Some 55 million people worldwide have dementia. According to the Alzheimer’s Association, 7 million people in the United States alone are living with Alzheimer’s disease, the most common form of dementia. Newer monoclonal antibody drugs that clear the amyloid plaques characteristic of Alzheimer’s disease were hailed as the first disease-modifying treatments for the condition, but research has raised concerns about their side effects.
Now, a new study has identified and synthesized a molecule that restores cognitive function in Alzheimer’s disease model mice by increasing gamma oscillations.The study, by researchers from The University of California, Los Angeles (UCLA), is published in Proceedings of the National Academy of Sciences (PNAS).Gamma oscillations are high-frequency waves in the brain that play a role in many cognitive processes and working memory — the type of memory used when dialing a phone number you were just told, or remembering an address when being given directions.
Even in the early stages of Alzheimer’s disease, these oscillations are reduced, and studies have suggested that aberrant gamma oscillations may be an early biomarker of Alzheimer’s, detectable before amyloid plaques start to develop.
Some studies have improved cognitive ability in people with mild to moderate Alzheimer’s disease using repetitive transcranial magnetic stimulation (rTMS), which has been shown to modify gamma oscillations.
In this study, the researchers aimed to enhance gamma oscillations by another method — using a molecule that targeted fast-firing nerve cells that are critical in generating gamma oscillations.
The molecule they identified — DDL-920 — acted on chemical receptors in these nerve cells that respond to the inhibitory chemical messenger known as GABA and reduce the gamma oscillations. DDL-920 led to more powerful gamma oscillations from the nerve cells.The study tests a small molecule called DDL-920, which boosts these gamma oscillations. Unlike current FDA-approved treatments that focus on removing beta-amyloid plaques, DDL-920 targets brain circuitry in a different way.While this approach offers a fresh perspective on enhancing cognitive function and memory in Alzheimer’s, it’s important to note that the research is still in the early stages using mouse models.
Having established that DDL-920 increased gamma oscillations, the researchers then used an Alzheimer’s disease mouse model to determine whether this resulted in improved cognitive function.
They gave DDL-920 orally twice a day to 3-month old Alzheimer’s disease model mice. As a comparison, a similar number of AD model mice and wild-type mice were given a vehicle (inactive compound).
The mice were then tested in a Barnes maze — an elevated circular platform, with 20 holes, one of which leads to an escape tunnel — to assess their spatial learning and memory. After several days of training in a maze with an escape tunnel, the tunnel is closed. Learning and memory is then assessed by how long the mice spend in the region where the escape tunnel was.
Following treatment, the Alzheimer’s disease model mice could recall the location of the escape hole at the same rate as the wild-type mice. Untreated Alzheimer’s disease model mice took significantly longer.Treatments that target Alzheimer’s from all angles and all stages of the disease are essential, and that’s why strategic research funding that works to diversify the therapies in the pipeline is so important. All evidence-based paths to treatment of Alzheimer’s and all other dementia should be explored.The Alzheimer’s Association envisions a future where there are many treatments available that address these diseases in multiple ways, and can be combined into powerful combination therapies, most likely in conjunction with brain-healthy lifestyle guidance.
