Light and sound may slow Alzheimer’s by making the brain remove toxins

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A cross-section of a mouse’s brain highlighting neurons that seem to release a molecule that increases toxin clearance

Tsai Laboratory/MIT Picower Institute

A new explanation has emerged for why an experimental treatment for Alzheimer’s disease involving sounds and flickering lights may help slow cognitive decline. The frequencies involved seem to ramp up the brain’s waste disposal networks, which boosts the clearance of beta-amyloid and other toxic proteins that contribute to memory and concentration problems.

“Once we understand the mechanism, we can probably figure out how to further optimise this whole concept and improve the efficacy,” says Li-Huei Tsai at the Massachusetts Institute of Technology.

The treatment involves exposing people to lights flickering at a frequency of 40 times a second, or 40 hertz, and a low-pitched sound, also at 40 Hz. Typically, the stimulation is given for an hour a day.

Key to the novel approach is that large networks of brain cells naturally fire in sync with each other at different frequencies – known as brainwaves. Brainwaves of around 40 Hz are often seen when people are concentrating and when they are forming or accessing memories.

As it was known that visual or auditory stimulation at a certain frequency can boost brainwaves at that same frequency, in 2016, Tsai’s team decided to investigate if 40 Hz stimulation might boost cognitive abilities in people with Alzheimer’s.

Their group and others showed that this lowered amyloid build-up in mice with a version of Alzheimer’s and had cognitive benefits in small trials in people with the condition, with a larger trial ongoing. But it was unclear how the treatment might work, with another idea being that it boosts the function of the brain’s immune cells.

Now, it seems the special lights and sound work by enhancing the function of the brain’s drainage system, also known as the glymphatic system.

In the latest work, Tsai’s team carried out a series of experiments to study the treatment’s mechanism in mice that had been genetically altered so that they usually develop a build-up of amyloid as they get older and have worse memories than typical mice.

As expected, when the animals were exposed to the light and sounds, they had less amyloid. The new finding was that during the treatment, they had a greater amount of cerebrospinal fluid entering the brain and more waste fluid leaving it through the glymphatic vessels.

This seemed to be happening because nearby blood vessels were pulsating more, which could help push the glymphatic fluid through its vessels, and because of more water flowing into the glymphatic system.

The team also found that the activity of a specific type of brain cell, known as an interneuron, seemed to be triggering the increased glymphatic flow by releasing a molecule called vasoactive intestinal peptide. When the team chemically blocked this molecule’s production, the treatment no longer boosted amyloid clearance.

Maiken Nedergaard at the University of Rochester in New York, who helped discover the glymphatic system, says the finding fits with what we already know about it.“The brain, blood and cerebrospinal fluid are all contained within the skull. If the blood volume expands, the volume of the cerebrospinal fluid has to move since brain tissue is not compressible.”

In an accompanying article in Nature Medicine, Nedergaard says a better understanding of the mechanisms of toxin clearance in the brain “could be the key that unlocks [their] therapeutic potential”.

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