Monoclonal Antibody Therapies in Alzheimer's Disease

Monoclonal antibody therapies in Alzheimer’s disease aim to target and clear pathological aggregates of amyloid-β (Aβ) in the brain, a hallmark of the disease. These antibodies are engineered to bind specific epitopes on Aβ monomers, oligomers or protofibrils, thereby promoting their removal through microglial phagocytosis or complement activation. Advances in molecular engineering have yielded agents with greater selectivity for protofibrillar forms, which are increasingly implicated in synaptic dysfunction and neurotoxicity. Clinical studies have demonstrated that high-affinity binding to aggregated Aβ can reduce plaque burden, as measured by amyloid positron emission tomography (PET), and may slow cognitive decline in early stages of the disease. However, these therapies carry a risk of amyloid-related imaging abnormalities (ARIA), including vasogenic oedema and microhaemorrhages, necessitating careful patient selection and monitoring. Ongoing research focuses on optimising dosing regimens, minimising adverse events and exploring biomarkers to predict individual response and disease-modifying potential.

Research from Nature Portfolio

Recent studies have employed spatial transcriptomics and single-cell RNA sequencing to clarify the mechanisms of Aβ clearance following both active and passive immunisation. These investigations revealed distinct microglial activation states across different brain regions, characterised by upregulation of TREM2 and APOE pathways that correlate with enhanced antibody engagement and complement-mediated plaque removal. This work suggests that modulation of innate immune signalling could amplify therapeutic efficacy. A foundational structural analysis of antibody-Aβ interactions has further defined the molecular basis for selectivity, showing that certain antibodies bind a compact N-terminal epitope in aggregated Aβ with weak monovalent affinity but strong avidity for epitope-rich aggregates. These insights have informed the design of second-generation antibodies with improved safety profiles and aggregate specificity.

Monoclonal Antibody Therapies in Alzheimer's Disease publication trend

The graph below shows the total number of articles in monoclonal antibody therapies in alzheimer's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Amyloid-β (Aβ): A peptide that aggregates in the brain and forms plaques associated with Alzheimer’s pathology.

Monoclonal antibody: A laboratory-engineered immunoglobulin designed to bind a single, specific epitope.

Microglia: Resident immune cells of the central nervous system responsible for phagocytosis and inflammatory responses.

Epitope: The precise molecular region on an antigen to which an antibody binds.

Amyloid-related imaging abnormalities (ARIA): MRI-detected side effects of antibody therapy, including vasogenic oedema and microhaemorrhages.

Positron emission tomography (PET): A neuroimaging technique used to visualise and quantify amyloid plaques in vivo.

References

1. Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease. Nature Medicine (2025).
2. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease. The Journal of Prevention of Alzheimer's Disease (2022).
3. Lecanemab, Aducanumab, and Gantenerumab — Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer's Disease. Neurotherapeutics (2022).
4. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Scientific Reports (2018).
5. MR Imaging Features of Amyloid-Related Imaging Abnormalities. American Journal of Neuroradiology (2013).
6. Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimer's Research & Therapy (2022).