Affecting more than 5.5 million US citizens and around 44 million people worldwide , Alzheimer’s disease (AD) involves the pathological formation and deposition of beta-amyloid plaques in the brain, which slowly disrupt neural connections. However, procedures aiming to reduce amyloid-β have failed to reverse cognitive symptoms, indicating that cognitive decline is a more complex process than previously thought . Previous studies suggest that patients affected by the diseases exhibit not only abnormal brain function due to the plaques, but also an impairment in gamma oscillations — the brain waves that stand at the basis of elementary functions such as memory and attention. Studies related to gamma oscillations on mice models of Alzheimer’s disease elicited substantially reduced plaques in the visual cortexes of the subjects even before the onset of plaque formation . Determining how gamma oscillations affect molecular pathology in mice could have serious implications in possible treatment strategies.
Amyloid-β (Aβ) is a fragment of the amyloid-β precursor protein (APP). In its natural state, amyloid is a common component and plays a number of beneficial roles in the human body, including antimicrobial defence .
At the beginning of its life, Aβ is a solitary molecule. Later it starts congregating into soluble mobile clusters of small dimensions  and eventually forms the pathological plaques characteristic of Alzheimer’s.
Gamma Oscillations in the Brain
Distinct regions of the brain communicate with each other through the coordination of neural activity in certain populations of neurons. When the firing of these neurons is synchronized, the brain starts producing ‘rhythms’— fast fluctuations in the activity of said groups— found in the extracellular electric fields, which can be detected by performing sets of noninvasive procedures on the scalp (electroencephalography, or EEG) or invasive intracranial recordings within the brain itself . Alzheimer’s studies typically focus on the gamma oscillations, the component of these rhythms that corresponds to frequencies ranging from 30 Hz to 100 Hz. These neural vibrations play a central role in the normal evolution of cognitive processes like memory, consciousness, perception, and attention.
Several studies on neurodegenerative diseases have found disrupted gamma oscillations but have not yet determined the exact coaction between the hippocampal circuit property and the pathology . In the case of Alzheimer’s, the molecular pathology can be altered by any changes in the synaptic activity of the brain .
The Brain Wave Stimulation
Mice can be genetically programmed to develop AD and examined in the early developmental stages of the disorder as well as after amyloid starts accumulating and characteristic symptoms like memory deficits develop. Scientists observed impaired gamma rhythms during the essential learning processes generated when running a maze and then studied the correlation between the quantity of amyloid in the brain and the performance of the gamma oscillations level .
A first step included stimulating the hippocampal area—which is responsible for forming and retrieving memories—with gamma oscillations at a frequency of 40 Hz for an hour. This stimulation technique, co-pioneered by Edward Boyden and also known as optogenetics, is a precise, noninvasive way to control activity in populations of neurons by directing light beams towards them . The procedure resulted in a 40%-50% decrease in the levels of amyloid-β proteins in the affected areas.
Even though the stimulation at other frequencies did not lead to the same favorable results, these preliminary experiments opened the way towards looking for alternatives to produce the same outcomes through less invasive techniques. One of the first such devices consisted of a strip of LED lights set to flicker at distinct frequencies and to drive oscillations to the brain .
In the case of Alzheimer’s, amyloid is produced more abundantly, while the microglia—immune (glial) cells of the central nervous system, with roles against certain infections, and meant to clear out the excess protein in the brain —inflame and drop in efficiency. Researchers found that gamma entrainment produces results both by lowering the amyloid-β generation rate and by enhancing the abilities of the microglia.
Subjects were treated as follows :
a) Those suffering from early-stage AD underwent therapy for an hour. The procedure managed to halve amyloid levels in their visual cortices, and the effect lasted for around 24 hours before returning to the initial state.
b) The mice found in more advanced phases of the disease were subjected to longer-term treatments—an hour a day for the duration of a week. This lead to decreases in the quantity of both amyloid plaques and free-floating protein in the brain.
The same steps were repeated on multiple models of mice, leading to similar outcomes .
Studies conducted on gamma entrainment demonstrate that inducing non-invasive light flickers to the visual cortex at 40 Hz result in substantial declines in the amount of amyloid-β peptides.
By extrapolation, the ability to replicate the experiment on various types of mice could mean that these improvements are not particular for one specific category of vertebrates, encouraging further research in this direction.
However, because gamma oscillation stimulation is unlike any other medical approach in the domain, it is yet to be determined whether it can be used as a therapeutic means in human Alzheimer’s disease cases.
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