Alzheimer's & Dementia

New compound flips memory back on in Alzheimer's cases

A new molecule that switched memory and cognition back on in mice with Alzheimer's could one day do the same for humans, as illustrated in this generative image
A new molecule that switched memory and cognition back on in mice with Alzheimer's could one day do the same for humans, as illustrated in this generative image

Instead of focusing on fighting the plaques linked to Alzheimer's, researchers took a look at boosting electrical oscillations in the brain. The molecule they invented got the job done in mice, offering hope for a new treatment path for humans.

While it's becoming more and more clear that plaques in the brain are a symptom and not necessarily the cause of Alzheimer's disease, most of the current treatments for the condition work by blasting these plaques away. The FDA-approved drugs lecanemab and aducanumab work this way but, while they might be able to slow the degree of cognitive decline, they can't reverse the cognitive and memory-degrading effects of the disease.

“They leave behind a brain that is maybe plaqueless, but all the pathological alterations in the circuits and the mechanisms in the neurons are not corrected,” says Istvan Mody, a professor of neurology and physiology at UCLA Health.

Seeking an alternative treatment option, Mody and his team turned to gamma oscillations – high-frequency brain waves that have been associated with memory and other cognitive processes. These frequencies are often degraded in people with Alzheimer's and previous research has shown that stimulating Alzheimer's patients with auditory, visual or transcranial signals that mimic gamma oscillations led to reduced plaques. Once again though, no cognitive improvements were seen.

This time around, the researchers looked to boost gamma oscillations from inside, rather than outside, the brain. They created a molecular compound called DDL-920 that worked to inhibit the action of the chemical messenger known as GABA, which serves to dampen gamma oscillations in fast-firing structures known as parvalbumin neurons. With GABA inhibited, the thinking was that the gamma oscillations would be boosted back to normal levels and memory and cognition would improve.

In mouse tests, that's exactly what happened. When mice that were genetically modified to have Alzheimer's disease were given the compound, their previously poor performance in a maze improved to equal that of healthy mice. What's more, it only took two weeks of twice daily oral dosing for the improvement to be seen. The researchers also did not notice any visible side effects during the testing phase.

“There is really nothing like this on the market or experimentally that has been shown to do this,” said Mody, who is lead author on the study describing the research that has just been published in the journal PNAS.

Mody says a good deal more research will be required to see if the treatment will be safe and effective in humans, but if it is, he says the discovery offers a brand-new way to treat the disease. He also says DDL-920 could be effective in treating other conditions with hallmarks that include reduced gamma oscillations such as autism spectrum disorder, depression, and schizophrenia.

Source: UCLA Health

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7 comments
disciple
GABA is an important neurotransmitter I believe. What will be the side effect from inhibiting GABA one has to wonder. Will this new drug have any other side effects like cause cancer, predispose to diabetes, cause heart disease etc. I think its a little too early to know if this will be a true beneficial treatment for Alzheimers but one has to hope...
undrgrndgirl
lets get it to human trials asap!
Karmudjun
Thanks for a great article Michael! This is really cutting edge research. If only there had been nicotine inhibitors available in the years leading up to WWII, we might not have dealt with such serious heart disease and lung cancers of our history. I think disciple has a legitimate question regarding CNS GABA inhibition but no understanding of GABA's effects. Will depression increase with CNS GABA inhibition, stress, anxiety, HTN, etc? If human trials prove this approach effective against Alzheimer's, what will the side effects cause? The plus of memory retention may outweigh the personality side effects.
michael_dowling
We can't seem to get past the idea that plaques are related to Alzheimer's. I recall a study that examined the brains of nuns who donated their remains to science in their will,and there was NO correlation between plaque deposits and dementia. Some of the worst plaque deposits were seen in nuns who were cognitively normal at death!
Rick O
As Michael_dowling mentions, there has been a lot of focus on the plaques as a cause, instead of an effect. This is the first study that I recall seeing which seems to have a good lead on the root cause. If age and genetics are the root cause of changes in GABA (my best guess), which then causes Alzheimer's and USUALLY causes plaques, proper regulation of that seems to be as close to a "cure" as we can get. If this is true, this is one of the most important finds and fixes of all time. I don't typically suggest such a thing, but if it's true, these researchers need a Nobel Prize and statues made in their honor!
bobmeyerweb
disciple: that's why it takes years to approve new drugs. Lots and lots of trials to prove efficacy AND safety before approval.

Undrgrndgirl: see disciple's comment, and mine above, for why it won't go to human trials rapidly.
Eggster
@Karmudjun might have something to offer on this ... I recall reading that the brain stops healing/regenerating following an injury as some sort of protective measure. Some lab had developed a compound that re-initiated this process, but I haven't come across any references to it since then.

Anyway, the point is that, regardless of the cause, a two part solution may be required to address alzheimers, dementia and other neurological injuries - 1.) address the cause 2.) restart the regenerative process.