Our meta-analysis investigated the potential impact of PDE5Is on the risk of AD. According to our findings, the use of PDE5Is significantly reduced the risk of AD in comparison to those who did not use it. Upon subgrouping the medications into sildenafil, vardenafil, and tadalafil, only sildenafil was found to reduce the risk of AD significantly. interestingly, subgrouping by sex showed significant effects for female but not male participants. However, these results are limited by the low number of studies.

Significant heterogeneity in the primary analysis limited the robustness of our studies. Some of the heterogeneity was resolved by the exclusion of Braun et al. [20]. The results of this study were not significant. While most studies investigated the use of PDE5Is in ED or benign urological conditions, this study was conducted among prostate cancer patients. The study included a low number of participants (5,937) men enrolled in the Cancer of the Prostatic Strategic Urologic Research Endeavor registry (CaPSURE) from 1998 to 2019. It is worth mentioning that the participants were not randomly selected and represented a younger and healthier cohort with lower incident AD rates compared to the general population. Consequently, there is a possibility that cases of AD might have been missed in this study.

Similarly, Adesuyan et al. [21], which had a young population, also reported a significant but weak negative association between the use of PDE5Is and the risk of AD. Adesuyan et al. [21] discovered that there was a reduced risk of AD in older adults who used sildenafil, but there was no significant evidence for a reduced risk with tadalafil or vardenafil. The association varied across different subgroups, with sildenafil showing a reduced risk in older men and individuals with a history of hypertension and diabetes.

Our overall findings may be affected by the dosage used and the duration of use, which requires further investigation. the current studies have some limitations that need to be considered when interpreting the results. For instance, all of the studies except Adesuyan et al. [21] did not investigate dose–response relationships due to the complexity of studying multiple drugs and the need for recorded data on the duration of PDE5I treatment. They recommended further studies to explore the role of single versus multiple prescriptions of PDE5Is and dose–response analyses. They conducted all analyses assuming individuals remained exposed after PDE5I initiation, regardless of subsequent discontinuation or treatment changes, similar to an intention-to-treat approach in randomized clinical trials.

The dose–response relationship between PDE5Is and their cognitive effects finds resonance in animal trials. In a recent systematic review of mice trials, two PDE5Is, icariin and icariside II, were found to have better cognitive effects with larger doses [9]. These drugs were associated with better resulting maze tests and decreased hippocampal deposition of β-amyloid -an important hallmark of AD. Notably, PDE5Is, particularly sildenafil, can cross the blood–brain barrier. Additionally, Sildenafil has been shown to suppress Aβ-42 and p-Tau, which play crucial roles in AD pathogenesis [23]. This suppression leads to the clearance of protein aggregates, shedding light on potential mechanisms underlying the effects of PDE5Is on AD risk.The observed reduction in AD risk aligned with previous research suggesting potential therapeutic effects of PDE5I. Fang et al. [19] found that sildenafil might have therapeutic effects in reducing the risk of AD. They evaluated the association between sildenafil usage and the risk of AD by analyzing data from large patient databases. Their findings showed that sildenafil usage was significantly associated with a reduced risk of AD, with a 69% reduction in risk. Even after adjusting for comorbidities like coronary artery disease, hypertension, and type 2 diabetes, sildenafil usage was still linked to a decreased risk of AD across various drug cohorts. These findings suggested that sildenafil might offer a potentially beneficial effect in reducing the risk of AD.

Henry et al. [18] noticed that patients with AD had a decreased likelihood of using PDE5Is compared to those without AD across all three FDA-approved indications for PDE5Is. This association was consistent in both males and females, with either sildenafil or tadalafil among patients with different comorbidities. Huo et al. [22] also found that sildenafil was significantly associated with a 62% lower risk of Alzheimer's disease in men and a 47% lower risk in women. It is worth mentioning that this study relied on retrospective data from the IBM MarketScan Database, which might have inherent biases and limitations in data accuracy. Additionally, the study did not account for potentially confounding variables such as lifestyle factors, genetic predisposition, or other medications that could influence the risk of Alzheimer's disease.

PDE5Is have established efficacy in the treatment of various conditions, such as erectile dysfunction (ED) and pulmonary hypertension [6]. However, considering the potential role of PDE5Is in preventing AD, it is important to consider the long-term side effects. Generally, PDE5Is are considered safe drugs, and commonly reported adverse events include headache, dizziness, and flushing [24]. Nonetheless, it is important to note that rare adverse events, such as hearing loss and priapism, may occur. Till now, the available evidence suggests that long-term use of PDE5Is is generally safe [25], but caution should be exercised, particularly of contraindications such as concomitant use with nitrates or alpha-blockers [26]. Our study is the first systematic review and meta-analysis aimed at exploring the risk of AD in users of PDE5Is compared to non-users. We included six studies with a substantial number of participants. Previous systematic reviews [11, 12] did not incorporate any longitudinal human studies or perform a meta-analysis of the available evidence. Additionally, we investigated the importance of the type of PDE5Is and the sex of participants. Although our initial findings suggest a potential association between PDE5I use and a decreased risk of AD, it is essential to exercise caution when interpreting these results due to the following limitations:

Firstly, the limited number of available studies restricted our ability to thoroughly investigate publication bias. Secondly, our analysis displayed high heterogeneity, which prompted us to conduct subgroup and sensitivity analyses. Although heterogeneity was not resolved, we deemed it appropriate to proceed with the meta-analysis considering the comparable designs of the included studies. Thirdly, the observational study designs employed in the included studies do not establish causal relationships but rather indicate associations. However, given the nature of our study, this design was the most practical and suitable approach. Fourth, the quality of evidence evaluated using the GRADE approach was determined to be very low for all outcomes. As the first meta-analysis on this topic, this underscores the importance of additional high-quality studies to strengthen the overall evidence base. Lastly, due to limited available data, we were unable to assess the dose–response relationship or the duration of PDE5I use.

Overall, while our study has notable limitations, it provides valuable insights into the current understanding of the association between PDE5I use and AD. As the world population continues to grow, the need for strategies to prevent AD development will increase [3]. PDE5Is are relatively safe, inexpensive, and widely accessible drugs [7] that can potentially play a role in these future prevention strategies.

Further research with larger sample sizes is necessary to enhance the robustness of the evidence in this field. Rigorous study designs and comprehensive assessment of dose–response relationships and treatment duration are also needed. It is important to investigate the relationship between PDE5I use and other types of dementia. Additionally, exploring the role of age, sex, and other covariates should be considered to determine the effectiveness of PDE5Is in reducing the risk of AD. By addressing these research gaps, we can advance our understanding of the potential benefits of PDE5Is in preventing AD and develop more targeted and effective approaches to combat this devastating neurodegenerative disease.