No new drugs to treat Alzheimer’s disease have been approved since 2003. It’s not for lack of trying: Hundreds of clinical trials have tested potential new therapies.
The numbers are startling: Alzheimer’s drug candidates have a 99.6 percent failure rate, according to research published in Alzheimer’s Research & Therapy. In contrast, cancer drug trials have an 81 percent failure rate.
Why do these trials fail? Alzheimer’s is a complex disease that’s still not fully understood. The changes to the brain happen over decades. This makes it hard to diagnose the disease, identify “targets” for Alzheimer’s drugs and to know when administering the drugs which will be most effective.
There is one positive thing to emerge from these trials: The failures of some of these drugs have provided important insights for researchers. Here are some of the reasons the trials have failed–and what we’ve learned.
- The therapy starts too late
Some trials fail because treatment began too late. Increasingly, the research shows that the therapies being tested may be better suited to preventing or slowing the progression of Alzheimer’s in very early-stage patients. But these patients often don’t display symptoms, making it harder to identify them. This means that some of the “failed” compounds actually may work, if given to the right patient. That leads to the second issue.
- The patients in the trials aren’t the ideal candidates
Enrolling the right patients in trials may be essential, but it’s also difficult. It’s especially tough to find early-stage patients. Until recently, this has been a huge hurdle. Not only were some of the patients too far along–some of those enrolled didn’t have Alzheimer’s. That’s because it’s hard to make a diagnosis based solely on symptoms.
But that’s changing. The National Institute on Aging (NIA) at National Institutes of Health (NIH) and the Alzheimer’s Association are updating their guidelines for the diagnosis of Alzheimer’s disease in research. The new guidelines call for identifying physiological changes in the blood, cerebrospinal fluid and the brain instead of symptoms. These developments make it easier to identify and enroll pre-symptomatic patients and exclude those who may not have the disease.
- The presence of other types of dementia may impair treatment
There are many types of dementia, and new research (published last year in the Journal of Neuroscience) suggests that Alzheimer’s patients who also have vascular cognitive impairment and dementia (VCID) don’t benefit from the treatments being tested. At least 40 percent of Alzheimer’s patients are believed to have VCID.
- It may be time to look for other targets
Amyloid-beta –protein pieces–has been the focus of most Alzheimer’s drug-development efforts for more than 20 years. Amyloid-beta can interfere with the synapses–the part of the nerve cell involved in transmitting signals to other nerve cells. In addition, it clumps together and forms deposits in the brain, producing the plaques Alzheimer’s is known for.
But given the failures in recent years, researchers are looking at other potential targets, including the tau protein. Tau accumulation is also associated with Alzheimer’s disease. Studies looking at both tau and amyloid-beta in patients are now underway.
- One target at a time is not enough: Cocktail time
Until very recently, Alzheimer’s trials have tested only tested one drug at a time. But in cancer, HIV and other conditions, multi-drug “cocktails” have been successful. This may make sense for Alzheimer’s. For instance, if both amyloid-beta and tau are culprits, could both be targeted at the same time? Researchers are exploring the possibility.
Next steps
Five FDA-approved Alzheimer’s drugs are on the market today, but they only treat the symptoms, not the underlying causes. Current studies are looking at prevention — or at least dramatically slowing the disease’s progression.
In addition to the research into amyloid-beta and tau, scientists are looking at some other approaches.
For instance, evidence continues to demonstrate that brain health is tied to heart and blood vessel health. In fact, the Alzheimer’s risk appears to increase as a result of hypertension, heart disease, diabetes and other conditions that damage the heart or arteries. Several studies are exploring this connection. Some are looking at the impact of hypertension medication on preventing or treating Alzheimer’s disease. They are also looking at whether lifestyle factors with known heart benefits–exercising on most days and eating a heart-healthy diet–may help prevent or delay Alzheimer’s disease.
Researchers – -and, of course, patients and families– hope these new approaches, coupled with the lessons from past failures–will yield a way to prevent and/or cure Alzheimer’s.
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