Shingles vaccine proves most promising drug for prevention of Alzheimer’s disease

Alzheimer's disease impacts tens of millions of families throughout the world, and projections state that more than 100 million people will be affected by the year 2050. The impact is not merely a financial one, although global costs now top 800 billion dollars annually.

The true impact can be felt in the somber moments, when a name slips away, or when someone is unable to recognize the people who care for them. Currently available treatment options are limited, and for many individuals, a meaningful impact is never made. This reality has caused scientists to explore safer, simpler, and more accessible options.

The process of developing a new drug from nothing can take over a decade of testing and research, and even then, there is no guarantee. Repurposing medications that are already safe makes the pathway faster and far more hopeful for those waiting for better care. Repurposing has been done in many other therapeutic areas.

For example, many drugs that were developed for infections or blood disorders became important treatments for cancer, depression, and Parkinson's disease. Now, researchers wish to translate that work into Alzheimer’s science.

The team, led by researchers at the University of Exeter and fully supported by the Alzheimer’s Society and various National Institute for Health and Care Research centers, undertook the challenging task of identifying medicines that had been studied for various conditions that provide the most evidence for lowering the risk of Alzheimer’s or slowing the disease progression.

A newly published article in Alzheimer’s Research and Therapy describes the project. The goal was to identify currently available medicines that have been approved for other conditions and that have strong evidence for reducing Alzheimer’s risk or slowing disease progression.

To equitably and systematically assess the findings and reach a balanced conclusion, investigators used a structured Delphi process with dementia specialists from university, clinic, and industry-based research. Twenty-one experts participated in the assessment and discussed 80 existing pharmacotherapies over several rounds in a systematic way.

They reviewed whether each pharmacotherapy is thought to be protective in cell and animal models, whether it passes into the brain, whether it has known toxicity and safety in its use in older adults, and whether it has any evidence from human populations.

Ultimately, the expert panel was narrowed down to eight, then three pharmacotherapies. The final recommendations were a vaccine for shingles, sildenafil, and riluzole. Each pharmacotherapy works differently, and all three have long histories of off-label use in older adults.

The most robust candidates turned out to be the older live attenuated shingles vaccine, known as Zostavax. This live coattenuated vaccine was first approved to prevent shingles and its painful postherpetic neuralgia, but research indicates that after vaccination, people experience shingles at rates greater than 50%. Researchers suspect two courses of action may help to prevent disease in the brain.

There is a steadily growing body of evidence reporting that the varicella-zoster virus is related to increased risk for dementia because it alters immunological pathways that are protective to the brain. Zostavax may prevent both acute disease and chronic alterations to the immune pathways that impact the pathophysiology of dementia.

A review of nearly 1,000,000 vaccinated subjects reported a 16% decrease in the likelihood of subsequent diagnosis of dementia. The lower likelihood of dementia was replicated in other large study cohorts from the United Kingdom and Australia. Given that this vaccine has been safe for multiple years and requires no more than two doses, it was rated the most practical and promising candidate for a large clinical trial by experts.

Sildenafil, best known for its use in erectile dysfunction, was first trialed as a heart treatment. It utilizes a mechanism to allow for increased blood flow to the penis during arousal by inhibiting an enzyme that breaks down cGMP, a chemical messenger that promotes relaxation of blood vessels.

In an Alzheimer’s model, sildenafil appears to reduce the pathological change of tau, stimulate the growth of new nerve cells in the brain, and improve the brain’s use of oxygen. Some large insurance database studies suggest there may be a decreased risk of developing Alzheimer’s with long-term use, but the results have not been consistent. There are a few small human studies that have evaluated the drug’s effects specifically on brain function and overall cognitive changes, but clearly larger trials are warranted.

Riluzole, a longtime treatment for amyotrophic lateral sclerosis, also earned a place on the list. It affects several brain chemical pathways involved in stress, inflammation, and communication between nerve cells. In Alzheimer’s models, riluzole improves learning and memory, reduces oxidative stress, and lowers abnormal tau levels. A small trial in people with probable Alzheimer’s showed promising brain imaging results, though it was too small to confirm clear cognitive improvement.

In order to ensure that the scientific ranking was aligned with real-world priorities, the team had a lay advisory group of caregivers. The caregivers reviewed simple summaries of each candidate and communicated their concerns. They valued the shingles vaccine's potential for simplicity of administration—given only once or twice with no daily pills or regular blood tests required. 

The caregivers also appreciated the scientific rationale for the efficacy of riluzole based on its indirect action on nerve regeneration, and also the potential mechanistic rationale for sildenafil, while still having concerns about long-term use and monitoring. When asked to rank the candidates the caregivers selected the shingles vaccine first, sildenafil second, and riluzole third.

The experts who created the study now suggest clinical trials for all three candidates. Each medication has a different potential. The shingles vaccine can prevent dementia at the population level. The sildenafil and riluzole medications may both provide treatment options for people who are currently living with the disease, or pre-symptomatically in individuals at high risk for Alzheimer’s disease. 

Because all three drugs already have stable safety profiles, they can all be tested in a more timely manner, and additionally, new trial platforms like PROTECT can easily and cost-effectively monitor treatment and (non)-treatment of large groups of people online. 

Researchers caution that these three medications should not be routinely prescribed for the purpose of treatment. Regardless, the work shows genuine momentum and lays out a clearer path into a future for larger clinical trials that may provide a meaningful trajectory for progress much faster than relying solely on new agents.

If confirmed in trials, these three medicines could change how Alzheimer’s is prevented and treated. A simple shingles vaccine could lower dementia risk for millions of older adults and reduce the global burden of care.

Sildenafil and riluzole may offer new ways to protect nerve cells and slow decline. Because all three drugs already exist, they could reach the public far faster and at lower cost than new experimental therapies, making advanced care more accessible to people around the world.

Research findings are available online in the journal Alzheimer's Research & Therapy.

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