Any updates?
Also:
Got my LDL results back, and they could be lower.
I did some reading on pterostilbene, and it can increase LDL, yet can possibly reduce Alzheimer’s.
Any info on this?
I’ll get round to it some time. Very busy time in the clinic + ER these days. Come the New Year will have a bit more time.
I think statins are a wonderful choice as it looks solid in regard to decreasing risk of AD, the longer you are on them the better. The recent Mendelian Randomization study saw >70% reduction, and with ezetimibe like mutations >80% reduction in AD. However, this would be the effect of using them lifelong.
Then over the short term, a well done trial looked like 60% rate reduction I believe (from memory) for ApoE4 carriers who went on a statin - albeit this was a short study.
I’d say skip the pterostilbene as if it has benefit, it’ll be small … treat the LDL / ApoB with a combination of Ezetimibe and a Statin would be my take on it.
As usual, consult your physician … but two drugs that hit your LDL, each of which decreases risk of AD … if worried about AD … I’d jump on that plan.
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PREPRINT
Rapamycin enhances neurovascular, peripheral metabolic, and immune function in cognitively normal, middle-aged APOE4 Carriers: genotype-dependent effects compared to non-carriers
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It would be nice for them to do a prospective trial with randomization into 1mg per day, 6mg per week, and placebo of each.
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I saw a recent study on dual orexin receptor inhibitors clearing amyloid. Any thoughts on it being a potentially useful addition?
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Kidney Function, Alzheimer Disease Blood Biomarkers, and Dementia Risk in Community-Dwelling Older Adults
https://www.neurology.org/doi/10.1212/WNL.0000000000214446#sec-2
Quote:
“Impaired kidney function has been linked to altered concentrations of blood biomarkers of Alzheimer disease (AD), but the underlying mechanisms and its potential role in dementia development remain poorly understood. We explored the associations between estimated glomerular filtration rate (eGFR), blood-based biomarkers of AD, and dementia development.”
“The aims of this study were (1) to explore the cross-sectional association between estimated glomerular filtration rate (eGFR) and a comprehensive panel of AD blood biomarkers; (2) to quantify the hazard of dementia across different eGFR values over a 16-year period; and (3) to investigate the potential modifying effect of kidney function in the association between AD blood biomarkers and dementia.”
“The possible mechanisms by which kidney dysfunction alters the circulating levels of AD blood biomarkers are not yet fully understood—and include peripheral mechanisms, direct effects on neuropathology, or both. Indeed, it is plausible to hypothesize that reduced GFR impairs the peripheral clearance of these molecules, subsequently leading to an increase in their blood levels.35 Nonetheless, it is also plausible that a decline in kidney function is directly implicated in neuropathology,16,18 and that biomarker levels increase as a mere consequence of it. In fact, both the accumulation of uremic toxins and the release of neuroinflammatory cytokines that accompany CKD have been associated with neurotoxicity and nonspecific brain damage,17,36,37 which could contribute to dementia development. Of note, the older age and the higher comorbidity burden among participants with impaired kidney function might indicate the presence of underlying mixed brain pathology, which could also partially account for the elevated levels of biomarkers—especially NfL—observed in this subgroup.”
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These agents are looking excellent to me. The issue is they are a controlled substance in the U.S., which requires a physician willing to Rx a controlled substance for prevention of AD … (which I will and am doing, but good luck getting this to make sense to your local Internist or Family Physician). Importation can result in criminal prosecution as it is a DEA scheduled agent. Albeit I really don’t see this as a addictive agent and think it has been misclassified.
Now on @CronosTempi 's post on kidney function this is complex and likely a couple of combined factors. To get significant decrease in kidney function, some unhealthy things have to be occurring in your body (including just getting older) and yes, many toxins and other inflammatory particles are renally cleared - knock down renal function - and yes, more of them remain. I would suggest that if one controls for these items, the kidney function decline is associated, but not the root cause of increasing AD risk.
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Would be great if you could post a link to the study.
My plan for individuals with ApoE4’s in regard to lab monitoring for progression (and this will evolve as additional tests come forward) is periodic (likely yearly for those not too adverse to the cost) of Beta Amyloid 42:40 ratio and p-Tau 217. This paired with the detailed brain MRI every 3 years with Neuroquant and yearly CNS Vital Signs, is what my approach is right now for monitoring. There are a lot of new tests coming forward, but most aren’t accessible and these ones have good evidence.
On the prevention side, I’m goaling for doing less things, especially on the supplement side. As much as one can make a decent argument for 100+ items on their own, the issue is the practicality and added benefit to adding item 101 to one’s growing list of drugs and supplements.
So my focused stack is:
Rapamycin cyclically with blood monitoring
SGLT2-i
Low dose GLP if tolerated
Telmisartan if needed
+/- items like Methylene Blue/NAD agents/NAC Ethyl ester
Statin
Ezetimibe
Low dose doxycycline and lithium
Dasatinib + Quercetin/Fisetin q2-3 months
Omega 3 optimization with agents that get into the brain
Homocysteine/Vitamin D optimization
I suspect that list gets 90% of any benefit on prevention based upon what I know right now.
Each of these agents has rationale, risks/benefits, and will be working through somewhat different pathways.
Lifestyle and making your brain do things it isn’t currently good at are huge factors. For example with CNS Vital Signs, what I’ve been doing is testing individuals, then picking out 2-3 areas of low %tiles on sections of the test, and then having them work on activities that specifically strengthen these … and retest yearly. Then pick another few low performing areas and make the brain work on these for the next year.
