Can (Martin) Zhang, MD, PhD

Dmitry Prokopenko, PhD

Sean Miller, PhD

One hallmark of Alzheimer’s disease (AD) is the buildup of amyloid plaques outside brain cells. These plaques are made up of amyloid beta (Aβ), a protein fragment produced when a larger protein—amyloid precursor protein (APP)—is cut inside cells.

Because APP moves through cells and undergoes several processing steps before being broken down into Aβ, researchers see an opportunity to intervene earlier in this process, before harmful plaques form.

In a recent study led by Sean Miller, PhD, of Yale School of Medicine, along with Dmitry Prokopenko, PhD, and Can (Martin) Zhang, MD, PhD, of Mass General Brigham Neuroscience Institute, scientists highlighted the role of a specific intracellular protein called GBF1 in the trafficking and maturation of APP, and explored whether modulating this pathway could reduce Aβ generation. GBF1 emerged from the team’s genetic analyses as a gene of interest linked to Alzheimer’s disease risk.

Across multiple AD models, including human postmortem brain tissue and well-established mouse models, the researchers found that pathological changes in GBF1 closely co-occurred with amyloid plaques and other abnormal protein aggregates. Supporting this link, blocking or turning down GBF1 lowered amyloid-beta levels in lab-grown cells.

Together, these findings discover a new regulatory protein of disease pathogenesis and suggest that Alzheimer’s disease treatments could potentially target earlier cellular processes that drive amyloid buildup, rather than focusing only on clearing plaques once they’ve formed.

Published in Alzheimer’s & Dementia on April 16, 2026 | Read the paper: “Intracellular protein GBF1 displays significant associations with amyloid pathology in Alzheimer’s disease”

Summary reviewed by: Sean Miller, PhD, co-lead author; Dmitry Prokopenko, PhD, co-lead author; Can (Martin) Zhang, MD, PhD, senior author