Alrighty, I have repeated the process, this time with the GFJ boost. I ate one ‘extra large’ grapefruit at 6am, then ate a second ‘extra large’ grapefruit at 10am along with 5mg of sirolimus. This led to a serum level of 4.3mg/nl @ 100 hours, which seems to be close enough, particularly as I am apparently a rapid metabolizer. 
On a side note, the 40hz research looks very interesting. I plan to acquire or build something soon, so will post results/thoughts when I have more to share.
Thanks again to everyone!
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@DrFraser You mention Ambien sleep medication as smth to avoid, which has been my impression as well… I quit it a long time ago - but I am still a severe insomniac. I have 2 questions, if I may:
PS None of questions or answers constitute medical advise in any capacity
Paging @DrFraser as I know you’re particularly keen on apoE4 specific remedies. From what may be called a Socratic line of questioning with ChatGPT re: my genomic data, I tried to tease out solutions that are currently available as opposed to merely experimental, for structure correction of apoE4. And what popped out that was interesting was off label use of bexarotene. I’ll let you take the research from here but it looked very promising from what I could tell. I see zero mention of this drug on this forum so I’m very interested in anything you can tell us re: side effect profile beyond what can be easily googleable. All I see is it’s toxic to the liver so I wonder if it too can be a candidate for intranasal delivery.
59vw
#264
I realize you want Dr. Fraser’s advice but if you don’t mind I suggest you listen to Peter Attia’s interview of sleep expert Ashley Mason PhD. I found the podcast very educational and helpful.
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Thank you for this information! I’m APOE4/4 62years old and have no time to wait for clinical trials. I’m doing most of your list already but am unfamiliar with SGLT2, can you please elaborate on how I might add this to my “stack”?
A couple of things, with agents working on the Orexin pathway like Suvorexant is that it’s probably not going to have the same detrimental effects of GABA or anticholinergic agents. We don’t know the long term risks as Orexin is a complex pathway and has multiple effects - but yes, it seems like sleep architecture is preserved and it doesn’t knock off REM sleep.
The main issue is cost for a lot of people as insurance is unlikely to cover it and it looks like ~$500/month with a GoodRx coupon.
I personally stay away from drugs that are new unless there is a compelling reason to use them … maybe there is in this case - but I’d love to have more individuals use it and get a better idea on longer term safety and it would be a great thing for the manufacturer to do a trial on ApoE4 homozygotes who already have mild cognitive impairment, because you won’t even really need a placebo group as we know the progression pretty well in this group.
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My concern with this is toxicity and also a lot of off target effects as it is a retinoid and has effects on gene regulation in multiple areas.
So systemic use would require it to be a wonder drug and the toxicity closely managed, and hopefully able to take it for short durations intermittently to decrease risks.
Given the unknown other effects of using it long term on overall mortality, especially unintended effects, I not jumping on this one - I’ll let others experiment, but not ready to do this one yet.
The intranasal is interesting - as this agent doesn’t seem to cross the human blood brain barrier much. That would limit systemic toxicity, but are there other effects on the brain that might happen that are unintended?
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amuser
#268
‘Overcoming Insomnia’ transcript.
Title 341 - Overcoming insomnia.pdf (464.1 KB)
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If you were under the protocols I utilize, I’d have safety concerns on this as you’ll end up having potentially 130 hrs above 3 ng/mL. That is longer than I like to have someone potentially immunosuppressed - even with the 100 hours - I only do that on individuals with ApoE4’s and I’ve not seen any excess infections or adverse outcomes yet - but have very small numbers on the every 14 day protocol.
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Here is a brief summary of some of the publications on this - all of it associations - but a fair bit of data.
You can read about their mechanism, risks/benefits and chat with your doctor about them. Most physicians won’t prescribe to you for this indication. Obviously on this forum, individuals sometimes choose to self manage at their own risk.
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A large population-based cohort study (n = 106,903) in Diabetes Care 1 II found that SGLT2 inhibitors were associated with a 20% lower risk of dementia compared to DPP-4 inhibitors (aHR 0.80, 95% CI 0.71–0.89). This effect was strongest for dapagliflozin (aHR 0.67, 95% CI 0.53–0.84) and empagliflozin (aHR 0.78, 95% CI 0.69–0.89), while canagliflozin showed no significant association (aHR 0.96, 95% CI 0.80–1.16). The study used a 1-year lag to reduce reverse causality and relied on validated dementia algorithms, but as an observational study, it cannot establish causality.
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A network meta-analysis (27 studies, including 3 RCTs, 19 cohort studies, and 5 case-control studies) in Diabetes/Metabolism Research and Reviews 2 I reported that SGLT2 inhibitors reduced dementia risk by 59% compared to non-users (OR 0.41, 95% CI 0.22–0.76). SGLT2 inhibitors ranked highest for dementia prevention (SUCRA = 94.4%). However, the evidence is limited by indirect comparisons and reliance on observational data for cognitive outcomes.
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A meta-analysis (n = 4,855) in Diabetes/Obesity & Metabolism 3 I showed that antidiabetic agents, including SGLT2 inhibitors, improved cognition in Alzheimer’s disease and mild cognitive impairment. However, the primary evidence focused on pioglitazone, limiting direct applicability to SGLT2 inhibitors.
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A prospective study (n = 162) in Diabetes Care 4 II found that empagliflozin improved cognitive scores in frail older adults with diabetes and heart failure (MoCA: 19.80 ± 3.77 to 22.25 ± 3.27, p < 0.001). While promising, the study focused on a specific population and had a short follow-up (1 month).
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