Skip to cookie consent Skip to main content

Research Spotlight: Uncovering ApoE3 Christchurch’s Multi-Pathway Defense Against Alzheimer’s

Joseph Arboleda-Velasquez, PhD headshot

Joseph Arboleda-Velasquez, PhD, co-senior author, Paula Perez-Corredor, MS, and Said-Arévalo Alquichire, PhD, co-lead authors, all of the Schepens Eye Research Institute of Mass Eye and Ear, published a paper in Alzheimer’s & Dementia, “ApoE3 Christchurch and tau interaction as a protective mechanism against Alzheimer’s disease.”

Q: How would you summarize your study for a lay audience?

ApoE3 is one version of a gene that plays a key role in brain health. Our study focuses on a rare form of this gene, called ApoE3 Christchurch (ApoE3Ch), which may help protect against Alzheimer’s disease.

We became interested in this variant after learning about a woman with a strong genetic risk for early-onset Alzheimer’s who remained mentally healthy for decades. To understand why, we ran lab experiments and analyzed brain tissue. We found that ApoE3Ch interacts with tau—a protein that forms harmful clumps in Alzheimer’s—and helps prevent this buildup. It also supports a brain-protective system called Wnt signaling, which helps keep brain cells healthy.

These findings suggest that ApoE3Ch may protect the brain in more than one way and could help create new therapies that mimic its effects

Q: What knowledge gap does your study help to fill?

We wanted to understand how ApoE3Ch might protect people at risk of developing Alzheimer’s. Specifically, we asked whether this variant interacts directly with harmful proteins like tau and whether it activates other protective pathways in the brain.

Our goal was to uncover how ApoE3Ch works at a biological level and whether those mechanisms could lead to new ways to prevent or treat Alzheimer’s.

Q: What methods or approach did you use?

We used mass spectrometry—a technique that identifies and measures proteins—to map how ApoE3Ch interacts with other proteins in the brain. We compared these interactions to those of the more common ApoE3 version to see what makes ApoE3Ch unique.

To confirm our findings, we ran a series of lab experiments, including tests in special cell lines designed to detect tau buildup. We also tested the effects of ApoE3Ch in a mouse model that mimics Alzheimer’s-related brain changes.

Q: What did you find?

We found that ApoE3Ch binds more tightly to tau than the standard ApoE3, helping to prevent it from forming toxic clumps. This effect was seen in both lab tests and living models.

We also discovered that ApoE3Ch interacts with a protein called Dkk1, which normally blocks Wnt signaling—a pathway that supports brain cell health. By binding to Dkk1, ApoE3Ch may help keep this protective pathway active.

Q: What are the implications?

These findings suggest that ApoE3Ch may protect the brain in two important ways: by preventing tau buildup and by supporting Wnt signaling. Together, these effects offer a strong, multi-layered defense against Alzheimer’s-related damage.

This opens the door to new treatment strategies, including the possibility of using ApoE3Ch itself—or therapies inspired by it—to help protect against Alzheimer’s.

Q: What are the next steps?

We’re now working to turn these discoveries into potential treatments. One approach focuses on developing therapies that mimic ApoE3Ch’s ability to support brain-protective pathways.

We’re also expanding our research to explore how ApoE3Ch interacts with other Alzheimer’s-related proteins. To fully understand its long-term effects, we plan to test these strategies in both lab and clinical settings.

Authorship: In addition to Perez-Corredor, Said Arevalo-Alquichire and Arboleda-Velasquez, Mass General Brigham authors include Said Arevalo-Alquichire, Randall C. Mazzarino, Michael O’Hare, Andres F. Muriel-Torres, Timothy E. Vanderleest, William P. Miller, Lina Pineda-Lopez, Shivani Patel, Nihat Polat, Leo A. Kim

Paper cited: Perez-Corredor, P., et al. “ApoE3 Christchurch and Tau Interaction as a Protective Mechanism Against Alzheimer’s Disease.” Alzheimer’s & Dementia, 2025. DOI: 10.1002/alz.70396  

Funding: This work was supported by grants from the Remondi Family Foundation, the Edward N. & Della L. Thome Memorial Foundation, the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, and the Good Ventures Foundation

Disclosures: Joseph F. Arboleda-Velasquez is listed as a co-inventor on a patent related to therapeutics based on the ApoE3 Christchurch findings filed by Mass General Brigham. Joseph F. Arboleda-Velasquez and Leo A. Kim are co-founders of Epoch Biotech, a company developing therapeutics inspired by the Christchurch variant. All other authors report no conflicts of interest 

Media contact

Ryan Jaslow
Program Director, External Communications (Research)
rjaslow@mgb.org