Actress Rita Wilson became an ambassador for the Alzheimer’s Association after her mother died of the disease in 2014. To lower her risk of developing the disease, she eats healthfully and exercises. She also keeps an eye on the latest research. Here’s what she’s finding.
For decades, researchers have doggedly studied various drugs and therapies to treat Alzheimer’s disease, which affects 5.8 million people in the United States, according to an annual report released by the Alzheimer's Association. That number is expected to rise to 14 million by 2050.
Despite years of study, no effective treatment has emerged. And in January 2018, the pharmaceutical giant Pfizer announced it would halt funding for investigations into Alzheimer’s and Parkinson’s disease. The news was disappointing, but not surprising to many people in the research community.
Scientists initially focused on eradicating clumps of the amyloid-beta protein that form plaques on the brain, which contribute to the disease. While some of the drugs reduced the accumulation of amyloid, none succeeded in stopping or reversing dementia.
“In the search for potential causes of dementia and Alzheimer’s disease the notion that the accumulation of abnormal proteins such as amyloid and tau might be toxic for nerve cells and cause dementia gained such momentum in the scientific community that it became the conventional wisdom,” says Zaven S. Khachaturian, PhD, former director of the Office of Alzheimer Research at the National Institutes of Health and the current editor-in-chief of the journal Alzheimer's & Dementia.
While amyloid-beta clumps have been implicated in Alzheimer’s, their role remains unclear, says Eliezer Masliah, MD, director of the division of neuroscience at the National Institute on Aging. “Are they killing neurons, or are they good markers of the disease? They are definitely part of the disease process, and they are definitely good markers. We need to understand if they’re good targets for therapeutics or not.”
Other trials have focused on tau, a protein that forms threads that get tangled inside neurons, impeding their ability to communicate with one another. Studies looking at anti-tau drugs have only recently begun early stage clinical trials which primarily focus on safety.
Only five drugs have been approved by the US Food and Drug Administration (FDA) to treat the cognitive symptoms of Alzheimer’s. Three of them—donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon)—are from a class of drugs called cholinesterase inhibitors. They prevent the breakdown of acetylcholine, an important chemical messenger in the brain associated with learning and memory. A fourth drug—memantine (Namenda)—regulates another chemical messenger, glutamate, which is also important for information processing, storage, and memory retrieval. The fifth FDA-approved drug is a combination of donepezil and memantine. All five drugs address early symptoms only; none has been shown to be effective in the long run.
Despite Pfizer pulling out, researchers are hopeful they will find a cure one day. The National Institute on Aging’s budget for 2019 is $3.08 billion, three times higher than in 2013. About $425 million is designated for Alzheimer’s and related dementias research.
“We have not been hugely successful in terms of intervention, but that’s okay. We are far better in terms of understanding some of the elements of pathophysiology that we didn’t know before,” says Arthur W. Toga, PhD, provost professor of neurology, behavioral sciences, and radiology at the University of Southern California (USC) in Los Angeles and director of the neuroimaging laboratory at USC’s Keck School of Medicine. “We know about the accumulation of amyloid-beta and tau in the brain, and we can chart it using imaging. We can measure changes in these and related proteins in cerebral spinal fluid, and we can witness changes in the structure of the brain as the disease progresses,” he says. “We also know about dysregulation of the blood-brain barrier altering the brain’s ability to clear the accumulation of misfolded proteins.”
All this information gives researchers a better handle on disease-modifying therapies, Dr. Toga says, allowing them to try the drugs earlier in the hopes that it might slow progression.
“One of the holy grails is to find a noninvasive way to definitively diagnose the disease,” says Dr. Khachaturian. The thinking is that earlier detection will lead to more effective and earlier interventions.
In the past, a definitive diagnosis of Alzheimer’s could only be determined in an autopsy. Now, researchers can detect tau in PET imaging scans and analyze cerebral spinal fluid for levels of certain biomarkers for the disease—tau tangles, amyloid-beta, and neurofilaments—in the living brain, says Dr. Masliah. “That’s a huge advance in the field.”
Researchers are also focusing on the role that systemic inflammation may play in the brain, says Dr. Masliah. They theorize that inflammation and vascular changes limit the amount of energy the brain receives, which can kill nerve cells. “This is one of the most extraordinary advances in the field,” he says. “A lot of treatment focuses on amyloid, but we are beginning to realize we need to target inflammation and the vascular pathology.”
These diagnostic tools are still only used in clinical trials, says Dr. Masliah. A PET scan for Alzheimer’s is not part of standard diagnosis in the primary care setting—it’s not FDA approved or covered by insurance. “But the FDA has approved brain scans for amyloid and tau as well as spinal taps for clinical trial studies.”
And investigators continue to explore the important role that lifestyle may play in the disease. Finding out which behavioral changes in a person’s lifestyle could reduce the risk of dementia is important, says Dr. Khachaturian, but the research will have to prove more than an association. “Diet, lifestyle, and exercise have positive effects. They may delay onset. But we should be studying the underlying biology of these factors to understand the detailed molecular mechanisms that lead to their protective effects.”
For more about Alzheimer’s disease, read Alzheimer's Disease: The Basics, our one-page resource about the disorder.
