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Erectile dysfunction drugs were associated with reduced risk of Alzheimer's disease, electronic health record (EHR) data from 270,000 men in the U.K. suggested.

Over a median follow-up of about 5 years, men who started taking phosphodiesterase type 5 (PDE5) inhibitors were less likely to have an Alzheimer's diagnosis than nonusers (adjusted HR 0.82, 95% CI 0.72-0.93), reported Ruth Brauer, PhD, of the University College London, and co-authors.

Alzheimer's risk dropped further for men who had more than 20 prescriptions for PDE5 inhibitors, the researchers wrote in . For those issued 21-50 prescriptions, the HR was 0.56; for those with more than 50 prescriptions, the HR was 0.65.

PDE5 inhibitors are anti-hypertensive agents. Four -- sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra) -- are approved to treat erectile dysfunction because of their vasodilatory effects on the corpus cavernosum. Sildenafil also is approved to treat pulmonary arterial hypertension (PAH).

In rodents, sildenafil has been shown to improve memory and cognitive function, help synaptic plasticity and learning, and reduce amyloid burden. Tadalafil also has improved memory and lowered amyloid in animal studies. "However, evidence of neuroprotective effects in humans is not conclusive," Brauer and colleagues wrote.

The findings conflict with ones reported from a recent NIH DREAM study, which showed no difference in Alzheimer's and dementia diagnosis rates with PDE5 inhibitors compared with other PAH drugs among Medicare recipients.

But they're in line with a previous case-control analysis of insurance claims data that suggested sildenafil users were 69% less likely to develop Alzheimer's disease than non-users, noted Sevil Yasar, MD, PhD, and Lolita Nidadavolu, MD, PhD, both of the Johns Hopkins University School of Medicine in Baltimore, in an .

"One major limitation of all three studies is that they have all used insurance claims or EHR data, which relies heavily on diagnosis by providers, which may lead to underdiagnosis or misdiagnosis of dementia, thus leading to misclassification bias," Yasar and Nidadavolu wrote.

Brauer and colleagues studied 269,725 men in U.K. primary care records with a new diagnosis of erectile dysfunction between 2000 and 2017. Patients with a history of cognitive impairment or dementia were excluded. Those who had a prescription for a PDE5 inhibitor (sildenafil, tadalafil, vardenafil, or avanafil) were compared with those who didn't.

The mean age at cohort entry was 58.5 years. Median follow-up was 5.1 years, during which 1,119 men were newly diagnosed with Alzheimer's disease.

Overall, 749 men exposed to PDE5 inhibitors developed Alzheimer's, which corresponded to a crude incident rate of 8.1 per 10,000 person-years at risk. Among unexposed men, 370 developed Alzheimer's, corresponding to a crude incident rate of 9.7 per 10,000 person-years.

The primary result was consistent in a sensitivity analysis that included a 1-year lag period to partly account for prodromal Alzheimer's, but not one with a 3-year lag.

In subgroup analyses, Alzheimer's risk was lower than those who started on sildenafil compared with men who didn't use PDE5 inhibitors (adjusted HR 0.81, 95% CI 0.71-0.93). PDE5 inhibitor exposure in men ages 70 and older, and in those with a history of hypertension or diabetes, also was associated with a lower risk of Alzheimer's.

Additional data from in vitro and in vivo studies could strengthen analyses that examine links between PDE5 inhibitors and Alzheimer's, the editorialists noted. "These include in vitro studies exploring the role of inflammation and clearance of beta-amyloid," Yasar and Nidadavolu wrote. Blood and cerebrospinal fluid biomarkers of inflammation and endothelial function or imaging to assess neuroinflammation and vascular changes also could help evaluate potential mechanisms associated with PDE5 inhibitor use.

"In the end, however, further observational studies exploring mechanisms will not prove a causal association," they emphasized. "A well-designed randomized controlled trial is needed before [PDE5 inhibitors] can be prescribed for Alzheimer's disease prevention."

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