The Clinical Study of Synaptic Plasticity-based Lencanumab for the Treatment of Early Alzheimer's Disease

Alzheimer's disease (AD) manifests itself in cognitive decline, impaired ability to perform daily life, and a variety of behavioral and psychiatric symptoms, seriously endangering the health of the elderly. The prevalence and disability rates of AD in China remain high, and the lack of effective treatment options has brought a heavy burden to patients and their families. Early intervention is regarded as an effective strategy to improve clinical symptoms, delay disease progression and maintain current quality of life. The humanized monoclonal antibody lencanemab (Lecanemab) was approved by the U.S. FDA in July 2023 for the treatment of mild cognitive impairment or mild dementia caused by AD, and was officially approved in January 2024 in China. Lencanemab highly targets soluble and insoluble neurotoxic β-amyloid (Aβ) proteins, reducing pathogenic Aβ plaque deposition and preventing its formation in the brains of AD patients, thus reducing neurotoxicity and improving patients' cognitive functions. In addition, lencanumab may also play a neuroprotective role by modulating synaptic plasticity and regulating neural network activity in brain neurons. However, there is a lack of clinical studies to prove this mechanism. In this study, we will enroll consecutive patients with early AD treated with lencanemab infusion as well as those receiving conventional anti-dementia therapy, and comprehensively assess the effects and intrinsic molecular mechanisms of lencanemab on synaptic function and neural networks using magnetic resonance imaging, molecular imaging positron emission tomography (PET), neuropsychological assessment, and analysis of blood cerebrospinal fluid samples.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer's Disease; Functional Magnetic Resonance Imaging; Lecanemab
• Intervention / Treatment: Drug: Lecanemab treatment group; Drug: Conventional anti-dementia treatment group

Detailed Description

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, impairment of daily living activities, and various behavioral and psychiatric symptoms. The most widely accepted hypothesis regarding the pathogenesis of AD is the amyloid cascade hypothesis. This hypothesis posits that the abnormal deposition of neurotoxic beta-amyloid (Aβ) is a key factor in the onset of AD. In the past two decades, anti-Aβ monoclonal antibodies aimed at reducing cerebral Aβ plaques have increasingly attracted attention in the field of AD drug development.

The humanized monoclonal antibody CAb (Lecanemab) highly targets soluble and insoluble A β[1,2] to reduce pathogenic A β plaques and prevent their formation in the brain of AD patients. Large global phase III clinical trials, including China, show that Lecanemab can slow the rate of cognitive decline in mild cognitive impairment (MCI) and mild AD within 18 months of treatment compared with placebo. However, the intrinsic mechanism by which Lecanemab delays disease progression by clearing pathogenic A β is not well understood. Previous studies have suggested that Lecanemab may have a role in improving synaptic plasticity. An animal experiment showed that the A β antibody can reverse the long-term enhanced (LTP) synaptic function defects caused by soluble A β oligomers and improve synaptic plasticity [4]. Synaptic plasticity is closely related to cognitive function. It refers to the ability to establish new connections between neurons or existing connections in the brain, which is manifested by changes in ultrastructure and functional changes of synapses, such as [5] of neurotransmitter level, neuroexcitability, electrical activity or changes in the number of postsynaptic receptors. It was shown that soluble A β oligomers are able to strongly inhibit synaptic plasticity in the normal rodent hippocampus, damage synaptic architecture, and ultimately lead to impaired cognitive [6]. Based on this, the scientific hypothesis is proposed that "Lecanemab may effectively reduce A β toxicity and protect synaptic function defects in AD brain". However, further clinical studies on the mechanism of Lecanemab on synaptic plasticity.

The purpose of this study is to prospectively evaluate the impact of continuous use of luncanemab infusion therapy on brain neural networks and synaptic plasticity in early Alzheimer's disease (AD) patients, and to explore the underlying molecular pathological mechanisms. According to the inclusion and exclusion criteria, eligible subjects are included in the screening visit period. During the screening visit, informed consent is signed, and demographic assessments are completed, along with the collection of past medical history, medication history, physical examination, and laboratory tests. Baseline neuropsychological scales, resting-state fMRI, three-dimensional structural MRI, Amyloid-PET, and blood and cerebrospinal fluid sample data are also collected. Patients are divided into a luncanemab treatment group and a conventional treatment group based on whether they receive luncanemab, and are followed up for data collection over a period of 12 months. This includes four neuropsychological assessments at 3 months, 6 months, 9 months, and 12 months of follow-up; collection of neuropsychological, resting-state fMRI, three-dimensional structural MRI, Amyloid-PET, and blood samples at baseline and at the 12-month follow-up, in accordance with patient wishes for cerebrospinal fluid sample collection; and two resting-state fMRI, three-dimensional structural MRI assessments, and blood sample collection at 6 months and 12 months of follow-up.

