The scientist who uses light to fight Alzheimer’s


Li-Hue Tsai, from the Massachusetts Institute of Technology, tests a non-invasive treatment to appease the symptoms of the disease with visual and auditory stimuli.

Every morning, Li-Hue Tsai tastes a little of his own medicine. The neuroscientist sits in front of a device that emits pulses of light in front of her eyes at a frequency of 40 hertz. In recent years, Tsai, who runs the Picower Institute of Learning and Memory at the Massachusetts Institute of Technology (MIT), has discovered that visual stimulation with LED light eliminates the buildup of amyloid proteins in the brains of mice, a lesion similar to that of people with Alzheimer’s. The intervention also reduces the tangles of tau protein, another defining feature of the disease. Animals even recover part of their memory and cognitive capacity. The finding is very preliminary – neuroscientists have lost count of the times that Alzheimer’s has been cured in mice without this translating into a valid treatment for people – but it is a glimmer of hope in a bleak panorama.

Alzheimer’s treatment by light

Every three seconds a new case of dementia is diagnosed in the world, up to 80% of the total is due to Alzheimer’s disease. More than a century after the disease was discovered and after several decades of research, not a single effective treatment has been achieved. Its causes are not even clear. In addition to the accumulation of the two mentioned proteins, the brain suffers inflammation, diabetes-like symptoms and others that could be due to viral or bacterial infections. The situation is devilish, because the disease begins to develop about 20 years before patients notice the first symptoms. When they are diagnosed it is already too late.

Tsai (Taipei, Taiwan, 1960) believes that Alzheimer’s probably has several causes, which is not a single disease, but several, such as cancer. His scientific career, developed in the US, began with the research of CDK5, a molecule found in cancer cells that was crucial for both the normal development of the brain and its pathologies. If you modify the genetics of the mouse to produce much of this enzyme, the animals lose their memory, their neurons die en masse and the brain is filled with plates of amyloid protein, the closest thing to Alzheimer’s in rodents. Since coming to MIT in 2006, Tsai has sought ways to avoid these symptoms with non-invasive interventions in the brain. Before offering a conference at the Ramón Areces Foundation on aging and memory, the researcher explains to Materia her approach to one of the greatest social challenges of our era.

I do not think that Alzheimer’s can be cured, but I can control it so that it does not affect too much in daily life

Question: Do you think it is possible to cure Alzheimer’s?

Answer: It is very unlikely. To say that we can cure Alzheimer’s disease is like saying that we can cure aging; very unrealistic. But I do believe that we should be able to find ways to control the disease, much like type two diabetes, cardiovascular disease or atherosclerosis. There must be ways to manage it so that it does not affect you too much in daily life.

Question: Women have twice the risk of Alzheimer’s disease than men. Do you know why?

Answer: There may be many different reasons. My laboratory published a genetic analysis of all cells of the prefrontal cortex of 48 people, half with high amyloid protein, half without it. Half were men and the other, women. One of the most surprising results is that women have a much higher burden of disease, at least in the levels of gene expression. This study suggests that the way we treat women may be different from the way we treat men.

Question: Your team is testing a non-invasive method against Alzheimer’s and Parkinson’s. What does it consist of?

Answer: It is based on a decade of research with totally unexpected results. When neurons fire synchronously, they generate waves that move through the brain. There are many different frequencies that cover several orders of magnitude. One of these frequencies are the gamma rhythms, which range between 30 and 80 hertz. These waves are especially intense during intense cognitive activities such as when we use working memory [that deals with reasoning and decision-making], attention or spatial thinking. And we discovered that in mice model of Alzheimer’s disease this activity is interrupted in the presymptomatic stage, before they show cognitive deterioration or a manifest pathology.

Question: And what did they do then?

Answer: The first thing was to try to restore these gamma rhythms using optogenetics [a technique that implants light electrodes in the brain to control it]. We could not believe it, because when we improved gamma activity, amyloid levels were reduced. We also discovered that other types of brain cells, such as microglia [immune brain cells], respond strongly, change their appearance, their morphology, their function, they become more capable of engulfing amyloid, which contributes to the elimination of protein.

