP (second most common), and PSEN2 (rare).


- I watched a suite of protein-change presentations. There were some key takeways. 

-- The stage of disease changes whether or not genes were up or down regulated. For example, in early Alzheimer's a patient's CDK5 gene may be upregulated. In late stages, the same CDK5 gene may by downregulated. Blood vs. CSF samples also differed. For example, the CDK5 gene in blood could be upregulated but downregulated in the CSF.

-- Some gene expression changes 30 years in advance of onset, but most change between year 12.5 - 17.5.  

-- When testing blood protein expression in AD, FTD, and LBD, about 40-50% appear to be Alzheimer's specific with the rest shared between the 3 diseases.

-- Common themes in Alzheimer's expression appeared to be related to autophagy, mitotic cell cycle, and ubiquitin. Other themes related to Anavex specifically included: DNA damage, protein modification, protein transport, response to stress, apoptosis, GTPase, signal transduction, mitochondria, and protein folding.

-- Protein/gene expression analysis seems to change a lot depending on whether the patient is amyloid negative, tau positive, or any combination thereof. 


- In earlier stages of disease, proteins related to the following are changed more:

-- Protein ubiquitin, synaptic transmission, cellular detoxification, and repsonse to superoxide (oxidative stress).

---Expressed in the cytoplasms, mitochondria, and plasma membrane


- In later stages of disease, proteins related to the following are changed more:

-- Pyruvate metabolism, aromatic biosynthesis process, nucleotide catabolic, ATP metabolic process

--- Expressed in cytosol 


----- In all cases, the cell type most affected by a large margin was the neuron.


- Increasing a5-GABA-A receptor function could remediate the reduced function of SST+ neurons in the prefrontal and hippocampus.

--This appeared to be highly effective in improving cognition in three seperate mice models (chronic stress model, aging model, and amyloid load models).

--- It is highly likely Blarcamesine enhances a5-GABA based on biologic function, noted improvement in GABA, and STRING analysis.