This is a very informative post, and I appreciate your efforts to share the latest research on the potential benefits of PDE5Is for brain health and Alzheimer's disease prevention. While I’m not an expert on this subject, my own research has led me to arrive at some additional conclusions that might add context to the points you raised.

First, there is this serendipity of scientific discovery. A molecule that was developed to treat heart conditions works astonishingly well on our (male) small brain (as insinuated by our women), located at an anatomically lower level of the male anatomy. That was good news, not only for us guys of a certain age, but also for that molecule's manufacturers (Pfizer). Then there was the discovery that it might even work on the big brain of the male anatomy. How much better can it get? I mean, God obviously didn’t give us enough blood to operate both brains at the same time, now we have Pfizer to remedy this shortcoming.

But fun aside, we must not lose sight of the fact that there are challenges and limitations that need to be addressed before PDE5Is can be widely used for these purposes.

One of the main challenges is the selectivity of PDE5Is. This selectivity may be a gift, but also a curse. As you mentioned, PDE5Is increase the levels of cGMP, which is not only produced by PDE5, but also by other PDE isoforms, such as PDE2, PDE3, and PDE9. These isoforms not only have different tissue distributions and functions, but they may also be involved in the pathophysiology of Alzheimer's disease and other neurodegenerative disorders. Therefore, inhibiting just PDE5 may not be sufficient or optimal to address Alzheimer’s, but may also have unwanted effects on other organs and systems.

Then there is the dosing and the duration of PDE5I treatment. As you noted, the studies that showed a reduced risk of Alzheimer's disease with PDE5I were based on observational data. The inherent problem with observational data is confounding and bias. The optimal dose and duration of PDE5I treatment for cognitive purposes also remain unclear. Most certainly it will depend on the individual characteristics and disease stages of the patients. Too high or too low doses may have adverse effects or not be the desired ones. One of my friends, for example, who tried sildenafil for ‘recreational’ purposes during a weekend with his girlfriend had a 48-hour priapism, which he described as utterly unpleasant. Therefore, more studies are needed to determine the optimal dose and duration of PDE5I treatment for different populations and outcomes.

A third challenge is the safety and tolerability of PDE5Is. Although PDE5Is are generally well-tolerated and have a favorable safety profile, they are not without risks and contraindications. PDE5Is can interact with other medications, such as nitrates, alpha-blockers, and antihypertensives, and may cause serious complications of cardiovascular, vision, hearing, and kidney function.

In summary, I like your post for raising the potential of benefits of PDE5Is for brain health and Alzheimer's disease prevention. However, I also urge caution and prudence in the use and interpretation of PDE5Is, as they are no magic bullet, and may have limitations and drawbacks that we might only discover along the way.