Women have a much higher burden of disease

Question: But optogenetics requires brain surgery …

Answer: Yes. But we discovered that it is possible to use a non-invasive method to induce gamma waves in the brain. Initially we used flashes of LED light at a frequency of about 40 hertz and we showed that by doing so, neurons fire exactly at 40 hertz in the visual cortex. These induced waves have a similar effect in reducing amyloid levels and also in the reduction of tau protein. Then we discovered that if the animals receive the stimulation every day, in a few weeks the increase in activity is transmitted to the rest of the brain, to the prefrontal cortex [epicenter of complex thinking] and we observed a reduction of amyloid and tau in different parts of the brain . This year we just published another article that shows that it is also possible to obtain similar results using acoustic stimulation, with sounds at 40 hertz. When we combine the two stimulations we can see that the gamma wave travels very rapidly through the brain and the effect is so powerful that it can prevent neurons from dying.

Question: What does light or sound have to cause these effects?

Answer: I do not think it’s light or sound, it’s how neurons are activated at a particular frequency due to light and sound. There are some specific biochemical changes in those cells or in other neurons that may release certain factors to recruit other types of cells. Microglia [cerebral immune system] happens to produce less inflammatory cytokines and neurons improve their synaptic function. They also show a very robust synaptic plasticity, greater gene expression and much less cell death. The blood vessels also respond firmly, dilate and increase blood flow. That also plays an important role in getting rid of a lot of junk in the brain, like amyloids and other protein aggregates, and it probably also provides more new nutrients to the neurons and helps them work.

Question: Have you tried it in humans?

Answer: At MIT we initially tested whether the method is safe for people and we have seen that it is extremely safe. We are now recruiting patients with Alzheimer’s in early stages to test it. We hope to have results next year. If they are positive, the next step is to expand the study to a larger population to see how people respond and define if there is a certain profile of people who respond better than others. As I said, Alzheimer’s is a very complicated collection of diseases and it is very unlikely that a particular treatment will work for everyone.

Question: Do you use the LED light?

Answer: It’s the first thing I do in the morning if I’m at home, where I have a device. I can tell you how I feel, but I want to warn you that this is only anecdotal, it is not controlled, so it has no scientific validity. I feel like I can sleep better. I feel I can organize better. I feel that I can work more efficiently.

With technology, human intelligence could be different in the future

Question: Can memory loss and dementia be prevented?

Answer: Clearly exercise, eat nutritious foods, lead an active social life is really very powerful at least to delay the onset of cognitive decline. It was shown by a very famous study called Finger [English acronym of Finnish Study of Geriatric Intervention to prevent cognitive deterioration and disability, which analyzed more than 2,000 people between 60 and 77 years old].

Question: Can treatments be created to recover forgotten memories and experiences?

Answer: In mice we have shown that if we change chromatin remodeling [the structure of DNA organization within the nucleus of each cell] we can facilitate the recovery of lost memories. Because what is memory? Most likely it is stored in the synapses, the connections between neurons. During aging and neurodegeneration many connections are lost. But if we can somehow empower the brain to reconnect, then memory recovers. At least experimentally it is possible. It’s a question of how to translate it to people. I think our light and sound therapy can do some of that. So I hope it works to help recover memory and learning.

When we combine light and sound stimulation we can see that gamma waves travel very quickly through the brain and prevent neurons from dying

Question: Do you think that thanks to technology, human intelligence will be greater than it is today?

Answer: With technology, human intelligence could be different. I suspect that younger generations have a brain connected very differently to our generation. You grew up with video games, screens. We did not have any of that, when we were little we played in the streets full of mud. I think our brains are connected differently. That is why it is likely that in this generation different types of memory capacities and different types of brain functions are improved, but also our generation probably has something that is being lost in the new generation.

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