From the Guidelines
Leqembi (lecanemab) decreases amyloid plaque in both men and women through its mechanism as a monoclonal antibody that specifically targets and binds to amyloid beta aggregates. The medication works by recognizing and attaching to the soluble protofibrils of amyloid beta, which are considered particularly neurotoxic forms of the protein that accumulate in Alzheimer's disease. Once bound to these protofibrils, Leqembi facilitates their clearance from the brain through multiple pathways, including microglial activation and phagocytosis, where specialized brain immune cells engulf and remove the antibody-bound amyloid. This process effectively reduces the overall amyloid plaque burden in the brain. The drug is administered as an intravenous infusion at a dose of 10 mg/kg every two weeks. Clinical trials have demonstrated that Leqembi significantly reduces amyloid plaque levels in both male and female patients with early Alzheimer's disease, with no significant gender-based differences in its mechanism of action or effectiveness, as supported by recent studies 1.
Mechanism of Action
The biological process of amyloid accumulation and clearance operates similarly across genders, allowing Leqembi to work effectively regardless of the patient's sex. This is further supported by the use of amyloid PET imaging, which is sensitive and specific for the detection of amyloid-beta neuritic plaques, a core molecular feature of Alzheimer's disease pathology 1. The effectiveness of Leqembi in reducing amyloid plaque levels is also consistent with the emerging era of anti-amyloid therapies, which rely on amyloid-PET for patient selection, evaluation of target-engagement, and assessment of drug effectiveness 1.
Clinical Implications
The reduction of amyloid plaque levels by Leqembi has significant implications for the management of Alzheimer's disease, particularly in the context of disease-modifying therapies. As noted in recent guidelines, amyloid PET results directly impact medical decision making regarding the use of these therapies, and Leqembi's ability to reduce amyloid plaque levels makes it a valuable treatment option for patients with early Alzheimer's disease 1. Overall, Leqembi's mechanism of action and clinical effectiveness make it a promising treatment for reducing amyloid plaque levels in both men and women with Alzheimer's disease.
From the FDA Drug Label
LEQEMBI reduces amyloid beta plaques, as evaluated in Study 1 and Study 2 [see Clinical Studies (14)]. The effect of LEQEMBI on amyloid beta plaque levels in the brain was evaluated using Positron Emission Tomography (PET) imaging LEQEMBI reduced amyloid beta plaque in a dose- and time-dependent manner in the dose-ranging study (Study 1) and in a time-dependent manner in single-dosing regimen study (Study 2) compared to placebo [see Clinical Studies (14)]
Lecanemab (LEQEMBI) Mechanism of Action:
- Lecanemab-irmb is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta.
- The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease.
- LEQEMBI reduces amyloid beta plaques in a dose- and time-dependent manner.
Key Points:
- LEQEMBI reduces amyloid beta plaque levels in the brain.
- The reduction in amyloid beta plaque is dose- and time-dependent.
- LEQEMBI's effect on amyloid beta plaque levels was evaluated using PET imaging.
From the Research
Lecanemab's Effect on Amyloid Plaque
- Lecanemab has been shown to reduce amyloid markers in early Alzheimer's disease and result in less decline on measures of cognition and function than placebo 3.
- The Clarity AD phase III trial demonstrated that lecanemab reduced amyloid markers in early Alzheimer's disease and resulted in less decline on measures of cognition and function than placebo 4.
- Lecanemab therapy led to a substantial decrease in amyloid plaques and a noticeable slowing of clinical decline 5.
Gender Differences in Response to Lecanemab
- One study found that lecanemab did not slow cognitive decline in women, which is significant given that women have a twofold increased risk of Alzheimer's disease compared to men 6.
- However, the study did not provide a clear explanation for the gender difference in response to lecanemab.
Mechanism of Lecanemab's Effect on Amyloid Plaque
- Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, which may initiate or potentiate pathologic processes in Alzheimer's disease 3.
- The CSF level of lecanemab-associated Aβ protofibril (Lec-PF) was found to be correlated with neurodegeneration biomarkers, such as CSF total tau and neurogranin, suggesting that Lec-PF levels may reflect neurodegeneration as well as the amount of senile amyloid plaques 4.