Phosphodiesterase Type 5 Inhibitors in men with erectile dysfunction might lower the risk of Alzheimer's disease as they did heart disease based on recent scientific evidence.

This story does not include health advice. It is for information, inspiration, and awareness purposes.

Photo byEsther AnnonUnsplash

PDE5Is and nitric oxide offer benefits beyond the heart and male reproductive organs; they may also enhance brain function and prevent Alzheimer’s disease.

Recently, I penned a story titled “If Viagra and Cialis Don’t Work, Here’s Another Option to Solve Erection Problems for Men” that gained viral attention for valid reasons. I received many appreciation messages from elderly readers. The central theme of the narrative was to highlight how the nitric oxide pathway could address erectile dysfunction issues, improve sexual health, and also support heart health if PDE5Is do not work for them.

As I outlined in that story, a close connection exists between the brain, heart, and male reproductive organs. Hence, a molecule aiding one may also benefit the other two organs. I am intensely interested in drug repurposing research as it involves exploring existing drugs for new therapeutic uses, offering a cost-effective way to find new treatment options, and lowering the burden of healthcare costs globally.

A decade ago, Viagra was prohibitively expensive due to its patent and the prevalence of spam messages inundating consumers’ inboxes with cheap offers from unreliable sources. However, this trend has since dissipated, and Viagra has become an affordable drug in many countries, available from reliable sources.

I recall some of my older male friends whose doctors prescribed Viagra for heart conditions, naturally resolving their erectile dysfunctions. Now, there is hope for them, as this multipurpose drug might also improve their cognitive health, which is quite exciting to me.

Research has explored the potential use of Viagra, or sildenafil, in women as well. For instance, a study conducted in 2003 found that sildenafil affects various sexual pathways in healthy women, potentially enhancing their sexual experiences. While such studies offer insights into the drug’s effects on female sexual function, its use in women remains off-label and is subject to further research and regulatory considerations.

Phosphodiesterase type 5 inhibitors (PDE5Is) are among the most widely repurposed drugs. Originally developed to treat hypertension and angina, sildenafil (Viagra), the first PDE5I, was also discovered to relax smooth muscles in the corpus cavernosum, making it effective for erectile dysfunction. This repurposing extended to pulmonary arterial hypertension, leading to sildenafil’s approval for this condition in 2005.

For example, in this 2005 randomized controlled trial, sildenafil, which inhibits PDE5, was investigated for its effects on patients with symptomatic pulmonary arterial hypertension. Patients were randomly assigned to receive a placebo or sildenafil (20, 40, or 80 mg) orally three times daily for 12 weeks.

The primary outcome measured was the change in the distance walked in six minutes. Sildenafil showed significant improvements in exercise capacity, mean pulmonary-artery pressure, and World Health Organization (WHO) functional class compared to placebo. Side effects like flushing and dyspepsia were observed. The study concluded that sildenafil enhances exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic PAH.

After this brief background, I want to update you with a new use case of Viagra and related drugs for brain health and their potential effects to lower the risks of Alzheimer's disease.

Fast Forward to February 2024, the Serendipitous Discoveries of Viagra from the Heart to Penis and Now to the Brain

A 2024 cohort study published in Neurology (a peer-reviewed journal) looked at 269,725 men over about 5.1 years. Among them, 1,119 were newly diagnosed with Alzheimer’s disease.

The study found that men who started using PDE5 inhibitors (PDE5Is) had a lower risk of Alzheimer’s disease compared to those who didn’t use them.

The risk decreased even more with higher prescription numbers: those with more than 20 prescriptions had a lower risk. Even when they adjusted for a one-year delay, the results were similar, but they varied with a three-year delay.

For those unfamiliar, a cohort study is a type of research design used in epidemiology to investigate the causes of diseases and other health-related outcomes.

In a cohort study, a group of individuals who share a common characteristic or experience, such as being exposed to a particular risk factor or having a specific condition, is followed over time to observe the development of diseases or health outcomes.

