Breakthrough Alzheimer’s Drug Has a Hidden Problem

Researchers in Japan found that although the Alzheimer's drug lecanemab successfully removes amyloid plaques from the brain, it does not restore the brain's waste-clearing system within the first few months of treatment.

The study suggests that by the time symptoms appear, damage to nerve cells and the glymphatic system is already well established, making short-term recovery unlikely.

Lecanemab's Surprising Limits in Alzheimer's Treatment

Researchers at Osaka Metropolitan University in Japan, led by graduate student Tatsushi Oura and Dr. Hiroyuki Tatekawa, reported that lecanemab, a drug designed to clear amyloid plaques from the brain, does not improve the brain's waste removal system in the early stages after treatment.

Their results indicate that the nerves of Alzheimer's disease (AD) patients have already sustained considerable damage, and that this waste-clearing function does not rebound quickly. The findings point to the need for treatments that target several biological problems at the same time.

The Complex Web of Alzheimer's Disease Mechanisms

The researchers' results add another piece to the long and complicated effort to understand how AD develops. Although it is the most widespread neurodegenerative disorder, it remains difficult to treat because many different factors contribute to its progression.

A major driver of nerve cell damage in AD is the accumulation of amyloid-β (Aβ) in the brain. In people without the disease, a network known as the glymphatic system circulates cerebrospinal fluid along the spaces surrounding arteries and into brain tissue. There, this fluid mixes with interstitial fluid to help remove metabolic waste products, including Aβ. The name "glymphatic system" comes from the involvement of glial cells in this process.

In AD, however, Aβ builds up and causes arteries to stiffen. This reduces the movement of fluid between the brain and the cerebrospinal fluid, which disrupts waste removal and leads to a series of harmful changes that produce AD symptoms.

Testing Lecanemab's Effects on Brain Clearance

Lecanemab, which was recently approved as a therapeutic option, is intended to lower Aβ levels. To study its effects, the Osaka Metropolitan University team examined the glymphatic system in patients both before and after lecanemab treatment, using the DTI-ALPS index to measure changes.

They found no meaningful difference in this index when comparing pre-treatment results with measurements taken three months after therapy.

What This Means for Future Alzheimer's Treatments

Based on these observations, the researchers concluded that while anti-amyloid drugs can reduce plaque buildup and slow additional cognitive decline, they may not be able to restore functions already lost. By the time symptoms appear, many patients likely have long-standing neuronal damage and glymphatic impairment that are difficult to reverse. The results emphasize how many interconnected factors drive AD and how few of them can be quickly repaired.

"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."

Reference: "Unchanged Early Diffusion Tensor Imaging Along Perivascular Space Index After Amyloid-Targeting Disease-Modifying Therapy in Alzheimer's Disease: A Preliminary Study" by Tatsushi Oura, Hiroyuki Tatekawa, Akitoshi Takeda, Ayako Omori, Natsuko Atsukawa, Shu Matsushita, Daisuke Horiuchi, Hirotaka Takita, Taro Shimono, Daiju Ueda, Yoshiaki Itoh and Yukio Miki, 8 September 2025, Journal of Magnetic Resonance Imaging.
DOI: 10.1002/jmri.70118

The study was published in Journal of Magnetic Resonance Imaging.