Significance
Wei et al., have studied the subunit composition of γ-aminobutyric acid type A receptors responsible for the tonic inhibition of parvalbumin positive interneurons and identified a small molecule (DDL-920) as a potent, efficacious, and selective negative allosteric modulator of these receptors. DDL-920 increases the power of γ-oscillations following oral administration and remedies the memory impairment of Alzheimer’s disease model mice in the Barnes maze.
A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer’s disease model mice
https://www.pnas.org/doi/10.1073/pnas.2400420121#core-collateral-metrics
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Not a lot of info on this new compound DDL-920 so I search for other possibly similar compounds using https://www.asklongevitygpt.com/
I find that this AI search engine provides good information but the references it provides in it’s reports are weird and not related to the information it provides, So i have to do a second step to double check the references. When I do that, I have, so far, found the information matches what I can find “manually” 
General Information
γ-Oscillations and Cognitive Function
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γ-Oscillations: These are high-frequency brain waves (30-100 Hz) associated with various cognitive processes, including attention, memory, and perception.
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Cognitive Enhancement: Enhancing γ-oscillations has been linked to improved cognitive function and memory.
Small Molecules of Interest
Several small molecules have been studied for their potential to enhance γ-oscillations and cognitive function. Here are a few examples:
- Donepezil:
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Mechanism: Donepezil is an acetylcholinesterase inhibitor that increases acetylcholine levels in the brain, which can enhance γ-oscillations.
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Studies: Research has shown that donepezil can improve cognitive function in patients with Alzheimer’s disease.
- Memantine:
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Mechanism: Memantine is an NMDA receptor antagonist that modulates glutamatergic neurotransmission, potentially affecting γ-oscillations.
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Studies: Memantine has been found to improve cognitive function in Alzheimer’s disease patients.
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I’ve been liking a couple of the AI research systems. Here is the latest one I’ve been using and the report it generated on the above compound.
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They’ve been curing alzheimers in mouse models for decades… the models are not very good and typically don’t translate well to humans, so I don’t get too excited about this type of research. We’ll see…
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Agreed.
Research has been focused on the Tau theory for the last 25 or 30 years and over $30B spent with nothing important to show for it. Not because “mouse”, but because of the politics of research funding. If you don’t subscribe to the Tau theory you don’t get research grants and Uni’s expect their top scientists to bring in research funding. So they toe the line on this one, as any research outside the line doesn’t get funding.
It seems like that is changing a bit with more focus on microbiome and other areas of interest. As evident by many calling AZ “type 3 diabetes” and looking at gylcemic control as well.
This is a new drug, not touted as a cure or preventative but something that may slow cognitive decline.
Like aging in general, until the actual cause of AZ is figured out, slowing it or finding ways to compensate for it are all we’ve got for now. The 2 drugs that have “similar” targets Donepezil and Memantine have shown memory benefits but are not a cure either.
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I have been taking Donepezil+Memantine for a few weeks as I am old and I am using it as a prophylactic. Very cheap from India.
No adverse reactions so far and no subjective benefits. I have only been taking it for three weeks. It may take months for benefits to show up, or again, it may be just a prophylactic intervention.
I see no reason for young people to take this.
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An ounce of prevention… or a few milligrams
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Jay
#8
desertshores, I’ve been thinking about trying Donepezil and Memantine for months, but what I read doesn’t indicate that either have much subjective benefit. Occasionally I use Galantamine and sometimes think I notice something, but it also is subjectively weak. If you’re still taking Donepezil and Memantine you’re at least 6 months into this test. So, have you noticed anything useful yet?
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At 84, I am just using it as a prophylactic. I take it at bedtime, and I do think it improves sleep a little and perhaps produces a few more dreams. I prefer it to galantamine. Honestly, I only use galantamine when I am bored and want to experience some crazy dreams.
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If you’re reading this thread, you are evidently interested in forestalling neurodegenerative decline. As am I.
Please, read up on intra nasal insulin. And then please suggest where to get it. My PCP has never heard of it!
My husband has tried donepezil and rivastigme and could not tolerate the GI sides. In any case, these two drugs work to slow the formation of amyloid and tau but the do not address what is now understood to be the root cause of AD: at its foundation it is a kind of metabolic disorder whereby the amyloid precursor protein (APP) is not processed properly. None of the current drugs, including lecanemab, addresses this root cause.
Research on intranasal insulin goes back well over a decade and it is in phase three trials. It has been shown to be effective and safe at correct doses. But no heat and light because it is not going to be a pharma money maker.
Would appreciate pointers to clinicians who would prescribe or any other ideas . . . .