Cohort studies can be prospective, where participants are followed forward in time, or retrospective, where researchers analyze data collected from the past. These studies are valuable for identifying associations between risk factors and outcomes and understanding diseases' natural history.

Researchers argued that PDE5I initiation in men with erectile dysfunction was associated with a lower risk of Alzheimer’s disease, particularly in those most frequently issued prescriptions.

The differences between primary and sensitivity analyses highlight the need to explore the optimal lag period. To enhance the generalizability of findings, a randomized controlled trial including both sexes and exploring various PDE5I doses would be beneficial to confirm the association between PDE5I and Alzheimer’s disease.

The Promising Role of PDE5Is in the Brain from Credible Sources Based on My Research Findings in the Literature

In this section, I will provide a distilled version of my literature review on the potential effects of Phosphodiesterase Type 5 inhibitors in men with erectile dysfunction in lowering the risk of Alzheimer’s disease using a few concepts.

In previous stories, I introduced cognitive function, neuroinflammation, cerebral blood flow, and neurodegenerative diseases like Alzheimer’s, which is a type of dementia. So, I won’t repeat them here to keep this story concise.

As documented in a recent paper on Neurology, PDE5Is increase cyclic guanosine monophosphate (cGMP), which is essential for various clinical effects. Studies like this one suggest that low cGMP levels and high levels of PDE enzyme in the brain may be linked to Alzheimer’s disease. Animal studies show potential neuroprotective benefits of PDE5Is, but human evidence is still inconclusive.

Tadalafil, a specific PDE5I, has shown improvements in cerebral blood flow, cognition, and neuroinflammation in men with erectile dysfunction. As documented in this 2015 paper, PDEIs boost cellular signaling by preserving cyclic nucleotides like cAMP and cGMP, which are crucial for cell functions, including brain plasticity and protection.

They are considered potential treatments for age-related cognitive decline and Alzheimer’s disease. Preclinical studies indicate that PDE2, 4, and 5 inhibitors enhance memory in aged animals and Alzheimer’s disease models.

The 2015 paper informs that limited human studies exist, but PDE1I vinpocetine shows promise for memory impairment. Some PDEIs like cilostazol and MK-0952 have been tested in mild to moderate Alzheimer’s disease patients, showing varied results. Developing PDEIs with clear cognitive benefits and targeting specific isoforms remain key challenges in treating age-related cognitive decline and Alzheimer’s disease.

This 2014 study aimed to analyze the levels of cGMP and cAMP in the cerebrospinal fluid of Alzheimer’s disease patients and study the expression of enzymes (PDEs) that break them down in the brain. The cohort included cognitively normal individuals, those with mild cognitive impairment, and mild Alzheimer’s disease patients.

Results showed that cGMP levels were lower in mild Alzheimer’s disease patients compared to controls and were linked to clinical dementia and Aβ42 levels in Alzheimer’s disease patients. Increased PDE5 expression was observed in the temporal cortex of Alzheimer’s disease patients.

These findings suggest that reduced cGMP levels in early Alzheimer’s disease stages might worsen amyloid pathology and cognitive decline, highlighting its potential role in Alzheimer’s disease development.

This 2019 systematic review in Behavioral Brain Research aimed to evaluate the efficacy of PDE5Is in preventing cognitive impairment in Alzheimer’s disease and to understand their underlying mechanisms. Fifteen animal trials were analyzed, all indicating that PDE5Is can prevent cognitive deficits in Alzheimer’s disease.

Significant improvements were observed in behavioral tests, including the water maze and contextual fear memory. The review suggests that PDE5Is may help prevent cognitive decline in Alzheimer’s disease by targeting tauopathy rather than Aβ-42.

The mechanism of action may involve reducing p-Tau, increasing CREB and BDNF, or suppressing apoptosis and inflammation. However, limitations such as a small number of studies, high risk of bias, and low reporting quality warrant further investigation into the efficacy of PDE5Is in preventing cognitive impairment in Alzheimer’s disease.

