My take home from that paper:
“a randomized controlled trial including both sexes and exploring various PDE5I doses would be beneficial to confirm the association between PDE5I and AD.”
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I suspect that no such trial is coming forward in the next years. I hope it does. What to do with data that repetitively shows a decreased risk of developing AD if you are on these drugs (which yes could be confounder - but I doubt it, given the range of data and multiple confirmatory reviews).
So if I have a 57 year old with homozygous ApoE4 … I’d feel compelled to provide them with this data, and if no contraindication would be pretty likely to Rx a PDE5-I to them regularly. Along with having the humility to recognize it isn’t a definite - but on a risk/benefit, so long as the patient understood the nature of the data, I’d think it a sensible thing to offer.
Certainly for that individual, IF it reduced their risk of progressing to AD by 50-70% that would be a gamble that virtually every informed person would take. I don’t think we’ll see too many patients wanting to wait for the definitive study unless they are 35 years old and have the benefit of waiting for clear guidance.
I guess that is much the gamble we make with Rapamycin … low risk of adverse outcome, benefit unknown … but the upside could be pretty good and worth the gamble.
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@DrFraser I’m 37, female, so not looking for any raging boners. But given that the hand I’ve been dealt is aope4/apoe3, I’m actually going to jump on the bandwagon in a year or two. Actually, any info on what it does for straight women? The standard guidance isn’t clear as they only talk about effectiveness or lack thereof in women for its intended purpose and I don’t need to bring my vagina out of depression or anything of the sort.
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I’d defer to other females in the group who are on these agents - but my understanding is very little change in sexual function with women (and similar in 50% of older men - with little benefit). Increasing nitric oxide seems to have vascular benefits by relaxing smooth muscle. There is probably some other pathway that is helping with neurocognitive decline.
My take on things is that Rapamycin is probably first line for those with ApoE4’s, but adding this and ?SGLT2 inhibitor along with optimization of lipids, BP, glycemic control, diet, exercise, etc … would be the successful strategy - that hopefully works.
At least you just have one E4 …
Anyway - no medical advice here - just my thoughts on this in general.
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Researchers that have studied this area have known this for the last 15+ yrs. It was supposedly refuted by stating there are no phosphodiesterase 5 recpotors in the brain. This of course was short sighted as there are phosphodiesterase 5 recptors in brain neurons.
PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease
Here is a comment from one of the actual researchers of the 2016 when the 2021paper was released. With references others might find helpful if they wish to go down the rabbithooe
Quote by:
Ottavio Arancio
Columbia University Medical Center"I read this manuscript with a lot of interest, as it shows human data that are consistent with the large amount of preclinical data published by my lab and others in the last 20 years, supporting the use of phosphodiesterase 5 inhibitors against Alzheimer’s disease. I still remember when I presented the first evidence at a meeting on phosphodiesterases. The major critique was that there is no phosphodiesterase 5 in the human brain. To address this issue, we published a manuscript (Teich et al., 2016) in which we demonstrated that phosphodiesterase 5 exists in human neurons and is a viable therapeutic target. I have dedicated more than 20 years to these studies; to see them supported by evidence in humans is very rewarding.
Regarding the mechanisms of the protective effect, the manuscript does not discuss the issue in depth, probably due to the fact that there is a large amount of work published on the topic, and it would have been hard to synthesize it in the discussion. We showed that phosphodiesterase 5 inhibitors counteract the reduction in activity of the NO cascade due to elevation of tau oligomers, re-establishing normal phosphorylation of the memory related molecule, CREB (Acquarone et al., 2019). The same cascade is also affected after elevation of Aβ oligomers (Puzzo et al., 2005, 2009).
Thus, the most likely scenario is that extracellular tau and Aβ oligomers downregulate the NO cascade, possibly by interacting with a transmembrane protein. Our work showed that APP is necessary for the damage of synaptic plasticity and memory by Aβ and tau oligomers (Puzzo et al., 2017).
As the authors point out, due to the nature of the use of sildenafil (mostly in a male population, without a specific regimen), the study has some limitations that will be addressed by a randomized controlled trial, possibly using inhibitors of phosphodiesterase 5 that can be administered for prolonged periods of time, as it is required in a chronic condition such as Alzheimer’s. Indeed, a prolonged use of sildenafil might incur side effects due to interaction of the drug with phosphodiesterase 6, 1, and perhaps 9, 10, and 11. A more specific phosphodiesterase 5 inhibitor could serve the purpose (see, for instance, Fiorito et al., 2013, 2017; Zuccarello et al., 2020).
