Alzheimer’s Researchers Probe New Treatment Paths

GAP President John Dwyer was quoted in the Wall Street Journal speaking about how the Centers for Medicare and Medicaid Services coverage decision limits Alzheimer’s patients.

The commercial failure of Biogen Inc.’s drug Aduhelm is putting new focus on the state of research into the causes of Alzheimer’s disease.

More than six million people in the U.S. are living with the progressive type of dementia, according to the Alzheimer’s Association, an advocacy group.

Aduhelm was hailed as a potential blockbuster that targeted a root cause of the disease by clearing a sticky protein known as amyloid from the brain. Abnormal accumulations of amyloid called plaque and tangles of another protein known as tau are characteristic features of the brains of people with Alzheimer’s.

“If you cut the brain open and amyloid plaque is absent, Alzheimer’s was not the cause of disease,” said Jeffrey Cummings, director of the Chambers-Grundy Center for Transformative Neuroscience at the University of Nevada, Las Vegas.

But research into the benefits of targeting amyloid in Alzheimer’s patients has been mixed. There are more questions than answers about the role amyloid plays in the development of the disease, neurologists say.

“Alzheimer’s is a complex disease. It’s unlikely that a single mechanism is contributing to it,” said Maria Carillo, the Alzheimer’s Association’s chief science officer.

Research assistants at the Alzheimer’s Disease Research Center at Columbia University examine amyloid plaque staining images.

Other potential causes and risk pathways that Alzheimer’s researchers are probing include dysfunctional tau metabolism and the possibility that tau buildup can spread among cells like an infection. There are also theories that Alzheimer’s could be a form of diabetes or the result of a viral infection. Exposure to toxic substances, head trauma and lifestyle factors like diet and exercise have also been identified as possible risks. The Centers for Disease Control and Prevention said Friday that getting more aerobic exercise and managing high blood pressure could reduce the impact of some risk factors for Alzheimer’s.

The amyloid hypothesis, posited in the 1990s, proposes that amyloid-plaque formation leads to a cascade of negative effects including the accumulation of tau, inflammation, cell death and the loss of synapses, the junctions through which nerve cells known as neurons communicate with each other.

“It was so compelling that it triggered the pharmaceutical industry to act,” said Scott Small, director of the Alzheimer’s Disease Research Center at Columbia University.Advertisement – Scroll to Continue

But new data has poked holes in the hypothesis. A 2020 meta-analysis of 14 clinical trials involving drugs that target amyloid found the medications largely effective at clearing at least some plaque, but the drugs mostly had no or a small effect on cognition among Alzheimer’s patients.

Two clinical trials involving Aduhelm were included in the analysis. One showed no cognitive benefit to patients, while the other suggested some benefit. Biogen halted the trials after an independent data-monitoring committee concluded the drug wasn’t helping patients.

Amyloid is secreted by neurons in brains both healthy and diseased. Excessive buildup of the protein or the inability to sufficiently clear it can lead to problems, according to researchers. But amyloid plaque has also been found in the brains of healthy people. Some research has suggested that a small amount of amyloid inside neurons could be necessary for brain health, Dr. Small said.

A slice of human cerebellum can be seen washed and mounted on a slide for study.
Dr. Sabrina Simoes, assistant professor of neurological sciences at Columbia University, explains how to use a new tool for detecting biomarkers in Alzheimer’s disease research.

For patients with a rare, inherited form of Alzheimer’s, research has linked certain genetic mutations to amyloid-plaque formation. For most Alzheimer’s patients, however, it is less clear what might trigger amyloid buildup.

Dr. Small and others think clues could be found inside neurons, in a system known as the endosomal-recycling pathway. Dr. Small compared a neuron to the New York subway system, where endosomes, a type of specialized structures inside cells, are a major junction.

“Proteins are flowing in and out, lines are converging at Grand Central Station,” he said. “If you have a defect there, you get traffic jams.”

Enlarged endosomes have been found in the brains of many Alzheimer’s patients, Dr. Small said. The pileups appear to promote amyloid buildup as well as synaptic loss. Causes of the jams could include rare genetic mutations as well as diabetes and obesity, Dr. Small said. Head injury and the gut microbiome—microorganisms that populate the gastrointestinal tract—could also play a role. Dr. Small is involved in Retromer Therapeutics Corp.’s work on a drug targeting a part of the endosomal recycling pathway.

Another theory is that a dysfunctional immune response involving cells called microglia could contribute to Alzheimer’s. Microglia account for about 10% of the cells found in the brain. They remove debris, pathogens and toxic proteins including amyloid plaque. When microglia aren’t functioning properly, possibly because of a genetic mutation or other age-related factors, their ability to clear plaque diminishes, said Beth Stevens, a neuroscientist at the Broad Institute of MIT and Harvard. Microglia are key players in neuroinflammation too, which can contribute to synaptic loss and cell death. They might also play a direct role in clearing synapses, which can lead to synaptic dysfunction and loss, Dr. Stevens said.

The buildup of amyloid might also impact microglia function, research has shown. “Amyloid can make these cells misbehave,” said Dr. Stevens. Future therapies for Alzheimer’s could involve enhancing the protective qualities of microglia and reducing their detrimental effects, she said.

More than 140 drugs are in the pipeline as potential Alzheimer’s treatments, including drugs that target tau and microglia function, according to a survey of registered clinical trials in the U.S. Three other amyloid-targeting monoclonal antibodies, which are in the same class as Aduhelm, are in development. One, called lecanemab, was submitted this month by co-developers Biogen and Japan-based Eisai Co. to the Food and Drug Administration for potential approval.

When the Centers for Medicare and Medicaid Services in April said it would limit coverage of Aduhelm to patients in clinical trials, it also said it would limit coverage of all monoclonal antibodies directed against amyloid. The public insurer said it could reconsider that decision if better data were presented.

A research assistant in the Alzheimer’s Disease Research Center at Columbia University views a slideshow during a lab meeting in Dr. Small’s office.

Some neurologists say the risks of amyloid-targeting monoclonal antibody treatments, including brain swelling, outweigh potential therapeutic benefits. Others say the drugs could have some positive effect, particularly if administered early in the disease’s progression. Researchers are attempting to identify potential biomarkers in the blood and cerebrospinal fluid that could be used to detect Alzheimer’s early. They say it could be a game-changer in Alzheimer’s treatment.

Even a small positive effect could benefit some patients given the dearth of other options, some neurologists say. No other therapy is expected on the market for at least five years, according to the Global Alzheimer’s Platform Foundation, which funds Alzheimer’s research.

“If you’re a patient with mild cognitive impairment, your only hope is one of these four drugs,” said John Dwyer, president of the foundation.

Originally posted by the Wall Street Journal on May 22, 2022.

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