Large Study Finds Viagra Is Linked to Almost 70% Lower Risk of Alzheimer's

#158

There’s no reason not to. It’s dirt cheap, at least from India.
It’s the one the study used.
There is no reason to think tadalafil is superior. At least there is no proof that it is.
Due to its long half-life, dosing is more problematic.
Maybe the shorter half-life of sildenafil will cause you less problems.

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#159

Indeed. Good that you wrote this - a reminder for me to get on board for sildenafil. Muscle cramps are less reported on sildenafil (quite uncommon) than with tadalafil and if they do show up I will know now to quit at once.

#161

How concerned should we be with the risk of viagra causing eye problems? I’m not talking about going blind, although going blind is no fun, but may there also be more subtle damage to the eye? The danger of damage being irreversible is giving me pause.

#162

Here is a fair summary on this topic:
Visual changes associated with Viagra (sildenafil) and Cialis (tadalafil) are generally reversible and temporary. These medications, which are phosphodiesterase type 5 (PDE5) inhibitors, can cause mild and transient visual symptoms due to their effect on phosphodiesterase type 6 (PDE6) in the retina. Common visual side effects include changes in color vision, light perception disturbances, blurred vision, and photophobia. These symptoms occur in approximately 3-11% of users and are usually non-permanent, resolving after discontinuation of the drug 12.

For sildenafil, visual effects typically last 3-5 hours, aligning with the drug’s half-life. In the case of tadalafil, effects may last longer due to its extended half-life of 17.5 hours. However, these effects are generally reversible once the drug is metabolized and eliminated from the body 23.

While serious vision-threatening complications such as nonarteritic anterior ischemic optic neuropathy (NAION) are rarely reported, there is a lack of conclusive evidence linking PDE5 inhibitors directly to these severe ocular events. The incidence of such complications in users does not appear to exceed that in the general population 36.

In summary, while sildenafil and tadalafil can cause visual changes, these effects are typically reversible. Patients experiencing visual disturbances should consult their healthcare provider for appropriate evaluation and management, which may include discontinuation of the drug if necessary.

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#163

Isn’t there also a type of retinal detachment linked to the PDE5 inhibitors? I believe it was serous retinal detachment. Still very rare, though.

#164

Thanks. 11% of users doesn’t strike me as rare. And to get rid of the effect you have to stop the medication altogether, there’s no “eventual adjustment”. I might be excessively risk averse, but I’ll pass on these meds.

#165

I had Gemini use my analysis and summary prompt for each of the dementia and Alzheimer’s risk for the above studies, then asked it to critically review these against all available peer reviewed and gold standard studies. Here’s the result:

The scientific evidence evaluated herein converges to test and validate three critical hypotheses regarding the clinical reality of these compounds:

  1. Tadalafil is unequivocally not neuroprotective. Evidence from recent, rigorous placebo-controlled trials indicates a total absence of cognitive or cerebral hemodynamic benefit, accompanied by significant adverse events and potential cognitive slowing.

  2. Sildenafil is highly unlikely to be neuroprotective, though its precise status remains mathematically open. While highly confounded observational claims databases suggest massive risk reductions, rigorous epidemiological controls and genetic proxies point heavily toward null or deleterious effects, leaving its clinical utility deeply in question pending the conclusion of ongoing mechanistic trials.

  3. Both agents harbor profound potential for neurotoxicity under conditions of sustained use. Lifelong genetic proxies and complex intracellular signaling dynamics suggest that chronic PDE5 inhibition may induce subcortical atrophy and exacerbate Alzheimer’s pathology through secondary messenger crosstalk, specifically involving cyclic adenosine monophosphate (cAMP) depletion and phosphodiesterase-2 (PDE2) hyperactivation.

Flawed Observational Data: Early claims that ED drugs prevent Alzheimer’s stem from “healthy user bias.” Men healthy enough for ED treatment inherently have better baseline cardiovascular and neurological health (Desai et al., 2022, Brain Commun).

• Tadalafil Fails in Trials: Gold-standard trials prove tadalafil offers zero cognitive or blood flow benefits, instead causing high dropout rates and potential cognitive slowing (PASTIS Trial, 2022; ETLAS-2 Trial, 2025).

• Sildenafil Lacks Efficacy: Rigorous, indication-matched studies demonstrate that sildenafil’s supposed neuroprotective benefits disappear when appropriately controlled (DREAM study: Desai et al., 2022).

• Genetic Evidence of Harm: Mendelian randomization reveals that lifelong genetic proxies for PDE5 inhibition increase Alzheimer’s and Lewy body dementia risk, causing brain atrophy (Brennan & Tinworth, 2025, Mol Neurobiol).

