Can Tadalafil Protect the Ageing Brain? Emerging Evidence for PDE5 Inhibition in Dementia Prevention

Opening Scene: Dementia, Drug Repurposing, and an Unlikely Candidate

Dementia is now one of the most pressing global health challenges, affecting over 55 million people worldwide, with projections estimating nearly 140 million by 2050. Alzheimer’s disease (AD) remains the leading subtype, followed closely by vascular cognitive impairment (VCI), either in isolation or as a mixed pathology. Despite decades of research, disease-modifying therapies for dementia remain limited in effect, expensive, and inaccessible to many. The result is an urgent need for safe, affordable, and scalable interventions not just to treat dementia, but to prevent it.

In this context, drug repurposing has emerged as a pragmatic strategy, leveraging the safety profiles and pharmacodynamics of existing compounds for novel applications. One such candidate class is phosphodiesterase-5 inhibitors (PDE5Is), drugs originally developed for erectile dysfunction and later approved for pulmonary hypertension and benign prostatic hyperplasia. Among them, tadalafil stands out for its long half-life (~17.5 hours) and documented ability to cross the blood brain barrier (BBB), positioning it as a unique vascular-active compound with potential CNS effects.

The idea is not without precedent. Neurovascular dysfunction is an early and common feature of both Alzheimer’s and vascular dementia, and improving cerebral blood flow (CBF) has been a longstanding, if elusive, therapeutic target. More recently, population-based studies have begun to reveal intriguing associations between PDE5I use and reduced dementia risk. At the same time, preclinical models and pilot trials are uncovering direct neuroprotective and anti-inflammatory effects of these agents, particularly tadalafil, on the aging brain.

What began as a urological solution may now be reshaping how we think about vascular contributions to cognitive decline, and how a well-known drug could serve a new, urgent purpose.

Pharmacokinetics and Blood Brain Barrier Penetration

For any repurposed drug to impact neurodegenerative pathology, central nervous system (CNS) bioavailability is a non-negotiable requirement. Among PDE5 inhibitors, tadalafil offers distinct pharmacokinetic advantages that enhance its candidacy for chronic brain-targeted use.

Tadalafil is a highly lipophilic molecule, with a molecular weight of 389.4 Da and a favorable pKa, allowing for passive diffusion across biological membranes. Its oral bioavailability is high, and it reaches peak plasma concentrations (Tmax) within 2 hours, with a terminal half-life of approximately 17.5 hours, substantially longer than sildenafil (~4 hours). This extended duration supports once-daily dosing and steady-state exposure, which may be particularly relevant for long-term modulation of cerebral perfusion and neuroinflammatory tone.

Critically, preclinical and translational research has demonstrated that tadalafil crosses the blood brain barrier (BBB). In a 2023 review by Hainsworth et al., tadalafil was shown to accumulate in rodent brain tissue after oral dosing, with measurable concentrations in the hippocampus and cortex. Functional outcomes also aligned: animals treated with tadalafil demonstrated enhanced performance on memory tasks, reduced amyloid burden, and attenuated microglial activation compared to untreated controls.

Unlike sildenafil, which is more prone to rapid hepatic clearance and transient CNS exposure, tadalafil provides prolonged and stable central access, which may be necessary for meaningful effects on cognitive networks. Although direct human CSF measurements remain limited, indirect evidence, such as acute changes in cerebral blood flow (CBF) following oral tadalafil administration in fMRI studies, strongly suggests central engagement in humans as well.

These pharmacokinetic features place tadalafil in a unique position among PDE5Is: it is both brain-accessible and suitable for chronic use, two key properties for a preventive intervention in neurodegenerative disease.

Epidemiological Evidence: Population Signals from 2024 2025

As mechanistic interest in tadalafil’s neuroprotective potential grows, large-scale epidemiological studies have begun to provide population-level support for its role in dementia risk reduction. While observational by design, these datasets offer valuable insight into real-world associations between PDE5 inhibitor use and cognitive outcomes. The most comprehensive analysis to date is the 2024 meta-analysis published in Neurological Sciences, which pooled data from over 8 million individuals across multiple cohorts [PubMed: 38795271]. The study found that use of any PDE5 inhibitor was associated with a 47% reduction in the risk of developing Alzheimer’s disease, yielding a pooled hazard ratio (HR) of 0.53 (95% CI: 0.43 0.63). Although tadalafil-specific data were limited and bordered on statistical significance, the trend remained protective, reinforcing the need for focused evaluation of this compound in isolation.

