Can Light and Sound Therapy Treat Alzheimer’s Disease? Part 2

(Posted on Tuesday, November 14, 2023)

Despite decades of research, investigators have been challenged to pinpoint the underlying causes of Alzheimer’s disease, and importantly, how to reverse it. It has been well established that beta-amyloid plaques and tau neurofibrillary tangles accumulate in the brains of those with Alzheimer’s. These toxic proteins block cell-to-cell signaling and trigger inflammation, causing significant damage to otherwise healthy brain cells. In advanced stages of Alzheimer’s disease, protein buildup that begins in the hippocampal learning and memory centers spreads through the rest of the brain leading to devastating neurodegeneration, or brain cell death.

Increasing evidence, however, suggests that the prevalence of beta-amyloid plaques and neurofibrillary tangles may be a consequence, rather than the cause, of Alzheimer’s disease. These proteins often start appearing decades before symptoms develop, and the degree that which they accumulate in the brain has not been shown to correlate with increased cognitive decline or neurodegeneration. Moreover, beta-amyloid targeting therapies often do not alter disease progression. Current FDA-approved drugs only treat symptoms associated with cognitive, behavioral, and psychological changes. Not to mention, these drugs are expensive and may not be effective for every individual diagnosed with Alzheimer’s. For example, the newly FDA-approved anti-amyloid intravenous treatment, lecanemab (brand name Leqembi), is projected to cost $26,000 per year, but strict eligibility requirements meant that only 17.4% of individuals with mild cognitive symptoms were able to participate in the clinical trials. Another drug called aducanumab, designed to clear beta-amyloid plaque, reportedly has been linked to increased brain swelling and bleeding in almost 40% of participants, suggesting that these drugs may not be safe.

Beta-amyloid plaques and tau neurofibrillary tangles may be a critical hallmark of Alzheimer’s disease, but there may be more to the story that we are only just beginning to uncover. Now the field seems to be open to new hypotheses that may explain how Alzheimer’s disease develops and progresses. From malfunctioning lysosomes to excessive inflammation to mitochondrial problems, our understanding of this disease continues to evolve.

Now, an emerging theory suggests that synchronized light and sound therapy may slow cognitive decline and neurodegeneration in mild to moderate Alzheimer’s disease. Unlike a drug or injection one would have to take every day, Cognito Therapeutics led by MIT researchers recently unveiled a specialized headset that delivers 40Hz auditory and visual stimulation directly to the brain. Recent clinical trials show promising results, but the underlying mechanism remains unclear. An emerging theory suggests that Alzheimer’s disease and related neurocognitive disorders may be linked to changes in how neurons communicate.

Neurons communicate by sending electrical signals across the nervous system. Millions of neurons may be firing throughout the brain at any given moment. The summation of these electrical nerve impulses creates rhythmic patterns of brain activity, called neural oscillations or “brain waves”. The subsequent electrical activity can be recorded and visualized using electrophysiological devices. When different groups of neurons start firing at the same time, distinct brain waves form. During periods of deep sleep, for example, the brain is less active allowing specific regions to synchronize their firing. This generates high amplitude, slow waves, known as Delta waves. While active and alert, on the other hand, the brain is processing information from multiple different inputs, so brainwaves occur much faster at smaller amplitudes.

Brainwaves are categorized based on frequency, or the number of times the wave repeats itself within a second. Simply put, faster waves have a higher frequency. At the highest range, gamma waves are generated when your brain is hard at work. Ranging from a frequency of 30 to 100 Hz, synchronization of gamma waves has been shown to correlate with enhanced cognitive function. Electrophysiological studies reveal that, during memory-related tasks, gamma waves play a critical role in bottom-up processing to detect stimulus inputs and top-down processing that interprets those inputs.

Emerging studies have found that abnormal brain activity, particularly related to reduced gamma wave activity, may be a hallmark of several neurocognitive conditions, including Alzheimer’s disease. In fact, there is evidence that changes to gamma wave patterns may occur well before the formation of amyloid and tau particles and the onset of cognitive symptoms. Compared to cognitively normal mice, Alzheimer’s mice models exhibit reduced gamma power, suggesting that neural activity is less synchronized, one study reports. As a result, MIT Professor and Neuroscientist Dr. Li-Huei Tsai and her team speculated that if gamma wave activity is reduced in Alzheimer’s disease, perhaps, artificially stimulating the brain may enhance synchronized firing and restore cognition.

How do you effectively stimulate the brain to induce long-lasting changes in neural activity? Several animal studies of Alzheimer’s disease have found that exposure to white-LED lights flickering at 30 to 50 Hz can enhance gamma activity in regions of the brain involved in learning and memory. It has been proposed that the increased synchronization of brain waves may offer a neuroprotective effect. Investigators found that 40 Hz light flickers, in particular, can generate consistent benefits to cognitive function and reduce the build-up of amyloid plaques. The mice used in these experiments were engineered to overexpress the gene that produces amyloid beta precursor proteins in humans (APP), as well as other Familial Alzheimer’s Disease (FAD) genes known to cause disease by inheritance. This allowed researchers to replicate the development of beta-amyloid plaques and corresponding neurodegeneration hallmarked by this disease. In early development, these mice models do not exhibit any signs of cognitive impairment often associated with Alzheimer’s disease, consistent with human pathology.

In one study, for example, Iaccarino et. al at MIT placed Alzheimer’s mouse models in a dark chamber with only a single LED light. The mice were exposed to one of five experimental conditions for an hour: fully dark, fully light, 20 Hz light flicker, 40 Hz light flicker, or 80 Hz light flicker. After the stimulation, investigators found that the mice that were exposed to the 40 Hz flight flicker condition had less plaque formation following the treatment. They also observed an increased recruitment of microglial cells, critical for regulating brain development and responding to nerve damage.

In a subsequent study, Martoell et. al replicated these findings using 40 Hz auditory stimulation. Mice in this study were exposed to 20 Hz, 40 Hz, or 80 Hz sound frequencies. Consistent with previous studies, the mice exposed to 40 Hz auditory stimulation performed better on spatial and recognition memory tasks and exhibited a marked reduction in amyloid plaque development. Compared to mice in other conditions, those that underwent 40Hz stimulation were more resilient to cognitive decline over time. To their surprise, investigators also reported that enhanced gamma activity was only observed when the mice were exposed to 40 Hz auditory and visual stimulation at the same time.

As the field has moved towards clinical trials, researchers and engineers at Cogntio Therapeutics designed a headset that could deliver personalized light and sound therapy. The results from ongoing Phase 3 clinical trials have yet to be revealed. It is possible that a future where Alzheimer’s disease could be treated at home for a relatively low cost may be closer than we can imagine.

Although early animal and clinical studies provided strong evidence that brain activity may be a possible target for treating Alzheimer’s disease, recent efforts to reproduce these results have been inconsistent. Larger studies are needed to validate the effectiveness of this novel therapeutic approach. Not to mention, there are still several questions regarding the underlying mechanism of this technology that remain. Next in this series, we will explore how light and sound therapy may generate molecular and structural changes in the brain.

Read the original article on Forbes.