• Neurotoxic Mechanism: Chronic PDE5 inhibition spikes cGMP, hyperactivating the PDE2 enzyme. This depletes essential cAMP, silencing mitochondrial biogenesis and promoting neurotoxicity (Banerjee et al., 2019, Int J Mol Sci).

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#166

I looked at both those negative Tadalafil trials.

There was a trend towards better blood flow but not significant in PASTIS. P value was .09 with an N of 55. They took a single 20 mg dose vs placebo.

The other used 20 mg daily and surprise - had a lot of dropouts for side effects. Especially in women.

Yeah - no crap - don’t give 20 mg daily to a woman.

It didn’t provide benefit in blood flow after a stroke. Ok. That isn’t the same at all as dementia.

And the 2022 DREAM study compared to Endothelin Receptor Agonists (ERA) and found no difference in a population with PAH. Except the ERAs are being studied as an Alzheimer’s prevention drug also. So this study just said that Sildafenil or Tadalafil is no better than ERA. But both types of medications might be beneficial. Not sure why this study only Sildafenil is mentioned in the above post when it also looked at Tadalafil. It is almost like they designed a study to not find a benefit.

I can’t find that 2019 article but found this when looking for spiking cgmp levels. It is a preprint with all the caveats.

Gemini obviously puts great weight into the 2 RCTs. But neither of these answers anything outside of blood flow in disease state. And one probably just lacked enough power. Neuro benefit or not, it isn’t just blood flow.

Yes, an old thread has been resurrected. I apologize for replying if there was a different way.

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#167

No studies have found that sildenafil or tadalafil increases dementia risk. If you can point to any, I would like to see it. Also, I couldn’t find any “good” studies on sildenafil or tadalafil that reported cognitive benefits for people who already have dementia, but they may offer some help in preventing dementia.

However, large observational studies indicate a reduction in all-cause mortality.

“50 million US men in the TriNetX database, found that both tadalafil and sildenafil were associated with significant reductions in deaths, cardiovascular disease, and dementia in middle-aged men over a three-year follow-up period. Key findings included a 34% reduction in mortality with tadalafil and 24% with sildenafil, a 27%/17% reduction in heart attacks, a 34%/22% reduction in stroke, and a 32%/25% reduction in dementia risk.”

“A separate study using US commercial insurance claims also found that tadalafil exposure was associated with lower adjusted rates of coronary revascularization, unstable angina, and cardiovascular-related mortality, with an overall mortality rate 44% lower in men exposed to tadalafil.”

“The proposed mechanism is primarily the drugs’ vasodilatory effects — they block the PDE5 enzyme, which helps maintain blood vessel flexibility, lowers blood pressure, and improves endothelial function.”

I see no downside to taking either tadalafil or sildenafil. It is so cheap from India that one of my suppliers gave me a bunch as a bonus, maybe just to fill the package. It is actually cheaper daily than many of my supplements.

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#168

Take a look at this study:

“Our findings suggest that while PDE5 inhibition may be associated with a lower risk of vascular dementia, possibly by preventing white matter hyperintensities, it may increase risk of Alzheimer’s disease and Lewy body dementia.”

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#169

Because my wife did extensive genealogy on both sides of our families for several generations back. I feel I have very little risk for Alzheimer’s disease. But, nearly everyone is at some risk for age-related dementia and, in particular, vascular dementia.
That is why I will continue to take tadalafil.

Alzheimer’s has a significant genetic component, particularly through APOE ε4 variants and, in early-onset cases, mutations in APP, PSEN1, and PSEN2.

Vascular dementia is among the most preventable forms of dementia.

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#170

The Viagra Paradox: Lifelong PDE5 Inhibition Protects Against Vascular Dementia but Increases Alzheimer’s Risk

A new drug-target Mendelian Randomization (MR) study published in Molecular Neurobiology by researchers at the University of Galway (Ireland) and the University of Oxford (UK) sharply contradicts the current enthusiasm for repurposing PDE5 inhibitors as pan-neuroprotectants. The impact score of this journal is 4.3, evaluated against a typical high-end range of 0–60+ for top general science, therefore this is a Medium impact journal.

Previous retrospective observational studies suggested that the prescription of PDE5 inhibitors was associated with a lower risk of dementia. However, this study utilizes genetic proxies for PDE5 inhibition to bypass the reverse causality and residual confounding that frequently plague observational research. The data reveals a highly divergent, tissue-specific impact of PDE5 inhibition on the aging brain. Genetically proxied PDE5 inhibition successfully reduced white matter hyperintensities, signaling a strong potential protective effect against cerebral small vessel disease and vascular dementia.