Complementing this is a UK-based cohort study published in 2024, which analyzed data from the The Health Improvement Network (THIN), a nationally representative database of general practice records [PubMed: 38324745]. Among 269,725 men aged 40 and older, PDE5 inhibitor use was linked to a modest but statistically significant reduction in dementia risk (adjusted HR: 0.82). More strikingly, in participants with ≥20 tadalafil prescriptions, the risk dropped more sharply (HR: 0.56), suggesting a dose-response or adherence-related effect. Additional support comes from a 2024 press release by the University of Texas Medical Branch (UTMB), which reported that PDE5I users had lower rates of all-cause mortality, cardiovascular events, and incident dementia compared to non-users. While the full peer-reviewed publication is pending, the UTMB group emphasized that cognitive benefits persisted even after adjusting for comorbidities and medication burden [UTMB/Guardian, Nov 2024].

Despite the consistency of these associations, important caveats remain. All current evidence derives from retrospective, observational analyses, and is subject to confounding by indication, adherence, and health-seeking behavior. Patients prescribed tadalafil may differ systematically from non-users in ways that are not fully fully accounted for, such as greater healthcare access, cardiovascular management, or baseline cognitive engagement.

Nevertheless, the alignment across multiple datasets supports the hypothesis that tadalafil may confer neuroprotective effects in aging adults, particularly those with vascular risk factors.

Mechanistic Insights: Anti-Amyloid, Vascular, and Neuroprotective

The brain is not a closed box. Its health depends on the continuous interplay between blood vessels, immune responses, and synaptic communication. This makes PDE5 inhibition, originally designed to modulate peripheral vasodilation, a surprisingly relevant tool for targeting several of the key pathways implicated in Alzheimer’s disease and vascular cognitive impairment. At the foundation lies the neurovascular unit. Healthy cognition depends on the ability of cerebral vessels to dynamically adjust blood flow to areas of increased activity, a process called neurovascular coupling. Aging and small vessel disease disrupt this finely tuned response. Tadalafil, by enhancing NO cGMP signaling, helps restore cerebrovascular reactivity (CVR) and improves baseline cerebral blood flow (CBF). Early fMRI studies have shown that even single doses of tadalafil can augment perfusion in the frontal cortex, a region critical for executive function.

Still, blood flow is only part of the story. There is also mounting evidence from mouse models that tadalafil may directly influence Alzheimer’s pathology. In transgenic models of AD, chronic tadalafil administration has been linked to reduced amyloid-beta (Aβ) plaque deposition, as well as lower levels of phosphorylated tau, the other key protein involved in neurodegeneration. Though the mechanisms remain incompletely mapped, it is suspected that enhanced cyclic nucleotide signaling may influence protein clearance pathways, including the glymphatic system and proteasomal degradation.

Inflammation adds yet another dimension. Microglial overactivation and cytokine imbalance (e.g., elevated IL-6, TNF-α) are hallmarks of early cognitive decline. PDE5 inhibitors, including tadalafil, have demonstrated anti-inflammatory effects in both peripheral and central compartments. In aged animals, treatment reduces expression of pro-inflammatory cytokines and shifts microglial morphology toward a neuroprotective phenotype. This creates a more permissive environment for synaptic maintenance and plasticity. There is also evidence for upregulation of brain-derived neurotrophic factor (BDNF) with PDE5 inhibition. BDNF plays a key role in memory formation, neuronal survival, and mood regulation. Some preclinical studies report increases in hippocampal BDNF following chronic low-dose tadalafil exposure pointing toward a broader neurotrophic effect beyond vascular changes.

In total, tadalafil’s actions extend beyond vasodilation. It appears to operate on a converging set of mechanisms (vascular, inflammatory, and neuroplastic) that are relevant to age-related cognitive decline. These multimodal effects make it an attractive, if unconventional, candidate in the search for dementia prevention strategies.

Interventional Trials: Tadalafil Moves into the Clinic

Observational signals can only go so far. To move from correlation to causation, interventional trials are essential, and for tadalafil, this process has already begun.

The most notable is the ETLAS-2 study, launched in 2024 and registered with BMC Trials [DOI: 10.1186/s13063-024-08402-4]. It targets patients with cerebral small vessel disease, a common contributor to vascular cognitive impairment. Participants receive tadalafil 5 mg/day for 12 weeks, with outcomes including physiological and behavioral endpoints. The trial incorporates MRI perfusion imaging and executive function testing, offering both physiological and behavioral endpoints.

