Summary: Researchers found that lecanemab, the Alzheimer’s drug designed to clear amyloid-β plaques, does not improve the brain’s waste clearance system in the short term. In a three-month study using MRI-based DTI-ALPS imaging, scientists observed no measurable recovery in glymphatic function after treatment.
This suggests that once neuronal and clearance system damage occurs, it may be too advanced to reverse quickly. The results emphasize the need for multi-targeted strategies to address Alzheimer’s disease beyond amyloid reduction alone.
Key Facts
- Study Finding: Lecanemab reduces amyloid-β but doesn’t restore glymphatic waste clearance after 3 months.
- Implication: Short-term therapy may not repair established neuronal damage in Alzheimer’s.
- Future Direction: Research will assess long-term effects and age-related factors influencing treatment outcomes.
Source: Osaka Metropolitan University
A group from Osaka Metropolitan University in Japan, led by graduate student Tatsushi Oura and Dr. Hiroyuki Tatekawa, found that treatment using the drug lecanemab to remove amyloid plaques in the brain does not change the waste clearance function in the brains of Alzheimer’s disease (AD) patients in the short term.
This suggests that even after treatment, the AD patients’ nerves are already damaged, and the waste clearance function does not recover in the short term. Their findings show the complexity of the disease and the need to address multiple disease-causing pathways simultaneously in the future.
Their findings add to the complicated process of unraveling AD’s mechanisms. Despite being the most common form of neurodegenerative disease, it is tricky to treat because of its multiple causes.
One cause of the nervous damage common in AD is the accumulation of the protein amyloid-β (Aβ) in the brain. In healthy patients, the glymphatic system moves cerebrospinal fluid along the spaces around the arteries into the brain tissue, where it mixes with interstitial fluid to carry away metabolic waste like Aβ. This is called the ‘glymphatic system’ after the glial cells involved in the process.
However, in AD patients, Aβ builds up, stiffening arteries and reducing the flow from the brain to the cerebrospinal fluid. This blockage triggers a chain of neurodegenerative processes, leading to AD symptoms.
The recently approved therapeutic lecanemab reduces accumulated Aβ. The team from the university’s Graduate School of Medicine evaluated the glymphatic system before and after treatment in patients who received lecanemab therapy, using the DTI-ALPS index.
Contrary to expectations, they found no significant change in the index between pre-treatment and 3 months after treatment.
They concluded that although anti-amyloid therapy can reduce plaque burden and slow further cognitive worsening, it may be insufficient to restore lost function. This suggests that neuronal damage and clearance system deficits have already been well established by the time the patient starts showing symptoms. Their findings show the range of factors involved in the progression of AD, many of which are not easily reversible.
“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.”
Funding: This study was supported by the Takeda Science Foundation (ROR ID: 02y123g31) and Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number: 25K19115). Data were obtained from the OASIS (OASIS-3, Longitudinal Multimodal Neuroimaging: Principal Investigators: T. Benzinger, D. Marcus, and J. Morris, supported by NIH Grants: NIH P30 AG066444, P50 AG00561, P30 NS09857781, P01 AG026276, P01 AG003991, R01 AG043434, UL1 TR000448, and R01 EB009352).
Key Questions Answered:
A: Not immediately. The study found that while lecanemab removes amyloid plaques, it does not restore the brain’s waste-clearing glymphatic system in the short term.
A: It suggests that clearing amyloid alone isn’t enough — nerve and clearance system damage in Alzheimer’s disease may require multi-targeted therapies.
A: Researchers are now exploring how age, disease stage, and long-term treatment duration affect glymphatic recovery and overall brain health.
About this neuropharmacology and Alzheimer’s disease research news
Author: Matthew Coslett
Source: Osaka Metropolitan University
Contact: Matthew Coslett – Osaka Metropolitan University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Unchanged Early Diffusion Tensor Imaging Along Perivascular Space Index After Amyloid-Targeting Disease-Modifying Therapy in Alzheimer’s Disease: A Preliminary Study” by Hiroyuki Tatekawa et al. Journal of Magnetic Resonance Imaging
Abstract
Unchanged Early Diffusion Tensor Imaging Along Perivascular Space Index After Amyloid-Targeting Disease-Modifying Therapy in Alzheimer’s Disease: A Preliminary Study
Alzheimer’s disease (AD) is characterized by the progressive accumulation of amyloid-β peptides in the brain parenchyma, and impairment of interstitial waste clearance via the glymphatic system is suggested as one contributing factor.
Recently approved disease-modifying (DM) monoclonal antibodies, such as lecanemab, are expected to slow cognitive decline by improving amyloid β clearance. Diffusion tensor imaging along the perivascular space (DTIALPS) index has emerged as a noninvasive surrogate marker suggested to be associated with glymphatic activity.
This index declines with normal aging and is significantly lower in patients with AD than in cognitively normal individuals. Although DM therapy (DMT) may affect the DTI-ALPS index, no studies have examined longitudinal changes in the DTI-ALPS index following DMT initiation.
Therefore, this study quantified the DTI-ALPS index in patients with AD before and 3 months after the initiation of amyloid-targeting DMT to generate provisional reference values for the longitudinal assessment of future DM-treated cohorts.