Conversely, the exact same genetic inhibition increased the odds of Alzheimer’s disease by 9% and Lewy body dementia by 32%. Furthermore, lifelong PDE5 inhibition correlated with volume reductions in critical subcortical structures, including the thalamus and putamen, which are regions linked to Alzheimer’s disease and global cognitive decline. The mechanistic driver appears to be related to cGMP-mediated alterations in neuroinflammation and amyloid-beta clearance pathways, specifically impacting complement proteins and neprilysin (MME). Ultimately, these findings suggest that chronic PDE5 inhibition may promote subcortical degeneration and increase Alzheimer’s risk, warranting a highly cautious approach to off-label clinical use for cognitive longevity.

Biohacker Analysis: Technical Specifications & Mechanistic Review

Study Design Specifications

  • Type: Two-sample drug-target Mendelian Randomization using human genomic data.

  • Subjects: Meta-analysis of GWAS data from individuals of European ancestry. Primary exposure data for blood pressure traits was derived from 757,601 individuals from the International Consortium for Blood Pressure and UK Biobank. Outcome datasets included large cohorts, such as 39,918 Alzheimer’s disease cases.

Critical Limitations

  • Lifelong vs. Acute Exposure: Mendelian randomization studies proxy lifelong genetic perturbation of a drug target. This lifelong genetic exposure does not perfectly model the pharmacological reality of an older adult taking sildenafil or tadalafil for a few years late in life, which may result in different magnitudes of benefit or harm.

  • Isoform Ambiguity: The genetic instruments cannot differentiate between specific PDE5 isotypes, such as the vascular-specific PDE5A3. Plasma protein assays currently fail to capture these distinct isotypes, meaning systemic genetic variations may not reflect the precise pharmacodynamics of targeted small molecules.

  • Ancestry Restraints: The GWAS summary statistics utilized are predominantly restricted to individuals of European descent, severely limiting the ability to assess these genetic effects across diverse global ancestries.

  • Missing Data: The study acknowledges a lack of direct clinical trial data testing pharmacological PDE5 inhibition against validated Alzheimer’s biomarkers, and data on the proportion of GWAS cases diagnosed via modern CSF biomarkers is unavailable. [Confidence: High]

Part 3: Claims & Verification

Claim 1: Pharmacological PDE5 inhibitors are associated with a reduced risk of Alzheimer’s disease.

  • Evidence Level: Level A (Human Meta-analyses of Observational Studies).
  • Citation: Sildenafil and risk of Alzheimer disease: a systematic review and meta-analysis (2025)
  • Verification Notes: Live searches confirm that multiple meta-analyses of retrospective patient cohort data show a statistically significant reduction in AD risk among PDE5 inhibitor users. However, these epidemiological findings conflict directly with the genetic MR data, emphasizing the high risk of “healthy user bias” and confounding-by-indication in the observational data (i.e., men prescribed PDE5 inhibitors may simply possess better baseline cardiovascular health).

Claim 2: PDE5 inhibition reduces white matter hyperintensity volume and protects against vascular dementia.

  • Evidence Level: Level C (Human Observational / Genetic MR) & Level B (Human RCTs).
  • Citation: The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment (2022)
  • Verification Notes: The specific claim of physical volume reduction is derived strictly from Level C genetic data. Live searches for clinical trials yield the Phase II PASTIS RCT, which tested single-dose tadalafil in older adults with small vessel disease. The RCT found only a non-significant trend (p=0.096) toward increased cerebral blood flow within white matter hyperintensities, failing to prove that pharmacological dosing translates to the structural volume protections implied by the genetic proxies.

Claim 3: Lifelong PDE5 inhibition increases the risk of Alzheimer’s disease and Lewy body dementia.

Claim 4: PDE5 inhibition reduces the physical volume of subcortical brain structures (thalamus, putamen).

Claim 5: PDE5 inhibition enhances memory performance and reduces hyperphosphorylated tau.

Claim 6: PDE5 inhibition alters plasma concentrations of neuroinflammation and amyloid-clearance proteins, such as upregulating MME (neprilysin).

Investigating Tadalafil and Cerebral Blood Flow This discussion provides direct clinical context from the lead investigator regarding the challenges of using PDE5 inhibitors to modify cerebrovascular hemodynamics in human patients.

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#171

So the consensus is turning away from the daily use of PDE5 inhibitors such as Tadalafil?

#172

I believe the evidence is still overwhelmingly positive

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#173

No. PDE5i’s were one of the top performers in the UK biobank study.
Plus they might be the reason for keeping the Dick alive to 100… Dick Van Dyke that is:
“(Sex is) important, and thank god for things like Viagra.” :pill: :women_with_bunny_ears:

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#174

No, I just think the primary benefit is more cardiovascular than brain.

