Experimental Alzheimer’s drugs have shown little success in slowing declines in memory and thinking, leaving scientists searching for explanations.
The new findings in the journal Nature, however, suggest that the brain’s drainage system—known as the meningeal lymphatics—plays a pivotal but underappreciated role in neurodegenerative disease, and that repairing faulty drains could be a key to unlocking the potential of certain Alzheimer’s therapies.
“THE LYMPHATIC SYSTEM IS HOW THE GARBAGE IS CLEANED OUT OF THE BRAIN. IF IT’S NOT WORKING, EVERYTHING GETS GUMMED UP.
“The lymphatics are a sink,” says co-senior author Jonathan Kipnis, professor of pathology and immunology at Washington University School of Medicine in St. Louis and a BJC Investigator. “Alzheimer’s and other neurodegenerative diseases such as Parkinson’s and frontotemporal dementia are characterized by protein aggregation in the brain. If you break up these aggregates but you have no way to get rid of the debris because your sink is clogged, you didn’t accomplish much. You have to unclog the sink to really solve the problem.”
Sticky plaques of the protein amyloid start forming in the brains of people with Alzheimer’s two decades or more before symptoms such as forgetfulness and confusion arise. For years, scientists have tried to treat Alzheimer’s by developing therapies that clear away such plaques but have had very limited success.
One of the most promising candidates, aducanumab, recently proved effective at slowing cognitive decline in one clinical trial but failed in another, leaving scientists baffled.
Kipnis, who is also a professor of neurosurgery, of neurology, and of neuroscience, identified meningeal lymphatics as the brain’s drainage system in 2015. A few years later, in 2018, he demonstrated that damage to the system increases amyloid buildup in mice. He suspects that the mixed and often disappointing performance of anti-amyloid drugs can be explained by differences in lymphatic function among Alzheimer’s patients. But proving this hunch has been challenging, as there are no tools to measure the health of a person’s meningeal lymphatics directly.
In this study, Kipnis and colleagues took an indirect approach to checking the drainage system in the brains of Alzheimer’s patients.
Thinking that the effects of a clogged drain might spill over onto microglia, the cells that serve as the brain’s cleanup crew, the researchers looked for evidence of lymphatic damage in the form of altered patterns of microglial gene expression. Microglia play a complicated role in Alzheimer’s disease: They seem to slow the growth of amyloid plaques early in the course of the disease but worsen neurological damage later on. The researchers disabled the meningeal lymphatics of a group of mice genetically prone to forming amyloid plaques,
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