This 2019 study on Clinical Psychopharmacology and Neuroscience aimed to explore the effects of daily low-dose tadalafil on cognitive function and cerebral blood flow in patients with erectile dysfunction and mild cognitive impairment.

Male patients aged 50 to 75 with erectile dysfunction and mild cognitive impairment were prescribed tadalafil 5 mg daily for eight weeks. After the treatment period, there was a significant improvement in both the International Index of Erectile Function and Montreal Cognitive Assessment (MoCA) scores.

Patients also exhibited increased relative regional cerebral blood flow in certain brain regions. These findings suggest that daily tadalafil use may enhance cognitive function and cerebral blood flow in patients with erectile dysfunction and mild cognitive impairment.

In patients with benign prostatic hyperplasia, low urinary tract symptoms, and erectile dysfunction (BPH/LUTS-ED), chronic inflammation is common.

A 2019 study in Nature investigated the effects of tadalafil treatment (5 mg/day) on peripheral inflammation, cognitive function, and auditory evoked potential (mismatch negativity, MMN) in these patients.

Nine BPH/LUTS-ED patients and 12 controls underwent psychometric tests, MMN assessments, and blood tests for interleukin levels and T-cell markers. BPH/LUTS-ED patients exhibited higher levels of inflammatory markers and poorer cognitive function than controls.

After tadalafil treatment, inflammatory markers normalized, and cognitive function and MMN parameters improved. These findings suggest that tadalafil may have anti-inflammatory effects and could be beneficial in treating cognitive impairment associated with inflammatory conditions like BPH/LUTS-ED.

These researchers, published in Nature in 2021, devised a novel approach using endophenotype disease modules to repurpose drugs for Alzheimer’s disease and identified sildenafil as a potential modifier of disease risk.

Analyzing insurance claims data for 7.23 million people, they found that sildenafil use was linked to a 69% reduced risk of Alzheimer’s disease (hazard ratio = 0.31, 95% confidence interval 0.25–0.39, P<1.0×10–8).

Propensity score analyses confirmed this association across various drug cohorts (diltiazem, glimepiride, losartan, and metformin) after adjusting for demographic and disease factors.

Additionally, sildenafil was observed to enhance neurite growth and reduce phospho-tau expression in Alzheimer’s disease patient-derived neuron models, providing mechanistic insights into its potential benefits for Alzheimer’s disease. Nonetheless, the observed association does not establish causality, necessitating further investigation through randomized clinical trials.

However, using a similar method, a 2022 study published in Oxford Academic couldn’t replicate the findings of Nature researchers. They said that their findings findings cast doubt on the potential of PDE5Is as repurposing candidates for Alzheimer’s disease and related dementia. Fair enough. Science is science. But scientists never give up.

While exploring the literature, I found that the 2022 study reached its conclusion hastily, relying on limited data. However, the 2024 study published in Neurology is particularly promising, as it boasts a larger dataset and demonstrates greater scientific rigor. It is this study that has sparked my enthusiasm and prompted me to write this article with great passion and interest.

As Neurology researchers pointed out, studies on drug distribution have revealed that both sildenafil and tadalafil (PDE5Is) can penetrate the blood-brain barrier, with sildenafil exhibiting higher permeability than tadalafil.

This valuable information suggests that these drugs can reach the central nervous system and inhibit PDE expression in brain cells, potentially contributing to neuroprotection.

The observed protective effect associated with increased cumulative prescriptions implies that repeated exposure may result in a higher accumulation of PDE5Is in the human brain, consistent with findings from animal studies demonstrating neurological benefits after chronic exposure to PDE5Is.

What I liked in the new study is that, as mentioned before, two previous observational studies have explored the connection between PDE5Is and incidents of Alzheimer’s disease. Their primary analysis revealed a reduced risk of Alzheimer’s disease, although not as pronounced as the 69% decrease reported by Fang et al.

They focused their study on men with erectile dysfunction, ensuring a uniform population, and utilized a comprehensive list of covariates in their PS model to adjust for baseline confounding and minimize selection bias.

