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.
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
120
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 routinely take cholinesterase inhibitors such as donepezil for treatment.
Capital Medical University Xuanwu Hospital
Beijing, China
RECRUITINGResting-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.
Time frame: 2 years
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.)
Time frame: 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.
Time frame: 2 years
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