Scientists Find Muscle-Building Supplement Improves Learning and Memory in Alzheimer’s

Highlights: 

• Oral supplementation with HMB restores the learning and memory of Alzheimer’s model mice. 
• HMB prevents the loss of neuron outgrowths called dendritic spines, important for connecting neurons. 
• Treatment with HMB enhances the electrical signaling responsible for strengthening neuronal connections, critical for memory formation. 

Recently, a drug developed by Biogen called lecanemab was approved by the FDA to treat Alzheimer’s. However, some of the more severe side effects of lecanemab include brain swelling, which can lead to death. Additionally, lecanemab’s proposed annual cost is about $25,000 per person. Therefore, a more cost-effective Alzheimer’s treatment with fewer side effects may be advantageous. 

Now, researchers from Rush University show in Cell Reports that HMB restores the cognitive function of Alzheimer’s model mice. Paidi and colleagues go on to show that HMB prevents brain cell deterioration and enhances the electrical signaling patterns responsible for forming new memories. Since HMB is commonly used by bodybuilders and combat sports athletes, it is known to be safe and well-tolerated. 

“This may be one of the safest and the easiest approaches to halt disease progression and protect memory in Alzheimer’s disease patients,” said Dr. Kalipada Pahan, principal investigator of the study. 

HMB Improves Cognition by Enhancing the Formation of New Memories  

To study Alzheimer’s disease (AD), Paidi and colleagues experimented with transgenic mice that harbor AD-linked human genes (5XFAD mice). These AD mice exhibit deficits in spatial learning and memory, as measured by the Barnes maze test, which involves mice learning to remember the location of an escape hole. The researchers showed that, compared to normal mice, the AD mice take longer to find the escape hole while making more errors in the process. 

However, feeding the AD mice 5 or 10 mg/kg/day of HMB for 1 month improved their ability to navigate the Barnes maze. Specifically, the HMB-treated AD mice took less time to find the escape hole and made less errors than the untreated AD mice. Furthermore, this occurred in a dose-dependent manner with the 10 mg/kg dose improving cognition more than the lower 5 mg/kg dose. These findings suggest that HMB can improve the learning and memory of AD mice. 

Our memories depend on the connections between the neurons in our brain. When enough of these connections are lost, so too are our memories. Anatomically, the part of a neuron that receives inputs from other neurons is called a dendrite. Each dendrite contains many outgrowths called dendritic spines where the axons (part of the neuron that sends signals) from other neurons make direct contact.  

As expected, Paidi and colleagues found that AD mice had less dendritic spines than normal mice in their hippocampus — the brain region associated with consolidating memories. However, HMB largely prevented this loss in dendritic spines, suggesting that HMB prevents the loss of neuronal connections in the brain. These findings also suggest that HMB preserves cognition by preventing the loss of synaptic connections. 

The NMDA receptor plays a critical role in the formation of new memories. The NMDA receptor is classified as an ion channel because it transports ions (electrolytes) into neurons. The transport of calcium ions (Ca²⁺) into neurons through NMDA receptors leads to the strengthening of connections between neurons, which is the basis for new memory formation. 

Paidi and colleagues found that NMDA-mediated Ca²⁺ transport into hippocampus neurons was diminished in AD mice compared to normal mice. However, treating AD mice with HMB prevented this decrease in Ca²⁺ transport. Since Ca²⁺ influx generates an electrical current, these findings suggest that HMB supports memory formation by enhancing the electrical signaling responsible for strengthening synaptic connections in the hippocampus. 

Overall, the findings of Paidi and colleagues suggest that HMB can prevent memory loss in Alzheimer’s mice by preserving neuronal connections in the hippocampus while promoting the strengthening of neuronal connections. 

Dr. Pahan adds, 

“If mouse results with HMB are replicated in Alzheimer’s disease patients, it would open up a promising avenue of treatment of this devastating neurodegenerative disease.”

Can HMB Help Slow Muscle and Brain Aging?

A study of highly trained combat athletes showed that HMB increases fat-free mass (including muscle) and reduces fat mass after 12 weeks of supplementation. Since the loss of muscle mass is associated with age-related muscle decline (sarcopenia), HMB could counter this aspect of muscle aging. Additionally, although not tested in healthy animals or humans, HMB could also counter aspects of brain aging such as memory loss. 

The authors of the study point out that the recommended dose of HMB for muscle building is 3 g per day. This dose is far greater than the dose used in their study, which the authors estimate to be 400 or 800 mg per day for humans. This means that the muscle-building dose covers the potentially neuroprotective dose. Notably, HMB should supplement a resistance training routine and will likely not build muscle or burn fat in the absence of exercise. HMB is a relatively inexpensive supplement and if bought in bulk form can cost as low as 18¢ per gram. 

How Does HMB Work?

In addition to the experiments mentioned above, Paidi and colleagues also repeated many of their experiments in AD mice deficient in PPARα, a receptor in the nucleus of cells often associated with the metabolism of fats. Paidi and colleagues found that the effects of HMB were abolished in PPARα-deficient AD mice, demonstrating that HMB acts on PPARα in the brain. In turn, PPARα activates the so-called master regulator of memory and learning called CREB, which activates multiple genes that promote neuroplasticity — the structural changes that occur in the brain to form what we call memories.