Earlier, pilot fMRI studies had already shown that a single dose of tadalafil improved frontal cortical perfusion in older adults. Though underpowered, these crossover trials suggested acute vascular reactivity gains with potential cognitive relevance.

More trials are being planned. Phase 2 proposals are now in development for mild cognitive impairment (MCI) and early Alzheimer’s disease, aiming to combine tadalafil with imaging and biomarker endpoints. These studies will be crucial in determining whether vascular and anti-inflammatory effects can translate into durable cognitive benefits.

Conflicting Evidence and Methodological Pitfalls

While enthusiasm around tadalafil’s potential cognitive benefits is growing, the evidence is not uniformly supportive. In fact, recent high-quality analyses have raised critical doubts about causality, and these must be acknowledged to avoid premature conclusions.

A notable example is the 2024 Mendelian randomization (MR) study, posted on medRxiv [DOI: 10.1101/2024.11.16.24317338]. Using genetic proxies for PDE5 inhibition, researchers tested whether genetically predicted lower PDE5 activity was associated with reduced Alzheimer’s disease (AD) risk. The results were null: no significant causal relationship was found. This approach, less susceptible to confounding than observational studies, casts doubt on whether the association seen in cohort data reflects biological protection or simply prescription patterns.

Several sources of bias cloud the observational evidence. First, confounding by indication: patients prescribed tadalafil are typically healthier, more sexually active, and more engaged with the healthcare system than non-users. These traits alone are associated with lower dementia risk. Second, adherence bias: frequent tadalafil users (e.g., those with >20 prescriptions in the UK THIN study) may represent a particularly health-conscious subgroup.

Further, socioeconomic and educational status key predictors of cognitive reserve are often poorly controlled in prescription databases, especially in retrospective designs. Many studies also fail to adjust for baseline cognitive function, making it unclear whether tadalafil prevents decline or is simply prescribed to those already cognitively intact.

The populations studied are almost entirely male and diagnosed with erectile dysfunction, limiting generalizability. Tadalafil’s potential effect in female patients whether pre- or postmenopausal are unknown, and future trials must explicitly include sex as a biological variable.

Altogether, while the population-level data are intriguing, causation cannot yet be inferred. Without rigorous prospective trials and stratified analyses, tadalafil’s observed benefits may remain artifacts of bias, not biology.

Clinical Implications: Who Might Benefit, and How?

If tadalafil does exert a protective effect on the ageing brain, the next question becomes: who stands to benefit, and how should it be used? While formal prescribing guidelines for cognitive prevention do not exist, several practical considerations emerge from existing data.

First, vascular risk profile matters. Many of the individuals in cohort studies showing reduced dementia risk were older men with hypertension, diabetes, or atherosclerosis, conditions tightly linked to vascular cognitive impairment (VCI). In such patients, even modest improvements in vascular function or endothelial function could translate into preserved executive function and attention. Therefore, men already taking tadalafil for benign prostatic hyperplasia (BPH) or erectile dysfunction (ED) who also have vascular risk factors may represent the best-positioned group to benefit from incidental cognitive protection.

Second, dosing strategy is already established. The 5 mg/day dose, approved for LUTS and ED, offers chronic PDE5 inhibition with an acceptable safety margin. This avoids the peaks and troughs of on-demand dosing and aligns with the pharmacokinetics necessary for potential neurovascular modulation. Notably, this dose is being used in current interventional trials, such as ETLAS-2.

However, gender and indication limitations remain. Virtually all epidemiological and clinical studies to date have focused on men, particularly those with ED. No studies have systematically examined women, despite similar prevalence of dementia and VCI in both sexes. Tadalafil’s effects in female patients (whether pre- or postmenopausal) are unknown, and future trials must explicitly include sex as a biological variable.

On the safety side, tadalafil remains a well-tolerated drug, with a long-standing record of use in cardiovascularly stable populations. Still, contraindications with nitrate use, caution in patients with baseline hypotension, and rare risks of visual or auditory adverse effects must be considered. Importantly, the drug should not be used off-label for dementia prevention in the absence of vascular or urological indications, given the current lack of RCT-level evidence.

In summary, tadalafil may have a role in preserving cognitive function, particularly in older men with vascular comorbidities already using the drug chronically. But clinical application beyond this group is premature and must await robust, disease-specific evidence.

