A recent analysis reveals that people with Alzheimer’s taking Alzheimer’s drug galantamine (Razadyne), approved nearly two decades ago, show moderate cognitive benefits as well as a reduction in mortality and severe dementia.
Experts still don’t know what causes Alzheimer’s. Most of the drugs approved to treat Alzheimer’s don’t reverse or modify the disease state. Instead, they simply improve the cognitive symptoms. Approved in 2003, galantamine (brand name Razadyne), a chemical substance first found inside of daffodil bulbs, remains one of the most successful such treatments for Alzheimer’s. Now, a recent analysis takes its symptomatic benefits a step further, finding that it may even reduce the risk of severe dementia.
Galantamine belongs to a class of drugs called cholinesterase inhibitors that increase the levels of brain signaling molecules, improving symptoms of Alzheimer’s. While this doesn’t reverse the course of the disease, and while these drugs may not be effective for every patient, they do have the potential to improve daily cognitive function, and with that, quality of life.
Dr. Andrew Budson, chief of cognitive and behavioral neurology at the Veterans Affairs Boston Healthcare System and professor of neurology at Boston University, explained how galantamine works: “One way to think about Alzheimer’s disease is as a clock that is ticking down until you run out of time, and your memory and other cognitive functions are gone,” Budson told Being Patient. “By blocking the metabolism of acetylcholine, the cholinesterase inhibitors drugs galantamine, donepezil, and rivastigmine can boost up memory equivalent to turning back the clock on Alzheimer’s disease by six to 12 months.
These drugs do not, however, change the rate at which the clock is ticking down,” he explained over email.
A recent report published in Neurology by Dr. Maria Eriksdotter and colleagues at the Karolinska Institutet showed that galantamine worked better than the other cholinesterase inhibitors. The study compared 11,652 people with Alzheimer’s using one of the three cholinesterase inhibitors to 5,826 non-users.
About three in five people taking cholinesterase inhibitors were prescribed donepezil (Aricept). Another one in five were prescribed rivastigmine (Exelon), and another one in five were prescribed galantamine. All three of these cholinesterase inhibitors conferred mild cognitive benefits.
Despite being less commonly prescribed, galantamine, however, stood out as the top performer: Among study participants, it reduced the risk of developing severe dementia by 31 percent while lowering the risk of mortality by 29 percent. Aricept and Exelon did not lower the risk of severe dementia significantly but lowered the risk of mortality by 22 percent and 14 percent respectively.
In a news release, Eriksdotter stated the importance of these findings: “Our results provide strong support for current recommendations to treat people with Alzheimer’s disease with cholinesterase inhibitors, but also shows that the therapeutic effect lasts for a long time.”
A new wave of Alzheimer’s treatments are designed to remove protein plaques, called beta-amyloid, that are deposited between dying cells. So far, aducanumab (Aduhelm) is the only one that has been approved. Even before its approval, there has been a shadow of doubt cast over the viability of this “amyloid hypothesis,” leading experts including Budson to wonder whether other approaches are needed for treating Alzheimer’s.
“The clinical trials have clearly demonstrated that this drug does remove amyloid plaques,” Budson said of Aduhelm. “What is still unclear, however, is whether it can truly slow down the ticking clock of cognitive decline — one large study suggested yes, while the other large study suggested no.”
How Galantamine Works
In Alzheimer’s, neurons in the basal forebrain begin to die. These neurons release acetylcholine into the junction between two neurons, allowing them to exchange information. The basal forebrain sends acetylcholine to other areas of the brain to modulate cognitive function, emotion, and episodic memory. Acetylcholine is also involved in cognitive arousal, attention, and perception.
After studying the daffodil bulb’s phytomedicinal properties, galantamine was purified and analyzed. Researchers discovered that galantamine prolonged the effects of acetylcholine in the brain, later classifying it as a cholinesterase inhibitor. Now, galantamine is approved to treat symptoms of mild-to-moderate Alzheimer’s and is mass-produced in a laboratory.
Galantamine increases the amount of time that acetylcholine will stay at the synapse by inhibiting the cholinesterase enzyme. In addition, galantamine also helps acetylcholine activate its receptors. Galantamine makes these receptors more permissive to activating, thereby modulating their activity. This two-pronged mechanism increases acetylcholine signalling and activation in the brain.
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Cholinesterase inhibitors’ effects on cognition have been debated, and few studies have investigated their long-term effects. But Aduhelm — which is potentially disease-modifying but also much higher-priced and more invasive (it is a spinal infusion, where as galantamine is just a tablet) — is still in trials to determine its efficacy, too.
Experts worry this approval could sway people towards the high-priced Aduhelm, even if there is less data behind the newly approved drug.
“When it comes to memory problems, we also always want to use medications to treat both the symptoms of memory loss, as well as the underlying disease process. It’s an easy decision,” Budson said.
“What is difficult today is answering the question of whether aducanumab actually slows the clock down or not,” he addd. “Given that about 40 percent of patients [in aducanumab trials] either had brain swelling or brain bleeding — symptoms that can hurt thinking and memory — the decision to take aducanumab or not is a difficult one.”