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Cui bai Wei; Phone Number: 83198319; Email: weicb@xwhosp.org

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Capital Medical University Xuanwu Hospital
    • Contact: Cui bai Wei, Ph.D; Phone Number: 83198319; Email: weicb@xwhosp.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

We will recruit 120 early Alzheimer's disease (AD) patients from 13 hospitals, including Xuanwu Hospital of Capital Medical University. Among them, 60 cases will be in the Lecanemab treatment group, and 60 cases in the conventional treatment group.

Description

Inclusion Criteria:

1. Age between 50 and 90 years.
2. Male or female patients.
3. Patients with MCI and mild AD.
4. MMSE score ≥20, CDR overall score of 0.5 or 1.
5. Amyloid-positive confirmed by Amyloid-PET or CSF.
6. Have a reliable caregiver to accompany the patient during study visits and supervise the use of study medication during the trial.
7. Agree to participate in the study and sign the informed consent form.

Exclusion Criteria:

1. Patients with cognitive impairment due to reasons other than AD.
2. A history of transient ischemic attack (TIA), stroke, cerebral hemorrhage, or seizure within the 12 months prior to screening.
3. A score of >17 on the Hamilton Depression Scale at screening, or any suicidal behavior within 6 months prior to screening, at screening, or at the baseline visit, as well as any psychiatric diagnosis or symptoms that interfere with the study procedure (such as hallucinations, anxiety disorder, or paranoia).
4. Patients with a bleeding disorder or receiving anticoagulant therapy, as well as any with malignant tumors, severe gastrointestinal, kidney, liver, respiratory, immune, endocrine, and cardiovascular system diseases that affect this study.
5. A hypersensitivity reaction to ranucimab or any other ingredient in the injection solution, or to any monoclonal antibody treatment.
6. Contraindications to MRI scanning, including those with a pacemaker/defibrillator or ferromagnetic metal implants (except for skull and cardiac devices approved as safe for MRI scanning).
7. A known or suspected history of drug or alcohol abuse or dependence within the 2 years prior to screening.
8. Participation in a clinical study involving any therapeutic monoclonal antibody or novel compounds for the treatment of AD within the 6 months prior to screening, unless it can be proven that the subject was in the placebo treatment group.
9. Planning to undergo surgery requiring general anesthesia during the study period.
10. A positive pregnancy test result, lactation, or pregnancy in females at screening or baseline.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Lecanemab treatment group; Early-stage Alzheimer's disease patients are given Lecanemab infusion treatment in conjunction with conventional anti-dementia drug therapy.	Drug: Lecanemab treatment group; Lecanemab treatment group: Lecanemab Injection Concentrate Solution (active ingredient at 100 mg/mL) is provided as a sterile aqueous solution containing 100 mg/mL of Lecanemab, 50 mmol/L citric acid, 350 mmol/L arginine/arginine hydrochloride, and 0.05% (w/v) polysorbate 80, with a pH of 5.0, and each vial is capable of being drawn into a volume of 5 mL. Lecanemab is to be administered via intravenous infusion over 60 minutes in saline solution. Lecanemab must be administered using an infusion system that includes a terminal 0.22 μM inline filter. The dosage of Lecanemab is 10 mg/kg. All subjects in the Lecanemab treatment group receive Lecanemab infusion therapy at a frequency of once every two weeks for a continuous period of 12 months.
Conventional anti-dementia treatment; Early-stage Alzheimer's disease (AD) patients commonly take cholinesterase inhibitors such as donepezil for treatment.	Drug: Conventional anti-dementia treatment group; Conventional anti-dementia treatment: Early-stage Alzheimer's disease (AD) patients routinely take cholinesterase inhibitors such as donepezil for treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting-state fMRI brain network metrics (Independent Component Analysis)	The Lecanemab treatment group and the conventional treatment group's longitudinal changes in Independent Component Analysis (ICA) indicators after 12 months of treatment compared to baseline. ICA is a statistical technique used for extracting mutually independent signals from multivariate data, capable of measuring levels of functional connectivity within and between networks.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other resting-state fMRI brain network indicators: functional connectivity (FC)	Functional Connectivity (FC) is an important concept in neuroscience, primarily used to describe and analyze the interactions between different brain regions. FC is defined by measuring the similarity between brain signals from two regions.	2 years
