Having witnessed the success of combination therapy in HIV, cancer and heart disease, the time has come for Alzheimer’s disease. At meetings convened by the Alzheimer’s Association and others, a consensus is emerging that the most effective Alzheimer’s treatments may be those that attack the disease on multiple fronts.

Looking back for a moment… In the 1980s, the world faced a new, unknown virus. HIV/AIDS was spreading virtually unchecked, devastating millions of lives and spurring lively scientific debate. Today, an HIV diagnosis is no longer a death sentence. AIDS-related deaths have fallen by 45 percent since their peak in 2005 according to UNAIDS, a United Nations program for global action against the spread of the virus. 

As researchers learned more about HIV, they developed new classes of antiviral medications—each attacking the virus in a unique way. Physicians eventually began prescribing two or more of these drugs together and emerging scientific evidence started revealing the most effective combinations. Today, a powerful three-drug antiviral “cocktail” is allowing people with HIV to live long lives.

Advances in understanding the progression of Alzheimer’s point to a number of underlying biological processes involved in the development of the disease. By leveraging this knowledge, we now have a singular opportunity to pioneer new approaches against Alzheimer’s, including combination therapies.

The Alzheimer’s Association has partnered with the Alzheimer’s Drug Discovery Foundation (ADDF) to challenge the research community to propose promising drug combinations to find more-effective treatments.

The joint effort, known as the Alzheimer's Combination Therapy Opportunities (ACTO) grant initiative, will provide $2 million this year for testing approaches that simultaneously target two or more processes believed to underlie, exacerbate, or occur in the disease. An ACTO-funded study must involve repurposed drugs—those that have been determined safe for use in treating other conditions. With some information about safety already available, there is the potential to deliver new treatments more quickly than testing novel drugs, which take an average of 12 years to make it to pharmacy. ACTO will announce its initial award the first half of 2017.

The predominant theory of how Alzheimer’s develops is that buildup of two characteristic lesions in the brain—amyloid plaques and tau tangles—leads to the death of nerve cells. Plaques are deposits of a protein fragment called beta-amyloid that build up in the spaces between nerve cells; tangles are twisted fibers of another protein called tau that build up inside the cells. The majority of Alzheimer's drug candidates currently being tested in clinical trials target species of amyloid and/or the plaques.

Numerous other studies suggest brain inflammation and problems with blood circulation in the brain play a role in the disease’s progression. Other studies have identified an additional abnormal protein in the brains of people with the disease—and that this protein may explain why some people have Alzheimer’s changes in their brain but do not experience dementia. Because of the complexity of Alzheimer’s and its multiple causal factors, it may not only be preferable to use combination therapy, but necessary.

Research on potential Alzheimer’s combination therapies in mouse models is showing promise. One study in mice found that using a combination of experimental anti-amyloid drugs could more effectively reduce amyloid plaque buildup and prevent new plaques from forming than either candidate alone. A second study in mice found that using leptin, a hormone that inhibits hunger, in combination with pioglitazone, an approved diabetes drug, could reduce both amyloid plaque accumulation and brain inflammation.

Our hope is that testing multi-drug approaches is just the initial stirring of the innovation pot for Alzheimer’s combination therapy. Currently, the best evidence for reducing the risk for cognitive decline as we age through lifestyle is also a combination approach, including regular physical activity, mental stimulation, and a brain/heart-healthy diet. [alz.org/10ways] This begs the question, could Alzheimer’s combination therapy also take the form of drug therapy plus lifestyle changes? A combined lifestyle-drug approach is now common for lowering risk of heart disease; many people pair healthy diet and exercise with cholesterol and/or blood pressure medications.

While combination therapy for Alzheimer’s is a promising strategy, studying it presents unique challenges. These include both science- and business-related obstacles.

For example, few companies have a diverse enough pipeline of Alzheimer’s therapeutic agents in development to carry out combination therapy trials alone. Most would need to collaborate with another company or research center while protecting their intellectual property. Fortunately, partnership models exist in ongoing Alzheimer’s prevention trials where companies, academic researchers, government, non-profits and private charities have joined forces to test potential Alzheimer’s drug therapies. This approach makes it possible for companies to negotiate intellectual property concerns and spread the risk of therapy development across multiple stakeholders. Nonetheless, there remain many issues to untangle in this area.

Another challenge is determining which treatment combinations to test. In April 2015, the Alzheimer’s Association convened an expert workgroup of leaders from academia and industry, and a former member of the U.S. Food and Drug Administration, to identify challenges and solutions to developing Alzheimer’s combination therapies. The group recommended that researchers collaborate to bring forward combinations of drug candidates previously tested in Alzheimer’s animal models and with known safety in humans. These candidates, they said, would yield the best chances for success and ensure speedier clinical trials.

At the same time, we need more basic research to better understand how Alzheimer’s develops and progresses. Calling on lawmakers to increase federal Alzheimer’s research funding is something virtually anyone can do. Those who want to get involved can visit alz.org/advocacy.

We are at a juncture of unprecedented promise in Alzheimer’s research. A few decades ago, we knew virtually nothing about how Alzheimer’s develops or progresses. Today we are looking at the possibility of combination therapies that attack the disease in multiple ways. With continued commitment from government, companies, academic researchers, and nonprofit research funders, we can unlock the combination to better Alzheimer’s therapy.

 

This post includes excerpts from “Challenges, solutions, and recommendations for Alzheimer’s disease combination therapy,” a review article published in March 2016 in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.