Researchers at Osaka Metropolitan University in Japan, led by graduate student Tatsushi Oura and Dr. Hiroyuki Tatekawa, discovered that the Alzheimer's treatment lecanemab, which removes amyloid plaques from the brain, does not improve the brain's waste clearance system in the short term.
The results indicate that even after treatment, the nerves of Alzheimer's disease (AD) patients remain damaged and the brain's natural waste-removal ability does not recover quickly. This finding highlights the disease's complexity and the need for therapies that target more than one biological pathway at once.
Alzheimer's Disease: A Complex and Multifactorial Disorder
The study adds to growing evidence that Alzheimer's is a multifaceted disease. It is the most common form of neurodegenerative disorder, yet remains one of the most difficult to treat because it develops through several overlapping causes.
One major contributor to nerve cell damage in AD is the buildup of the protein amyloid-β (Aβ) in the brain. In healthy individuals, a network called the glymphatic system circulates cerebrospinal fluid through spaces around arteries into brain tissue. There, it mixes with interstitial fluid to remove metabolic waste, including Aβ. The term "glymphatic" comes from the glial cells that play a key role in this process.
How Alzheimer's Disrupts the Brain's Cleanup System
In people with Alzheimer's, Aβ accumulates and causes arteries to stiffen, slowing the flow of fluids between brain tissue and cerebrospinal fluid. This disruption blocks the brain's ability to clear out waste, setting off a cascade of damaging neurodegenerative effects that lead to the symptoms of the disease.
Lecanemab, a recently approved antibody therapy, is designed to reduce the buildup of amyloid-β. To test its effects, the Osaka Metropolitan University team examined the glymphatic system in patients before and after receiving lecanemab treatment. They used a specialized imaging measure known as the DTI-ALPS index to track changes.
No Short-Term Improvement Detected
Despite expectations, the researchers found no significant difference in the DTI-ALPS index between pre-treatment and three months after therapy.
They concluded that while anti-amyloid drugs like lecanemab can lower plaque levels and slow cognitive decline, they may not be enough to restore lost brain function. By the time symptoms appear, both neuronal damage and waste clearance impairments are likely well established and difficult to reverse. This underscores how Alzheimer's involves a network of biological problems, not just plaque buildup.
Next Steps: Understanding Why the Brain Doesn't Recover
"Even when Aβ is reduced by lecanemab, impairment of the glymphatic system may not recover within the short-term," Oura said. "In the future, we want to look at factors like age, the stage of the disease, and degree of lesions in the white matter to further understand the relationship between changes in the glymphatic system due to lecanemab treatment and the outcome of treatment. This will help understand the best way to administer treatment to patients."
The research was published in the Journal of Magnetic Resonance Imaging.
