Alzheimer's Researchers Probe New Treatment Paths
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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 Carrillo, the Alzheimer’s Association’s chief science officer.
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. But new data have 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.
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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. 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.
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https://www.wsj.com/articles/alzheimers-researchers-probe-new-treatment-paths-11653220802 (subscription)
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