References:
Teich AF, Sakurai M, Patel M, Holman C, Saeed F, Fiorito J, Arancio O. PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease. J Alzheimers Dis. 2016;52(1):295-302. PubMed.Acquarone E, Argyrousi EK, van den Berg M, Gulisano W, Fà M, Staniszewski A, Calcagno E, Zuccarello E, D’Adamio L, Deng SX, Puzzo D, Arancio O, Fiorito J. Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade. Mol Neurodegener. 2019 Jun 27;14(1):26. PubMed.
Puzzo D, Vitolo O, Trinchese F, Jacob JP, Palmeri A, Arancio O. Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity. J Neurosci. 2005 Jul 20;25(29):6887-97. PubMed.
Puzzo D, Staniszewski A, Deng SX, Privitera L, Leznik E, Liu S, Zhang H, Feng Y, Palmeri A, Landry DW, Arancio O. Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer’s disease mouse model. J Neurosci. 2009 Jun 24;29(25):8075-86. PubMed.
Puzzo D, Piacentini R, Fá M, Gulisano W, Li Puma DD, Staniszewski A, Zhang H, Tropea MR, Cocco S, Palmeri A, Fraser P, D’Adamio L, Grassi C, Arancio O. LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent. Elife. 2017 Jul 11;6 PubMed.
Fiorito J, Vendome J, Saeed F, Staniszewski A, Zhang H, Yan S, Deng SX, Arancio O, Landry DW. Identification of a Novel 1,2,3,4-Tetrahydrobenzo[b][1,6]naphthyridine Analogue as a Potent Phosphodiesterase 5 Inhibitor with Improved Aqueous Solubility for the Treatment of Alzheimer’s Disease. J Med Chem. 2017 Nov 9;60(21):8858-8875. Epub 2017 Oct 23 PubMed.
Zuccarello E, Acquarone E, Calcagno E, Argyrousi EK, Deng SX, Landry DW, Arancio O, Fiorito J. Development of novel phosphodiesterase 5 inhibitors for the therapy of Alzheimer’s disease. Biochem Pharmacol. 2020 Jun;176:113818. Epub 2020 Jan 21 PubMed.
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My original use of Viagra was because I was having cold feet and unless it was placebo effect, I felt it helped with that (btw, didn’t mind the raging boners, I’m male lol, your post is pretty witty and funny). A very pragmatic way of looking at it, is that if it helps men against Alzheimer’s, there’s got a be a good probability that it should work for women the same way also. If I were you I’d try it in small doses and if you have no adverse effect, you might as well keep doing it.
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OK, I’m all for taking viagra (for the reduction in Alz. risk, of course)… but HIV Drugs… not so much. I’m sure in the USA if the insurance companies found out you’re taking an organ rejection drug, and an HIV drug, you’d have all sorts of problems.
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Any side effects from taking viagra for prevention? 
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As long as you don’t (mis)use the boner to stir the sugar in the coffee, all good
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Try microdosing cialis.
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I will at some point but for now I’m staying free of all meds. My strength on my leg (that had pain because of Cialis) has not turned to 100% yet. Once that happens, I’m going to start will 2 mgs of Cialis and see what happens. I am assuming my body would have gotten used to it a bit, and hopefully should be ok with smaller doses.
If you split a 5mg dose in 4 pieces you get 1.25mg which is high enough to provide benefits but not high enough to cause side effects. That’s the dose I’m personally using to get some PDE5i.
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That sounds like a plan. I will definitely try that and see what happens.
This based on your experience?
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FWIW, my neighbor reports that cannabis has cured his tinnitus. He grows his own now.
Very interesting! Haven’t smoked it in a long time, but if I knew it gets rid of tinnitus wouldn’t mind doing it for a while. Can you please do us a favor and ask him a bit more about it (i.e. how much he took/dose, perhaps what kind, sativa or indica? did he smoke it or used other means, how long it took etc…)
What dose would you start your hypothetical 57 yo male ApoE4 homozygote on? Just curious- 53 yo ApoE4/4 here. I’m going to email my own physician and ask him to give me a prescription.