Other resting-state fMRI brain network indicators: Granger Causality Analysis (GCA)	Granger Causality Analysis: Granger causality analysis is a statistical method used to analyze the causal relationships between variables.	2 years
Other resting-state fMRI brain network indicators: Spectral Dynamic Causal Model (spDCM)	Spectral Dynamic Causal Model (spDCM): A method for investigating the directed interactions between brain regions, also known as effective connectivity.	2 years
Rate of change in global cognition as measured by Clinical Dementia Rating (CDR)	Assess statistically significant difference in score between Lecanemab treatment group and conventional anti-dementia treatment using the neuropsychological scales CDR. CDR, a multidimensional scale for dementia severity, which scored 0-3, with higher scores indicating worse functioning.	2 years
Rate of change in the severity of cognitive impairment as assessed by Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-cog)	Assess statistically significant difference in score between Lecanemab treatment group and Conventional anti-dementia treatment using the neuropsychological scales ADAS-cog. ADAS-cog scores range from 0-70, with higher scores indicating better global cognitive function.	2 years
Rate of change in global cognition as measured by Mini-Mental State Examination (MMSE)	Assess statistically significant difference in score between Lecanemab treatment group and Conventional anti-dementia treatment using the neuropsychological scales MMSE. MMSE scores range from 0-30, with higher scores representing better cognitive function.	2 years
Rate of change in global cognition as measured by Montreal Cognitive Assessment (MoCA)	Assess statistically significant difference in score between Lecanemab treatment group and Conventional anti-dementia treatment using the neuropsychological scales MoCA. MoCA scores range from 0-30, with higher scores representing better cognitive function.	2 years
Alzheimer's Disease Composite Score (ADCOMS)	ADCOMS is a weighted linear combination of selected items from three commonly used scales; it consists of 12 scoring items, with scores ranging from 0 to 1.97, where higher composite scores indicate a greater severity of the disease.	2 years
The Integrated Alzheimer's Disease Rating Scale (iADRS)	iADRS combines two separate scales, namely ADAS-Cog14 (scoring range from 0 to 90) and ADCS-iADL (the second part of ADCS-ADL, scoring range from 0 to 56). The total score range for iADRS is from 0 to 146, with lower scores indicating poorer performance.	2 years
Five Levels Five-Dimensional Health Scale (EQ-5D-5L)	The EQ-5D includes a brief descriptive system questionnaire and a visual analogue scale (EQ VAS). The descriptive system covers 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each of which is divided into 5 different levels to define varying degrees of difficulty: 1 = no problems; 2 = slight problems; 3 = moderate problems; 4 = severe problems; 5 = extreme problems/unable to perform. By combining the levels of each dimension, a unique health state for the subject is defined.	2 years
Alzheimer's Disease Quality of Life Scale (QOL-AD)	The Alzheimer's Disease Quality of Life Assessment Scale (QOL-AD), also known as the Quality of Life Assessment Scale for Senile Dementia, can evaluate multiple dimensions, including behavioral abilities, physiological functions, psychological states, interpersonal relationships, etc. The total score is the sum of the scores of 13 questions.	2 years
Rate of change in activities of daily living as assessed by Alzheimer's Disease Cooperative Study-Activity of Daily Living (ADCS-ADL)	Assess statistically significant difference in score between Lecanemab treatment group and Conventional anti-dementia treatment using the neuropsychological scales like ADCS-ADL. ADCS-ADL scores range from 0-54, with higher scores indicating better completion ability.	2 years
Rate of change in psychobehavioral symptoms as assessed by Neuropsychiatric Inventory (NPI)	Assess statistically significant difference in score between Lecanemab treatment group and Conventional anti-dementia treatment using the neuropsychological scales like NPI. Patient assessment grading scores range from 0-144 in NPI, and caregivers distress grading scores range from 0-60, with 0 representing the best.	2 years
