Sildenafil halves AD risk

A systematic review and meta-analysis conducted by researchers from Singapore demonstrates an association between treatment with sildenafil, a phosphodiesterase-5 (PDE5) inhibitor, and the risk of Alzheimer's disease (AD).

“Our meta-analysis [of five studies (n=885,380)] showed that the use of sildenafil is associated with a reduced risk of developing AD by twofold,” said the researchers.

A pooled analysis of three studies (n=873,667) yielded a hazard ratio of 0.47 (95 percent confidence interval [CI], 0.27-0.82), corresponding to a p-value of <0.001. [Aging (Albany NY) 2025;17:726-739]

When all five studies were pooled, the risk of developing AD was numerically lower among participants who had been treated with PDE5 inhibitors as opposed to those who had not (risk ratio [RR], 0.70, 95 percent CI, 0.32–1.52; p<0.01). On sensitivity analysis that excluded one outlier (n=615,655), the reduction in AD risk among PDE5 inhibitor users vs nonusers became significant (RR, 0.55, 95 percent CI, 0.38–0.80; p=0.002).

The risk of developing AD remained significantly lower among male PDE5 inhibitor users vs nonusers (RR, 0.48, 95 percent CI, 0.32–0.72; p=0.002) in the sensitivity analysis.

Far-reaching effects

“The impact of AD is far-reaching, with secondary effects on caregivers, employment opportunities, and society. Therefore, it is imperative to manage and reduce the development of AD in at-risk patients,” the investigators explained.

Although the WHO has designated AD as a public health priority, there are currently no definitive treatments. [https://www.who.int/publications/i/item/dementia-a-public-health-priority, accessed 14 July 2025]

Among the PDE5 inhibitors, sildenafil has been shown to reduce the levels of amyloid-β peptide, a hallmark of AD, in the hippocampus of mouse models, the researchers noted. “Multiple pathways linked to the activity of sildenafil have been implicated, and the nitric oxide synthase/nitric oxide/cyclic guanosine monophosphate signalling pathway has been demonstrated to be key in slowing the progression of AD.”

What about other dementia subtypes?

The current meta-analysis supports the neuroprotective effect of sildenafil. However, it remains unclear whether sildenafil could reduce the risk of developing other subtypes of dementia, the researchers pointed out.

Animal studies have shown that sildenafil improved cognition and memory in mice with vascular dementia. It also promoted neurogenesis and improved neurological functional outcomes in mice who had ischaemic stroke. [Neurochem Int 2019;127:103-112; Stroke 2002;33:2675-2680]

More studies are thus warranted to ascertain the effect of sildenafil on AD pathology. “Further randomized controlled trials (RCTs) to ascertain if sildenafil use can reduce amyloid load in the brain will provide more conclusive evidence supporting its neuroprotective effect,” the investigators said.

“Future double-blind RCTs using a standardized diagnostic and monitoring protocol with correlation of imaging and biological markers will provide new insights. The dosage effect of sildenafil on the clinical and amyloid load on neuroimaging can also be further examined,” they added.

The researchers also recommended future studies evaluating the role of sildenafil in other dementia subtypes. Moreover, considering the low percentage of female participants in the meta-analysis, future studies should include more female participants, in view of the inherent risk of AD development in women. [Dialogues Clin Neurosci 2016;18:437-446; Front Glob Womens Health 2024;4:1324522]