Sildenafil Shows Potential as Alzheimer Disease Preventive Therapy

The therapy, already FDA-approved for individuals with pulmonary artery disease, was significantly associated with reduced likelihood of Alzheimer disease in both the 65-74 year range and those older than 75 years.

Using a developed endophenotype molecular network-based methodology, investigators concluded that sildenafil (Revatio) is a promising drug candidate for prevention and treatment of patients with Alzheimer disease (AD).1 The results, presented at the 2021 Alzheimer’s Association International Conference (AAIC), July 26-30, support a proof-of-concept of endophenotype-based drug discovery as well.

Presenting author Feixiong Cheng, PhD, assistant professor, Department of Molecular Medicine, Cleveland Clinic, and colleagues validated their network-based predictions of promising AD drug candidates using state of-the-art pharmacoepidemiologic analysis of 7.23 million US commercially insured individuals. Five comparison analyses were conducted: sildenafil (n = 116,412) vs a matched control (n = 460,356); sildenafil vs diltiazem (Cardizem; Valeant); sildenafil vs losartan (Cozaar; Merck) (n = 664,265); sildenafil vs glimepiride (Amaryl; Hoechst); and sildenafil vs metformin (Glucophage; Merck) (n = 723,082).

After 6 years of follow-up, investigators found that sildenafil use was significantly associated with a 69% reduced risk of AD compared with matched non-sildenafil use (hazard ratio [HR], 0.31 [95% CI, 0.25-0.39]; P <1 x 10-8). Specifically, the drug had a 65% reduced risk of AD compared to diltiazem (HR, 0.35 [95% CI, 0.29-0.44]; P <1 x 10-8), a 55% reduced risk compared to losartan (HR, 0.45 [95% CI, 0.35-0.55]; P <1 x 10-8), a 64% reduced risk compared to glimepiride (HR, 0.36 [95% CI, 0.28-0.45]; P <1 x 10-8), and a 63% reduced risk compared to metformin (HR, 0.37 [95% CI, 0.30-0.45]; P <1 x 10-8) in propensity score-stratified cohort studies.

Across all 5 drug cohorts, individuals with coronary artery disease (CAD), hypertension (HT), and type 2 diabetes (T2D) all had reduced likelihood of AD when using sildenafil. These results remained consistent even after excluding CAD, HT, and T2D. Notably, sildenafil usage was also significantly associated with reduced likelihood of AD in both mid-older (65-74 years) and older individuals (75-100 years).

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Sildenafil has 2 market names, including Viagra, which is used to treat erectile dysfunction, and Revatio, which is used to improve the ability to exercise in adults with pulmonary arterial hypertension (PAH). The therapy is in a class of medications called phosphodiesterase (PDE) inhibitors and treats PAH by relaxing the blood vessels in the lungs to allow blood to flow easily.

There have been several research projects that have evaluated in the drug in AD capacities. When administered to the Tg2576 transgenic mouse model of AD and to age-matched negative littermates (controls), the drug completely reversed their cognitive impairment.2 Such changes were accompanied in the hippocampus by a reduction of tau hyperphosphorylation and a decrease in the activity of glycogen synthase kinase 3ß (GSK3ß) and of cyclin-dependent kinase 5 (CDK5). Additionally, sildenafil increased levels of brain-derived neurotrophic factor and the activity-regulated cytoskeletal-associated protein in the hippocampus without any detectable modification of brain amyloid burden.

Most recently, investigators conducted a systematic review of sildenafil studies in AD, which showed the drug to significantly improve amyloid-beta levels except for the 2 that used the highest dosage.3 The therapy also decreased spontaneous neural activity, increased cerebral blood flow, and increased the cerebral metabolic rate of oxygen. Among all the data collected, investigators concluded that a randomized controlled trial of sildenafil, ideally with a PDE2 inhibitor, in patients with AD is warranted.

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REFERENCES
1. Cheng F, Fang J, Zhang P, et al. Sildenafil reduces the incidence of Alzheimer’s disease. Presented at 2021 AAIC Annual Meeting; July 26-29. Abstract 254
2. Cuadrado-Tejedor M, Hervias I, Ricobaraza A, et a. Sildenafil restores cognitive function without affecting B-amyloid burden in a mouse model of Alzheimer’s disease. Br J Pharmacol. Published May 31, 2011. doi: 10.1111/j.1476-5381.2011.01517
3. Sanders O. Sildenafil for the treatment of Alzheimer’s disease: a systematic review. J Alzheimers Dis Rep. Published online April 22, 2020.