This story is part of a series on the current progression in Regenerative Medicine. This piece discusses advances in Alzheimer’s therapy.
In 1999, I defined regenerative medicine as the collection of interventions that restore normal function to tissues and organs damaged by disease, injured by trauma, or worn by time. I include a full spectrum of chemical, gene, and protein-based medicines, cell-based therapies, and biomechanical interventions that achieve that goal.
An emerging combination of focused ultrasound therapy with a recently approved medication could be our best treatment for Alzheimer’s disease to date. In the New England Journal of Medicine, Dr. Ali Rezai and colleagues from West Virginia University describe an approach to reduce cerebral amyloid-beta load, a biomarker for neurodegeneration, in patients with Alzheimer’s. While in its preliminary stages, the combination treatment can potentially help thousands, if not millions, suffering from the disease in the near future.
While neurodegeneration is natural as we age, resulting in diminished motor function and memory, those suffering from Alzheimer’s disease experience accelerated deterioration. The typical Alzheimer’s patient will experience more severe memory loss, confusion, and motor decline, among other symptoms, at much earlier ages on average.
Among the many changes in the brain as an Alzheimer’s diagnosis progresses is the accumulation of amyloid-beta peptides in neural tissue. These peptides are produced in all people, not just those with Alzheimer’s, but those with the diagnosis fail to clear the peptide from the brain, leading to significant amyloid-beta loads and neurodegeneration. Defects in clearance are thought to be a leading cause of Alzheimer’s disease, and significant amyloid-beta load is found in over 90% of patients.
FIGURE 1: Amyloid-beta deposits in a healthy brain vs a brain with Alzheimer’s disease.
In the past few years, Biogen Inc. developed a treatment for amyloid-beta building called Aducanumab. The drug is a monoclonal antibody that binds the amyloid peptide and reduces buildup in the brain.
However, there have been difficulties delivering the drug to the brain due to the blood-brain barrier, a collection of endothelial cells that regulate the transfer of solutes between the nervous system and the rest of the body. As the nervous system is among the more delicate systems in the human body, the blood-brain barrier prevents toxins from entering the ecosystem while regulating hormones, nutrients, and water, ensuring the system runs efficiently.
Rezai and colleagues aimed to create an opening in the blood-brain barrier, establishing a controlled pathway for Aducanumab to be delivered more efficiently in Alzheimer’s patients.
To do this, they used focused ultrasound to form microscopic openings in the brain tissue. An ultrasound device uses sound waves to create defined images, most commonly for pregnancies or diagnoses. However, focused ultrasound can change the composition of the target by increasing blood flow or destroying tissue. In the figure below, you can see the slight reduction of brain tissue in the top right of the skull in the right two images compared to the far left image.
FIGURE 2: Blood–Brain Barrier Opening with Focused Ultrasound (FUS).
To test the combination therapy, the researchers enrolled three patients who had never taken Aducanumab and had been diagnosed with Alzheimer’s for at least a year. First, the cohort was given Aducanumab alone, without blood-brain barrier opening by focused ultrasound, monthly for six months. The doses ranged from 10 mL to 40 mL.
In the second six-month period, each patient preempted their treatment by opening the blood-brain barrier, which was closed within 24 to 48 hours following treatment.
With all three patients, a significant reduction in amyloid-beta load was found during the ultrasound portion of the experiment as compared to the ultrasound-free portion. In the 10 mL patient, ultrasound reduction was -109 compared to -1.5 during the non-ultrasound period. In the 20 mL patient, ultrasound reduction was -81.1 compared to 6.5 during the non-ultrasound period. Finally and most significantly, ultrasound reduction in the 40 mL patient was -166.6 compared to -8.5 during the non-ultrasound period.
These results are significant and eye-opening, but I must note a few fallbacks of the treatment and this study.
First and foremost, a study of just three participants is far from conclusive. For this treatment to gain real traction, studies of hundreds, if not thousands, of patients undergoing the same regime will be needed.
Second, opening the blood-brain barrier can cause significant side effects. While those studied by Rezai and colleagues only experience mild symptoms such as headaches, there are instances of brain damage, internal bleeding, and even death associated with improper blood-brain barrier safety.
Finally, there is the issue of cost. While focused ultrasound delivery would not be too expensive with continued progress and technology, Aducanumab is remarkably expensive. There are reports of the drug costing between $28,000 and $56,000 a year, out of the realm of possibility for many middle-class and poor Alzheimer’s patients. This cost would need to be driven down significantly before this is an accessible treatment.
Ultimately, though, the focused ultrasound drug delivery system has plenty of promise, if not with Aducanumab, than with other brain-targeted drug cocktails. This is likely not the last we will hear of this drug delivery mechanism, and I look forward to seeing how it is used in the years to come.
To read more of this series, please visit www.williamhaseltine.com