By treating PDE5I exposure as a time-varying variable, they accurately allocated person-time at risk, reducing immortal-time bias.

Their analysis, benefiting from the UK database, included additional crucial variables like blood pressure, alcohol status, BMI, and socioeconomic status, which are often unavailable in US insurance claims data.

So, the results of this extensive population-based study suggest a potential link between PDE5I use and a reduced risk of incident Alzheimer’s disease, particularly notable among people issued >20 prescriptions over a median follow-up of 5 years. Further investigation into the pathophysiologic mechanisms of PDE5I and neuroprotection is warranted.

Moreover, additional research is necessary to determine the optimal duration of the lag period, which is essential for addressing the prodromal phase of Alzheimer's disease.

To validate their findings on a broader scale, a randomized controlled trial involving both male and female participants without cognitive impairment, randomly assigned to receive a PDE5I or placebo in predefined doses, is recommended.

The primary outcomes should focus on changes in baseline cognitive function, offering a comprehensive evaluation of the potential therapeutic effects of PDE5I on Alzheimer’s disease.

Conclusions and Takeaways

In this story, my aim was to present the potential impact of PDE5Is on the brain and reference compelling research indicating their potential benefits in reducing the risk of Alzheimer’s disease, which has no cure yet. Just as Viagra serendipitously provided solutions as a repurposed drug, surprising scientists and clinicians alike, I advocate for its repurposing to promote brain health as well.

Although this story was mainly about Viagra, Cialis, or Tadafil as PDE5Is, I am also excited about their cousin nitric oxide. It is because nitric oxide can pass the blood-brain barrier as a small and highly reactive molecule that can diffuse freely across lipid membranes, including the membranes of endothelial cells that form the blood-brain barrier.

I’m enthusiastic about the multifaceted roles of nitric oxide in promoting neuroprotection, regulating cerebral blood flow, modulating inflammation, and combating oxidative stress. These diverse functions highlight its potential as a target for preventing neurodegenerative disorders and maintaining cognitive function and overall brain health.

As I covered in previous stories, nitric oxide is a crucial neuroprotective agent in various ways. It acts as a neurotransmitter and neuromodulator, facilitating synaptic plasticity, neuronal communication, and neurogenesis, which are vital for preventing neurodegenerative disorders like Alzheimer’s and Parkinson’s diseases.

Nitric oxide is a potent vasodilator, regulating cerebral blood flow by relaxing vascular smooth muscle cells in brain blood vessels. This ensures optimal delivery of oxygen, glucose, and nutrients to brain cells, promoting brain health and resilience against neurodegenerative diseases.

Additionally, nitric oxide possesses anti-inflammatory properties, mitigating neuroinflammation, a common feature of such disorders, by modulating immune responses and inhibiting pro-inflammatory cytokine production.

Lastly, nitric oxide acts as an antioxidant, scavenging free radicals and reactive oxygen species, thereby protecting neurons from oxidative damage and apoptosis, crucial for maintaining neuronal integrity and function.

So, as I mentioned in a previous story if Viagra or Cialis does not work, there is still hope for addressing erectile dysfunction and cognitive health using nitric oxide-producing nutrients or supplements.

The recent findings highlight the profound impact these drugs could have beyond their initial indications, offering hope for enhanced cognitive function and neuroprotection.

Through rigorous research and serendipitous discoveries, we witness the evolving landscape of drug repurposing and its potential to alleviate the burden of neurodegenerative disorders.

As we delve deeper into the complexities of brain health and the mechanisms underlying Alzheimer’s disease, the exploration of PDE5Is opens new avenues for preventive strategies and therapeutic interventions.

By embracing interdisciplinary approaches and leveraging serendipitous scientific discoveries, we can pave the way for a future where neurodegenerative diseases are managed and prevented.

Thank you for reading my perspectives. I wish you a healthy and happy life.

If you found this story helpful, you may also check out my other articles on NewsBreak. As a postdoctoral researcher and executive consultant, I write about important life lessons based on my decades of research and experience in cognitive, metabolic, and mental health.