The low dose doxycycline is an interesting one - I’m going to put out a video on this one in the next month. It seems to make a lot of sense - but in sub-antibiotic dosing.
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Thank you for sharing your updated strategy.
I’d be very interested to learn more about Dasatinib / quercetin / fisetin if you are willing to discuss them.
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There’s a whole thread about this paper (and others by the same group) here: Rapamycin as a preventive intervention for Alzheimer’s disease in APOE4 carriers: targeting brain metabolic and vascular restoration - #76 by adssx
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While it says “drugs” only 1 was tested, semaglutide in 2 large groups of 4,000 over 2 years with early stage Alzheimer’s.
More questions remain to be answered
• Wrong dose?
• Wrong timing?
• Wrong population?
• Not enough drug reaching the brain?
• Maybe GLP-1s help prevent, not treat?
• Or maybe we need better molecules entirely?
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Steve,
I think the issue is that once disease is present it’s a much tougher situation, we already have all the processes going with breakdown of the BBB, irreversible damage, etc.
I’m not seeing anything that looks that great for reversal of disease. There are some things that might help slow progression - but I’m not sure much in the prevention bucket will do much.
In the Mendelian Randomization review of Statins and Ezetimibe … looks like AD were 70+% and 80+% decreased respectively. I don’t think either of those will do anything once there is established disease.
My assessment at this point is monitor for very early disease (e.g. Beta Amyloid 42:40 ratio, p-Tau 217) and if any abnormalities, get aggressive to do everything to prevent progression.
Just like with sirolimus, we have a lack of data, and lots of anecdotes. We have a lot of data associating GLP-1 use with less diagnoses of AD - but association isn’t causation, but it is the best we have right now. The GLP-1 manufacturers need to get a bunch of ApoE4 homozygotes and start them on GLP-1’s age 60 … and a group at age 50 … there would be some answers in 10 years, as the control for both would have progression with their labs, even if not symptomatic disease as, I believe about 90% of ApoE4 homozygotes will have abnl B-Amyloid and P-Tau by age 70.
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Agreed on all your points, bigger and better trials for early prevention need to be conducted.
I’d guess that this info will be used to fine tune other GLP1 type peptides for a more focused therapy, if the mechanistic data holds up for that expenditure.
In the meantime, my weekly shot will continue 
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Looking at AD brains on autopsy, I am pessimistic about “reversal” of AD, unless it’s very early stage. The late AD brain is hollowed out by the disease, there’s massive loss of tissue and I don’t understand how you’re supposed to get it all back. You could reach for an analogy, like losing a limb - you can arrest early gangrene and save the leg, but once the leg has been removed any talk of “reversal” is pointless. Only it’s worse than that with AD. There is a future possibility of regrowing limbs salamander-like if we can crack the code, but the brain is not like a limb, it’s the repository of your identity, your memories and life experience - after a massive loss of tissue, all that is gone… even if you could reintroduce brain tissue, it’s no longer you, it’s a clean slate, tabula rasa. Early, limited damage that still has most brain tissue preserved at least has the potential of migration of function to any prospective new (or current) tissue. But once the massive AD damage has been done, the horse is out of the barn.
Bottom line, I think it’s a distraction to focus on AD reversal (unless very early MCI), prevention and amelioration is where it’s at. Although quite frankly I find it depressing that we seem to have so little in the way of pharma interventions after so much research effort over the decades. Still, no choice but to keep grinding forward.
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Hope this goes mainstream ASAP, would be good to know before it’s too late.
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IMO: Doesn’t really matter until someone actually produces a cure. The Alzheimer’s and dementia drugs that are now on the market only provide minor relief.
This falls into the category of testing that I never use because knowing the results of the test wouldn’t change what I am already doing.
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Knowing years before it became apparent, would be beneficial for those at risk. Agreed there is no cure but it can be slowed with lifestyle changes and some other drugs are showing promise in slowing it down. Plus there is some planning required to address the final stages. Something I’d like to participate in before it’s decided for me.
Just because dementias have no cure does not mean it’s useless to detect it as early as possible for some people. I’m one of those even though I don’t have the bad genes and it’s not in our family history, every familial generation has it’s weaknesses and strengths the previous generation didn’t have.
It’s not like prostate testing where it’s now becoming the standard to not do testing. AZ will put you in a care home for 10 to 15 years before it kills you. The cost of that is astronomical and can easily wipe out a lifetime of savings that could be better used by the living.
My solution is already in place, the MAID program will be used if/when appropriate.
I think this study is demonstrating changes in individuals who already have significant disease.
I think the use of p-Tau 217 / Beta Amyloid 42:40 ratio yields much more as a earlier warning (or if normal reassurance!) in regards to disease, probably 5-10 years or early before MCI occurs. I think that is a valuable piece of data that can be tracked yearly, and will have some individual really pursue everything known to delay disease progression.
Once you have significant disease, which was my take on this EEG study … we don’t have much in the way of action points or levers to pull. I think we do, at the point where a Beta Amyloid 42:40 is abnl, but the p-Tau 217 is still normal … or even if the p-Tau 217 is a little abnormal - this is likely early disease if no MCI … that is a valuable tool letting individuals know they must get very serious about everything.
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See:
- A researcher commenting on semaglutide: Predicting Alzheimers & Dementia (and minimizing risk) - #928 by adssx
- Liraglutide succeeded: Predicting Alzheimers & Dementia (and minimizing risk) - #940 by adssx
On semaglutide here’s another comment:
Here’s the video, worth watching (and short):
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