Breakthrough Discovery: How to Activate Your Immune System to Fight Alzheimer's

Scientists have studied how the immune system can help fight Alzheimer’s, a disease caused by the buildup of beta-amyloid protein (Aβ) in the brain. They analyzed the brains of patients treated with experimental vaccines and drugs that stimulate the removal of this protein. They found that certain cells in the immune system, called microglia, help eliminate Aβ and that genes such as TREM2 and APOE play an important role in this process.

Alzheimer’s disease (AD) is characterized by the accumulation of plaques of beta-amyloid protein (Aβ) in the brain, which contributes to the degeneration of neurons and the progression of the disease.

For almost 30 years, researchers have been trying to develop treatments that help remove this buildup of Aβ, and one of the main strategies involves immunization, that is, using the immune system itself to attack these plaques.

There are two main types of immunization: active and passive. Active immunization involves stimulating the patient’s body to produce its own antibodies against Aβ, while passive immunization involves directly administering these antibodies to the patient.

Both approaches have shown potential to reduce Aβ levels in the brain, but they may also cause inflammatory side effects.

Study authors David Gate and Lynn van Olst examine a computer image of a brain with Alzheimer's disease that was treated with amyloid-beta immunization. Credit: Northwestern University

To better understand how these immunizations work and how they affect brain cells, especially microglia (immune cells responsible for clearing waste in the brain), researchers conducted a detailed study.

Researchers at Northwestern University Feinberg School of Medicine, USA, analyzed brains from Alzheimer's patients who participated in clinical trials with active and passive immunization.

They compared these brains with those of Alzheimer's patients who did not receive immunization and also with brains from individuals without neurological diseases. The goal was to identify how microglia respond to immunization and which genes are involved in removing Aβ.

To analyze the changes in the brain, scientists used advanced molecular biology technologies, including:

• Spatial transcriptomics (ST): allows mapping which genes are being activated in different regions of the brain.

• Spatial proteogenomics: combines information about proteins and genes to understand how brain cells respond to treatment.

• Single-cell RNA sequencing (scRNA-seq): enables analysis of the genetic activity of individual cells in the brain, helping to identify differences between cell types.

A spatial transcriptomics machine holds brain tissue samples in David Gate’s lab in Chicago. Credit: Northwestern University

These techniques were applied to different groups of brains, including those from patients who received the experimental vaccine AN1792 (active immunization) and those who were treated with the drug lecanemab (passive immunization).

The researchers identified different patterns of microglial activation with each type of immunization. They found that microglia in the immunized brains showed specific patterns of activation associated with Aβ clearance. In addition, two genes, TREM2 and APOE, play a key role in the microglial response and Aβ clearance.

Activation of complement signaling (a mechanism of the immune system) also contributes to Aβ clearance after immunization.

Brown amyloid beta plaques are visible in the slide on the left, which contains a tissue sample from an untreated brain with Alzheimer’s disease. There are no plaques in the tissue sample on the right, which is from a treated brain. Credit: Northwestern University.

These findings help us better understand how the immune system responds to immunization treatments and what factors may influence their effectiveness.

By identifying genes that regulate the removal of Aβ, the study paves the way for the development of new therapies that enhance this process, making immunizations more effective and reducing side effects.

With this advance, scientists hope that future immunotherapies for Alzheimer’s can be improved, offering new hope for patients suffering from this neurodegenerative disease.

READ MORE:

Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease

Lynn van Olst, Brooke Simonton, Alex J. Edwards, Anne V. Forsyth, Jake Boles, Pouya Jamshidi, Thomas Watson, Nate Shepard, Talia Krainc, Benney MR Argue, Ziyang Zhang, Joshua Kuruvilla, Lily Camp, Mengwei Li, Hang Xu, Jeanette L. Norman, Joshua Cahan, Robert Vassar, Jinmiao Chen, Rudolph J. Castellani, James AR Nicoll, Delphine Boche and David Gate

Nature Medicine. 6 March 2025

DOI: 10.1038/s41591-025-03574-1

Abstract: 

Alzheimer’s disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aβ removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) in microglia across immunization approaches, which correlate positively with antibody responses and Aβ removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance. Importantly, our work uncovers potential molecular targets that could enhance Aβ-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD.