A recent discovery published in the journal Nature has opened doors to the possibility that preventing and treating Alzheimer's disease could be as easy as wearing specialized eyewear that delivers fast flickers of light. A research team at the Massachusetts Institute of Technology (MIT) conducted a series of elegant experiments. Their results showed that exposing flickering light to mice genetically engineered to model Alzheimer's disease significantly reduced levels of the pathological proteins thought to drive the disease.

Big Break in Treatment of Alzheimer's Disease

These new findings from the MIT research team could be a big break in the field of Alzheimer's disease. Since the first case of Alzheimer's disease was identified over 100 years ago, the number of people with the disease in the United States has grown to more than 5 million and is expected to increase. Researchers have made substantial progress in characterizing the molecular and protein dysfunction that occurs in Alzheimer's disease, but none of the current FDA-approved treatments can reverse, stop, or even slow down its progression.

Its hallmark pathology are beta-amyloid proteins that clump together and form toxic plaques outside of cells, and abnormal tau proteins that clump together and form toxic tangles inside cells. The most longstanding theory of Alzheimer's disease posits that beta-amyloid protein abnormalities drive the tau protein abnormalities. In turn these drive other markers of brain dysfunction of Alzheimer's disease, such as neuroinflammation and cell death. Traditionally, the death of cells and synapses (parts of cells that allow communication with each other) are likely responsible for dementia, an integral part of the disease. Even before beta-amyloid clusters into plaques, however, certain fragments of beta-amyloid are produced at too high a level and disturb brain function. Previous studies have shown that the pathological increase of the beta-amyloid fragments can induce abnormal brain rhythms.

New Insight for Improving Brain Function

"We gained some insight into something that may be contributing to Alzheimer's disease, and restoring rhythms related to improving brain function," says Dr. Emery Brown, an MIT neuroscientist and a co-investigator of the study. "We can do [light flicker exposure] noninvasively and translate the findings to humans, so there's a great potential for preventative therapy."

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The flickers of light the mice were exposed to occurred at 40 Hz, or 40 flickers of light per second, a frequency that falls within the gamma frequency range occurring naturally in the brain. Gamma rhythms in the brain are prominent when a circuit of cells coordinate their activity, and they are theorized to relate to cognitive processes such as memory. Several studies in animal models of Alzheimer's disease suggest that weaker gamma rhythms could be a consequence of Alzheimer's disease. The results from the recent MIT experiments show that the relationship between neuropathology in Alzheimer's disease and gamma rhythms are not unidirectional. Instead, they show that restoring gamma brain rhythms can reduce the levels of these toxic beta-amyloid fragments and other measures of pathology—and make the brain of Alzheimer's disease mice look more normal.

Optogenetics Reduce Beta-Amyloid Levels

Before the MIT researchers used flickers of light to induce gamma rhythms in the visual cortex, they used optogenetics to activate neurons in the hippocampus, a brain region important for normal memory function that is disproportionately affected by Alzheimer's disease pathology. Optogenetics is a technique that involves genetically modifying certain neurons to express opsins, light-sensitive ion channels that influence the excitability of the neuron when exposed to light. The researchers could induce gamma rhythms in the hippocampus by pulsing a light at 40 Hz frequency through an optic cable inserted in the hippocampus of young Alzheimer's disease mice. When gamma rhythms were induced with optogenetics for just one hour, beta-amyloid levels were reduced by almost half.

The researchers also tested to see if there was something important about inducing activity within the gamma frequency range in particular to produce the therapeutic effect. When they pulsed light at a slower frequency, faster frequency, or random intervals, they did not see a reduction in beta-amyloid. Although the MIT researchers did not exhaustively test every frequency range of brain rhythms linked to cognition, the results show strong support that gamma rhythms play an especially important role in the Alzheimer's disease brain.

Restore Brain Rhythms to Prevent and Treat

These initial experiments with optogenetics were exciting and they offered proof of the principle that restoring brain rhythms could help prevent or treat the protein abnormalities of the disease. But as useful as it can be in animal studies, optogenetics is not a technique easily applied to humans. The question of translating the basic science results into clinical application prompted Dr. Brown to suggest closing that gap. Would testing a different, noninvasive technique produce the same results in the Alzheimer's disease mice?

"When [co-investigators Dr. Li-Huei Tsai and Dr. Edward Boyden] told me the results that they were seeing with Alzheimer's disease mice using optogenetic techniques, I asked, 'Why not try inducing 40 Hz by light or sound so that the technology could be applied clinically?'" His idea proved successful. Noninvasive exposure to light flickering at 40 Hz successfully reduced beta-amyloid in the visual cortex, just as the invasive optogenetic 40 Hz light pulses successfully reduced beta-amyloid in the hippocampus.

Potential Preventative Therapy

One of the most important implications of these experiments is the preventative potential of this therapy. The experiments were done in relatively young Alzheimer's disease mice, before key neuropathology and memory loss symptoms had developed. Some researchers have found evidence that amyloid levels may be elevated in people for many years, perhaps even decades, before symptoms become apparent. The slow progression of the disease may mean that brain dysfunction has already progressed too far by the time symptoms are detected for treatments to be effective. This is one reason a major focus of research is to find biological markers — preferably noninvasive — that could help clinicians detect the earliest stages of Alzheimer's disease before widespread and irreversible damage occurs.

The effectiveness of the light flicker therapy in the mice suggests that, if these findings can be successfully translated to humans, inducing gamma rhythms with light flickers or other means could tackle the disease far before symptoms emerge and the brain dysfunction has begun. "Perhaps someone with an increased risk for Alzheimer's disease could consider doing this treatment preventively," says Dr. Brown. The ability of these therapies to treat the disease once it has begun should not be ruled out either, however. When the light-exposure therapy was given for one hour each on seven subsequent days to mice old enough to show more robust neuropathology and cognitive impairments, the same successful reduction in beta-amyloid levels was observed.

Additional Benefit of Inducing Gamma Rhythms

It is still not entirely clear how inducing gamma rhythms in the brain helps reduce Alzheimer's disease pathology. The MIT researchers did show that the mice exposed to flickering light also showed a robust increase of microglia in the same brain region. Microglia support the health of neurons by clearing out foreign substances and toxic debris in the brain. Specialized techniques to visualize microglia and beta-amyloid showed that those in the mice often occurred together. These results offered further evidence that the microglia were actively attacking and clearing the harmful fragments.

Light Exposure: Limits and Possibilities

Notably, the light exposure reduced harmful beta-amyloid fragments in the visual cortex of Alzheimer's disease mice, but not in the hippocampus and somatosensory cortex, which do not receive visual information directly from the retina. Although it is possible that longer treatment would have eventually affected these regions, the results suggest that the therapeutic effect of inducing gamma rhythms with sensory input might be limited.

One intriguing possibility is that inducing 40 Hz oscillations in the brains through tactile stimulation or sound would show the same therapeutic effect and reduce beta-amyloid levels in the auditory or somatosensory cortices. Dr. Brown at MIT pointed to the low risk and lack of expense to directly test these sorts of questions on patients.

Plans are currently underway for clinical trials to test if inducing gamma rhythms with light flickers, or potentially other sensory modalities, will show the same benefits in humans with Alzheimer's disease as in a mouse model. According to Dr. Brown, the MIT researchers are hopeful that these findings will translate into effective therapies to prevent or treat Alzheimer's disease. "We're cautiously optimistic."

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