Hamilton Anxiety Scale (HAMA)	Hamilton Anxiety Scale: Primarily used to assess the severity of anxiety symptoms in patients with neurosis and other disorders. The total score can be used to evaluate the severity of anxiety symptoms in patients with anxiety and depressive disorders and to assess the effects of various medications and psychological interventions. According to the data provided by the Chinese Scale Collaboration Group: a total score of ≥29 may indicate severe anxiety; ≥21 definitely indicates significant anxiety; ≥14 definitely indicates anxiety; over 7 may indicate anxiety; if less than 7, there are no anxiety symptoms.	2 years
Hamilton Depression Rating Scale (HAMD)	Assess statistically significant difference in score between Lecanemab treatment group and Conventional anti-dementia treatment using Hamilton Depression Rating Scale (HAMD):It is the most widely used scale in the clinical assessment of depressive states. The HAMD uses a 5-point rating scale for most items: (0) None, (1) Mild, (2) Moderate, (3) Severe, (4) Very Severe. A few items are rated on a 3-point scale: (0) None, (1) Mild-Moderate, (2) Severe. Result Analysis: <7 points are considered normal; 7-17 points are suspicious for depression; 18-24 points indicate mild or moderate depression; >24 points indicate severe depression.	2 years
Zarit Caregiver Burden Interview Scale (ZBI)	Assess statistically significant difference in score between Lecanemab treatment group and Conventional anti-dementia treatment using Zarit Caregiver Burden Interview Scale (ZBI). The score range is from 0 to 88 points, with the total score being the sum of the scores for 22 questions. The score range is from 0 to 88 points, with the total score being the sum of the scores for 22 questions.	2 years
Blood AD molecular pathology and synaptic structural protein content indicators	Assess statistically significant difference in score between Lecanemab treatment group and Conventional anti-dementia treatment using Plasma AD biomarkers (Aβ42, Aβ42/Aβ40, T-tau, P-tau181, P-tau231, P-tau217, NFL levels) and serum SV2A indicator concentration.	2 years
Cerebrospinal Fluid Synaptic Function Protein Content Assessment Indicator	Assess statistically significant difference in score between Lecanemab treatment group and Conventional anti-dementia treatment using Cerebrospinal fluid synaptic function protein content indicator (Neurotransmitter levels: Concentrations of neurotransmitters such as glutamate, acetylcholine, norepinephrine, epinephrine, dopamine, and serotonin; Neurotrophic factors: Concentration of Brain-derived Neurotrophic Factor (BDNF); Cerebrospinal fluid synaptic markers: Presynaptic Growth-associated protein 43 (GAP-43), Synaptic body-related protein 25 (SNAP25), and postsynaptic Neuronal Granulin (NRGN) markers.)	2 years
Neuroimaging biomarkers: Aβ-PET centiloid values	Assess statistically significant difference in score between Lecanemab treatment group and Conventional anti-dementia treatment using Aβ-PET centiloid values。 This is an indicator used to measure the level of amyloid deposition.	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood neuron-derived exosome transcriptomics-related indicators	Assess statistically significant difference in score between Lecanemab treatment group and Conventional anti-dementia treatment using Blood neuron-derived exosome transcriptomics-related indicators.	2 years

Collaborators and Investigators

• Sponsor: Cuibai Wei，Clinical Professor
• Collaborators: The First Affiliated Hospital of Anhui Medical University; RenJi Hospital; West China Hospital; Guangdong Provincial People's Hospital; The First Hospital of Jilin University; Wuhan Union Hospital, China; Zhejiang University; First Hospital of China Medical University; The First Affiliated Hospital of University of Science and Technology of China; Nanjing Brain Hospital; Eisai (China) Pharmaceutical Co.; Jinan Hospital, Xuanwu Hospital, Capital Medical University; The First Hospital of Chongqing Medical University
• Investigators: Principal Investigator: Cui bai Wei, Xuan Wu Hospital of Capital Medical University

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: March 7, 2025
• First Submitted That Met QC Criteria: March 7, 2025
• First Posted (Actual): March 12, 2025

Study Record Updates

• Last Update Posted (Actual): July 22, 2025
• Last Update Submitted That Met QC Criteria: July 19, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: functional magnetic resonance imaging; Alzheimer's disease; Lecanemab
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease
• Other Study ID Numbers: KS2024354

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No