New Data Could Support the Role Of Viagra for Alzheimer’s Prevention.

New evidence suggests that sildenafil (Viagra), the famous little blue pill used to treat erectile dysfunction (ED), may have a role in preventing Alzheimer’s disease (AD).

What is Alzheimer’s disease (AD)?

Alzheimer’s disease (AD) is a progressive neurodegenerative condition marked by memory loss, cognitive decline, and difficulties with visuospatial tasks¹. The neurological alterations in Alzheimer’s disease (AD) entail the accumulation of amyloid-β (Aβ) plaques and the hyperphosphorylation of tau proteins, forming neurofibrillary tangles, leading to eventual neurodegeneration.²

Sildenafil and its effects on AD

Sildenafil, a selective PDE5 inhibitor, has shown promising effects in various preclinical models of Alzheimer’s disease (AD), including modulating neuronal plasticity, reducing tau phosphorylation, improving cognitive impairment, decreasing amyloid-β (Aβ) plaque accumulation, and enhancing the level of brain-derived neurotrophic factor (BDNF).³

In a recent large-scale analysis of patient data from two databases, researchers found a 30%-54% reduced prevalence of AD among sildenafil users compared to non-users, even after adjusting for potential confounding factors. Mechanistic studies also showed decreased levels of neurotoxic proteins in brain cells exposed to sildenafil, supporting its potential neuroprotective effects.⁴

Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center and lead researcher of the study, highlighted the significance of these findings, emphasising the need for new therapies for AD. Using artificial intelligence to analyse data across multiple domains, the study provides further support for repurposing sildenafil as a treatment for AD.

The study published in March 2024 utilized real-world patient data from two databases, MarketScan Medicare Supplemental and Clinformatics, spanning different time periods. Propensity score-stratified analyses showed that sildenafil use was associated with a reduced likelihood of AD compared to control drugs.

Specifically, sildenafil demonstrated a 54% reduced incidence of AD in the MarketScan database and a 30% reduced prevalence in the Clinformatics database compared to control drugs like spironolactone.

These findings align with previous research indicating a potential protective effect of PDE5i treatment on AD risk. However, they contradict an earlier study published in Brain Communications in 2022, which found no link between ED medications and reduced AD risk.

The study also revealed that sildenafil reduced tau hyperphosphorylation in AD patient-induced pluripotent stem cell (iPSC)-derived neurons in a dose-dependent manner. RNA-sequencing data analysis further supported sildenafil’s targeting of AD-related genes and pathways, providing mechanistic insights into its beneficial effects on AD.

A previous study demonstrated that sildenafil increased neurite growth and decreased phospho-tau in AD patient iPSC-derived neurons, supporting its potential beneficial effect in AD.⁵ In vivo studies in mouse models have also shown improvements in memory, amyloid plaque load, inflammation, and neurogenesis with sildenafil treatment.⁶ Additionally, pilot trials have indicated beneficial effects of sildenafil in AD treatment, showing reduced neural activity in the hippocampus and improved cerebral metabolic rate and blood flow.⁷

The results indicate that sildenafil could be a promising candidate for repurposing in Alzheimer’s disease treatment, backed by evidence from both iPSC-derived neuron models and real-world patient data. However, Cheng emphasised the need for clinical trials to investigate sildenafil’s effectiveness in AD patients further.

References:

1. DeTure MA , Dickson DW ((2019) ) The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 14: , 32.
2. Rajmohan R , Reddy PH ((2017) ) Amyloid-beta and phosphorylated tau accumulations cause abnormalities at synapses of Alzheimer’s disease neurons. J Alzheimers Dis 57: , 975–999.
3. Cuadrado-Tejedor M , Hervias I , Ricobaraza A , Puerta E , Pérez-Roldán JM , García-Barroso C , Franco R , Aguirre N, García-Osta A ((2011) ) Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer’s disease. Br J Pharmacol 164: 2029–2041.
4. Gohel, Dhruv et al. ‘Sildenafil as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons’. 1 Jan. 2024 : 643 – 657.
5. Fang J, Zhang P, Zhou Y, Chiang CW, Tan J, Hou Y, Stauffer S, Li L, Pieper AA, Cummings J, Cheng F ((2021) ) Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease. Nat Aging 1: 1175–1188.
6. García-Barroso C, Ricobaraza A, Pascual-Lucas M, Unceta N, Rico AJ, Goicolea MA, Sallés J, Lanciego JL, Oyarzabal J, Franco R, Cuadrado-Tejedor M, García-Osta A ((2013) ) Tadalafil crosses the blood-brain barrier. It reverses cognitive dysfunction in a mouse model of AD. Neuropharmacology 64: , 114–123.
7. Samudra N, Motes M, Lu H, Sheng M, Diaz-Arrastia R, Devous M, Hart J, Womack KB ((2019) ) A pilot study of changes in medial temporal lobe fractional amplitude of low-frequency fluctuations after sildenafil administration in patients with Alzheimer’s disease. J Alzheimers Dis 70: 163–170.