It seems the data on PDE5 benefits for brain function is mixed; mostly good (Alz prevention), but that one MR study conflicting, but that is comparing lifelong systemic genetic variations … which is quite different than mid or late life PDE5 inhibition.

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#175

Executive Summary

The “Geroscience hypothesis” posits that certain existing medications might slow aging and extend lifespan independent of their primary disease indications. This retrospective study systematically evaluated the association between the 406 most frequently prescribed drugs and all-cause mortality using the UK Biobank registry.

Analyzing prescription and mortality data from over 500,000 UK participants aged 37 to 73, the data reveals that while 155 of the 169 statistically significant drugs were associated with increased mortality—predictably due to the life-limiting nature of the conditions they treat—14 specific drugs correlated with increased lifespans compared to health-matched controls. Notable life-extending candidates include the statin Atorvastatin, the PDE5 inhibitor Sildenafil, the NSAID Naproxen, and estrogen therapies such as Estradiol.

Class-wide analyses demonstrated that statins, estrogens, and SGLT2 inhibitors reduced overall mortality. Conversely, Metformin—a widely debated longevity candidate—demonstrated a strictly neutral effect on mortality, and ACE inhibitors were associated with an increase in mortality. While these epidemiological findings highlight prime candidates for future clinical repurposing, the fundamental limitation of confounding by indication remains unresolved. Determining true pro-longevity efficacy in healthy humans requires prospective, randomized controlled trials rather than retrospective database mining. [Confidence: High

Lifespan Analysis & Data

Note: Because this is a human epidemiological study, lifespan data is reported via Hazard Ratios (HR) rather than absolute maximum lifespan extension seen in murine models. Significant lifespan extension associations (survival probability) compared to matched controls:

  • SGLT2 Inhibitors (Class): HR 0.64 (95% CI 0.45-0.89).
  • Estraderm: HR 0.67 (95% CI 0.51-0.88).
  • Estrogens (Class): HR 0.76 (95% CI 0.67-0.85).
  • Sildenafil: HR 0.85 (95% CI 0.78-0.93). Dose-response indicated highest efficacy at 10mg (Tadalafil: HR 0.72).
  • Naproxen: HR 0.90 (95% CI 0.85-0.96).
  • Atorvastatin: HR 0.91 (95% CI 0.87-0.95). Dose-response was J-shaped (protective at 20mg, detrimental at 80mg).
  • Metformin: HR 1.01 (95% CI 0.95-1.07) — Neutral effect.

Mechanistic Deep Dive

  • SGLT2 Inhibitors: SGLT2i likely confer survival benefits through nutrient-sensing pathway modulation, mimicking a fasting state that downregulates mTOR and activates AMPK and autophagy. [Confidence: Medium]

  • PDE5 Inhibitors (Sildenafil): Extending beyond vasodilation, PDE5i enhance cGMP signaling. Retrospective evidence identifies potential protections against cardiovascular disease and Alzheimer’s disease pathology. [Confidence: Medium]

  • Atorvastatin: Beyond established lipid-lowering capabilities, statins exhibit pleiotropic anti-inflammatory properties that reduce systemic cardiovascular risk factors. [Confidence: High]

  • Naproxen: As a COX inhibitor, its correlation with reduced mortality highlights the role of chronic systemic inflammation (inflammaging) as a primary driver of functional decline. [Confidence: Low-to-Medium]

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#176

They gave me a strip of Tada Up with an order maybe a year ago. I’m healing from a broken bone and my AI said this could help because it may improve circulation? It found studies that said so. These were 20’s. I was aiming for 2.5 at first, bit a corner off a pill. Headache the next day, I’m not a fast learner so bit another corner off next day. Aching muscles especially in my back, but also legs. I think maybe I’ll get used to it so bit another corner off. Thought I was gonna die. I got every side effect on the package. Nasty drug does not agree with me at all.

#177

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What’s the mechanism?

It seems to work by blocking PDE5, raising cGMP, and activating a kinase (PRKG1) which helps normalize abnormal mitochondrial signalling

https://www.cell.com/cell/fulltext/S0092-8674(26)00173-X

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#178

@RapAdmin put it well, positive cardiovascular findings while concerning or at least not supported for Alzheimer’s and dementia benefits. Viability for use likely individual and I think limited basis at this point. It’s going out of my stack (2.5mg EOD) and sticking around for occasional fun if anything.

Healthy weight, good sleep, and regular exercise likely have dramatically higher benefits (as is so often the case).

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