Some Alzheimer's disease therapies in research may be more effective when combined with a treatment aimed at improving the drainage of fluid (and waste) from the brain, according to a mouse study.

Experimental drugs for Alzheimer's have shown little success in slowing memory and cognitive decline, leaving scientists searching for explanations.

However, new findings published in Nature suggest that the brain's drainage system, known as the meningeal lymphatic system, plays a crucial yet underappreciated role in the neurodegenerative disease, and that repairing "clogged drains" could be key to unlocking the potential of certain Alzheimer's therapies.

"THE LYMPHATIC SYSTEM IS HOW THE BRAIN CLEANS UP ITS GARBAGE. IF IT'S NOT WORKING, EVERYTHING GETS CONGESTED." “Lymphatics are a drain,” says co-senior author Jonathan Kipnis, a professor of pathology and immunology at the Washington University School of Medicine in St. Louis and BJC investigator. “Alzheimer's and other neurodegenerative diseases like Parkinson's and frontotemporal dementia are characterized by protein aggregation in the brain. If you break up these aggregates but have no way of getting rid of the debris because your drain is clogged, you haven’t done much. You need to unclog the drain to really solve the problem.”

Sticky amyloid plaques begin to form in the brains of people with Alzheimer's two decades or more before symptoms like forgetfulness and confusion arise. For years, scientists have tried to treat Alzheimer's by developing therapies that remove these plaques, but success has been very limited.

One of the most promising candidates, aducanumab, recently showed efficacy in slowing cognitive decline in a clinical trial but failed in another, leaving scientists puzzled.

Kipnis, who is also a professor of neurosurgery, neurology, and neuroscience, identified the 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 between Alzheimer's patients. But proving this hunch has been challenging, as there are no tools to directly measure the health of a person’s meningeal lymphatics.

In this study, Kipnis and his colleagues took an indirect approach to check the drainage system in the brains of Alzheimer's patients.

Thinking that the effects of clogged drainage might extend to microglia, the cells that act 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: they seem to slow the growth of amyloid plaques in the early stages of the disease but worsen neurological damage later on. The researchers disabled the meningeal lymphatics in one group of mice genetically predisposed to form amyloid plaques, leaving functional lymphatics in another group for comparison, and analyzed the gene patterns expressed by microglia.

Lymphatic dysfunction changed the microglia into a state more likely to promote neurodegeneration. Furthermore, when co-senior author Oscar Harari, assistant professor of psychiatry and genetics, compared gene expression patterns in microglia from mice and people, including 53 people who died with Alzheimer's disease and nine who died with healthy brains, the microglia of people resembled those of mice with damaged lymphatics.

“We found a signature in the microglia of mice with meningeal lymphatic ablation,” says Harari. “When we harmonized the human and mouse microglial data, we found the same signature in the human data.”

Another type of cell, endothelial cells lining the inside of lymphatic vessels, provided further evidence of the importance of the brain's drainage system. Co-senior author Carlos Cruchaga, professor of psychiatry, genetics, and neurology, identified the most highly expressed genes in lymphatic endothelial cells from mice. He found that genetic variations in many of the same genes have been linked to Alzheimer's disease in humans, suggesting that issues with the lymphatic vessels could contribute to the disease.

“In the end, while we are analyzing specific cell types and pathways, the brain is a large organ,” says Cruchaga. “The lymphatic system is how the brain cleans up its garbage. If it’s not working, everything gets damaged. If it starts working better, then everything in the brain works better. I think this is a very good example of how everything is connected, and everything impacts brain health.”

To find out if boosting lymphatic function could help treat Alzheimer's disease, the researchers studied mice genetically predisposed to develop amyloid plaques and whose lymphatics were impaired due to age or injury. They treated the animals with mouse versions of the experimental Alzheimer's drugs aducanumab or BAN2401, along with vascular endothelial growth factor C, a compound that promotes the growth of lymphatic vessels. The combination therapy reduced amyloid deposits more than the anti-amyloid drugs alone.

“There have been several antibodies that seem very effective at reducing amyloid deposits in mouse studies and now in humans,” says co-author David Holtzman, professor and chair of the Department of Neurology. “Some now also seem to delay cognitive decline in people with very mild dementia or mild cognitive impairment due to Alzheimer’s disease. However, the cognitive effects are not large, and one wonders if the dysfunction of the meningeal lymphatic system may partly account for the somewhat limited effects on cognition currently being observed. The meningeal lymphatic system seems to influence not only the progression of the amyloid component of Alzheimer's pathology but also the response to immunotherapy.”

“Perhaps a better understanding of this system is part of what’s missing in the field of Alzheimer's drug development, and with greater attention to this system, we will better translate some of these promising drug candidates into therapies that provide meaningful benefits to people living with this devastating disease.”

Support for the work came from the National Institute on Aging of the National Institutes of Health, PureTech Health, Cure Alzheimer’s Fund, Ed Owens Family Foundation, and Archer Foundation.

Unclogging the brain's 'drain' enhances Alzheimer's meds - Futurity