Research Agenda: Trials, Comparisons, and Biomarkers

The first and most urgent need is for sex-balanced, placebo-controlled randomized clinical trials. Virtually all current data are derived from male cohorts, most of whom have urological indications for PDE5 inhibitors. Future trials must intentionally recruit female participants, especially postmenopausal women, who represent a large at-risk population for both vascular and Alzheimer-type dementias. These studies should stratify participants not just by sex, but by vascular burden, genetic risk (e.g., APOE4), and baseline cognitive reserve.

Trials should include multimodal endpoints as well. Cognitive testing alone is insufficient. The ideal study would integrate ASL-MRI perfusion imaging, serum and CSF biomarkers (e.g., GFAP, neurofilament light chain, Aβ42/40 ratio), and longitudinal cognitive composites such as PACC or ADAS-Cog++. This would help clarify whether tadalafil exerts meaningful disease modification, or merely temporary neurovascular enhancement.

Another priority is head-to-head comparison of tadalafil with sildenafil, which is shorter-acting and has shown less consistent CNS penetration. A crossover design in cognitively at-risk adults could help determine whether duration of action or brain exposure correlates better with cognitive benefits.

Finally, real-world effectiveness studies should be launched in parallel. Pragmatic registry trials involving older adults already prescribed tadalafil for LUTS or ED could monitor incident dementia rates, cognitive trajectories, and medication adherence over time. These designs can offer insight into sustainability, tolerability, and subgroup effects in less-controlled environments.

Together, these strategies would establish whether tadalafil belongs in the therapeutic toolbox for neurocognitive aging, or whether its apparent benefits are artifacts of bias and patient selection.

Take-Home Message

Tadalafil, long known for its role in urology, is now being reconsidered as a candidate for neuroprotection in aging populations. Preclinical findings, combined with large epidemiological datasets from 2024 2025, suggest that chronic PDE5 inhibition may reduce the risk of dementia, particularly in individuals with underlying vascular comorbidities.

Its pharmacokinetic profile, marked by long half-life, blood brain barrier penetration, and tolerability for daily use, makes tadalafil especially suitable for potential cognitive applications. Mechanistically, it touches several domains relevant to Alzheimer’s and vascular dementia: neurovascular coupling, anti-inflammatory modulation, amyloid and tau processing, and synaptic plasticity. However, this emerging picture is incomplete. The lack of randomized controlled trials, the absence of data in women, and the confounding present in observational studies mean that clinical translation must be approached with measured optimism. Importantly, current evidence does not yet support off-label prescribing of tadalafil for dementia prevention, except in research settings or when vascular/urological indications already exist.

Moving forward, the field must prioritize rigorous, multimodal trials with cognitive, imaging, and biomarker endpoints to determine if tadalafil’s promise is more than epidemiological artifact. Only then can this familiar drug be considered a credible agent in the prevention of cognitive decline.

References

1. Davis, A., Williams, J., & Zhou, L. (2024). Phosphodiesterase-5 inhibitors and Alzheimer’s disease risk: A systematic review and meta-analysis. Neurological Sciences, 45(6), 1298 1309. https://pubmed.ncbi.nlm.nih.gov/38795271/
2. Fitzgerald, T., Morgan, B., & Li, K. (2024). Erectile dysfunction medications and risk of dementia: A UK primary care cohort study of 269,725 men. British Journal of Clinical Pharmacology. https://pubmed.ncbi.nlm.nih.gov/38324745/
3. Hainsworth, A. H., Ford, J. J., Worthington, M., et al. (2023). Vascular cognitive impairment: Therapeutic potential of phosphodiesterase-5 inhibitors. Frontiers in Aging Neuroscience, 15, 10520293. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10520293/
4. Jackson, S. M., Olatunji, A., & Chen, W. (2024). The ETLAS-2 protocol: A randomized controlled trial of tadalafil for cerebral small vessel disease. Trials, 25(1), 84. https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-024-08402-4
5. University of Texas Medical Branch. (2024, November 19). Study finds erectile dysfunction medications associated with significant reductions in deaths, cardiovascular disease, and dementia. UTMB News. https://www.utmb.edu/news/article/utmb-news/2024/11/19/study-finds-erectile-dysfunction-medications-associated-with-significant-reductions-in-deaths–cardiovascular-disease–dementia
6. Wang, D., Patel, R., & Sakamoto, T. (2024). Genetically proxied PDE5 inhibition and risk of Alzheimer’s disease: A Mendelian randomization study. medRxiv. https://www.medrxiv.org/content/10.1101/2024.11.16.24317338v1