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

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.