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This PDF lists several brands of intranasal insulin.
Insulin can also be delivered intranasally via different devices. There are different types of insulin available. These include:
• Regular (Humulin R, Novolin R, Velosulin R)
• Rapid-acting (Insulin glulisine – Aprida; insulin lispro – Admelog, Humalog; insulin aspart – Fiasp, NovoLog)
• Long-acting (degludec – Tresiba; detemir – Levemir, glargine – Basaglar, Lantus)
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According to this sketchy YouTube video by a biohacker, you can use regular insulin in a nasal spray bottle.
I don’t know what kind of insulin was used in the trials. Using insulin intranasally would probably not produce a big insulin spike in the blood.
Walmart sells a brand of insulin called ReliOn without a prescription.
“Novolin R and ReliOn insulin, while both are short-acting regular human insulin, are essentially the same medication but sold under different brand names. Novolin R is manufactured by Novo Nordisk and is available by prescription.”
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Thank you! True, he doesn’t inspire high confidence in his methodological rigor, but it is great to know where to get the insulin and the spray bottles. The bottles do meter the spray, which is key. The whole thing does seem sketchy but the research is real and for me personally what risk there might be seems well worth the benefit.
BTW it seems that the benefits are catalyzed by the addition of empagliflozin.
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So, I stopped off at my local Walmart pharmacy on my way to the gym this morning to see if I could buy insulin without a prescription. Indeed, you can ( in Nevada) buy several varieties without a prescription.
The YouTube video I posted was old, and I was unsure of the brand.
This is the brand I bought because I believe it is the one used in the YouTube video. It cost ~$25.
Unfortunately, the paper posted by @steve_combiby suggests that it may not provide any benefit to cognitive function, at least in the short term.
The results from the referenced studies are inconsistent. Some do show some benefits.
I’m going to give it a try to see if it has any subjective cognitive benefits, such as reducing brain fog and improving focus.
I will compare it with my nasal Semax, which I quite like.
It is apparently safe.
"Safety: Most studies find no increase in adverse events in patients who receive intranasal insulin compared to placebo at doses up to 160 IU; most side effects are related to intranasal delivery itself, including nasal irritation, rhinitis, and nose bleeds.
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Thank you again. I bought the Novolin N at Walmart’s and the Snoot bottles and just took a first dose. After I have worked up to two doses per day I will start my husband on it.
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Today, I started my intranasal insulin experiment. I purchased Novolin R from Walmart for around $25 and 10 mL nasal spray bottles from Amazon.
To determine how much each pump of the spray bottle would be, I filled a bottle with 10 mL of distilled water and checked to see how many pumps it would take to empty it.
Serendipitously, it took ~100 pumps. The Novolin R contains 100 units/mL, so each 10 mL bottle contains 1000 units of insulin. Therefore, each pump will include approximately 10 units of insulin.
I snorted one pump in each nostril for ~20 units of insulin.
It was only mildly irritating and produced a lingering, slightly chemical smell that, to me, resembled some phenolic items, such as electronic circuit boards.
I measured my blood glucose before and 30 minutes after inhaling, and there was no discernible change.
Subjectively, I felt nothing. Though in my case, it would be primarily a prophylactic treatment.
So, starting tomorrow, I will dose twice a day, morning and night, for the next 50 days.
The price is nominal; insulin plus a bottle costs around $0.60/day.
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Tim
#17
If I were concerned about AD, I’d consider getting a lumbar puncture–a spinal tap–which can detect tau and other markers with an accuracy of 92%. Often covered by Medicare.
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I’ve been reading the book How not to study a disease & finding it very interesting.
The disease is Alzheimer’s & more generally dementia, but I think the lessons he draws apply to more than just Alzheimer’s, but to medical research & developing treatments in general.
Herrup presents a new and sweeping vision of the field that includes a redefinition of the disease and a fresh conceptualization of aging and dementia that asks us to imagine the brain as a series of interconnected “neighborhoods.” He calls for changes in virtually every aspect of the Alzheimer’s disease research effort, from the drug development process, to the mechanisms of support for basic research, to the often-overlooked role of the scientific media, and more.
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I read an article in the 80’s (Omni Magazine) about the financial incentives in AD research that take it off track, even then, and not allowing for enough “outside” the box research. This is not a very new issue but an important one.
But all is not lost, even with that massive financial failure. A lot has been learned and while there is still no “cure” and very little improvement in the treatments, the primary research in this area revealed more of what we don’t know, than what we do know and that is half the battle.
Which fits in this;
“the concepts of known knowns, known unknowns, and unknown unknowns”
Especially with something as complex as human health.
