Published online in Cell on September 25, the study analyzed protein activity in brain tissue from nearly 200 individuals. The researchers discovered that disruptions in communication between neurons and supporting brain cells called glia—specifically astrocytes and microglia—are closely linked to the progression of Alzheimer’s disease. One protein in particular, called AHNAK, was identified as a top driver of these harmful interactions.
“Alzheimer’s is not just about plaque buildup or dying neurons; it’s about how the entire brain ecosystem breaks down,” said senior author Bin Zhang, PhD, Willard T.C. Johnson Research Professor of Neurogenetics and Director of the Center for Transformative Disease Modeling at the Icahn School of Medicine. “Our study shows that the loss of healthy communication between neurons and glial cells may be a major cause of disease progression.”
Most Alzheimer’s research has focused on the accumulation of amyloid plaques and tau tangles. But these protein buildups alone don’t explain the full story, and some treatments targeting plaques yield only modest benefit. In this study, the team took what’s known as an “unsupervised” approach—an analysis that doesn’t begin with assumptions about which proteins matter most—by examining brain tissue samples from nearly 200 individuals with and without Alzheimer’s disease.
“This study took a broader view, examining how more than 12,000 proteins interact inside the brain,” said co-senior author Junmin Peng, PhD, Member and Professor of Structural Biology and Developmental Neurobiology at St. Jude Children's Research Hospital. “Using state-of-the-art proteomics profiling technology, we quantified protein expression across the brain, enabling a comprehensive view of proteomic alterations and interactions in Alzheimer’s.”
Using advanced computational modeling, they built large-scale networks that mapped how these proteins interact and pinpointed where communication breaks down in disease, enabling identification of entire systems that go awry, rather than focusing on a single molecule. The most critical of these systems is glia-neuron communication, which lies right at the center of the proteomic networks of Alzheimer’s. In healthy brains, neurons send and receive signals, while glial cells support and protect them. But in Alzheimer’s, this balance appears to be lost: glial cells become overactive, neurons become less functional, and inflammation rises. This change was consistent across multiple independent datasets.
By analyzing how the proteomic networks shifted in Alzheimer’s, the researchers identified a number of “key driver” proteins—molecules that seem to play outsized roles in triggering or accelerating the disease.
AHNAK, a protein found mostly in astrocytes, was one of the top-ranked drivers. The team found that AHNAK levels rise as Alzheimer’s progresses and are associated with higher levels of toxic proteins in the brain, such as amyloid beta and tau. To test its impact, they used human brain cell models derived from stem cells. Reducing AHNAK in these cells led to a drop in tau levels and improved neuron function when co-cultured in the lab.
“These results suggest that AHNAK could be a promising therapeutic target,” said co-senior author Dongming Cai, MD, PhD, Professor of Neurology and Director of the Grossman Center for Memory Research and Care at the University of Minnesota. “By lowering its activity, we saw both less toxicity and more neuronal activity, two encouraging signs that we may be able to restore healthier brain function.”
While AHNAK is a strong candidate for future drug development, the research also provides a broader framework for understanding and treating Alzheimer’s. The study identified more than 300 proteins that have rarely been studied in the context of the disease, offering new directions for research.
It also showed that different biological factors, like gender and genetic background, may influence how these protein networks behave. For instance, people with the APOE4 gene, a known genetic risk factor for Alzheimer’s, showed distinct patterns of network disruption compared to those without the gene.
While more work is needed to study AHNAK and other key proteins in living systems, the comprehensive data from this study is publicly available to researchers worldwide, accelerating progress across the field.
“This study opens up a new way of thinking about Alzheimer’s, not just as a buildup of toxic proteins, but as a breakdown in how brain cells talk to each other,” Dr. Zhang added. “By understanding those conversations and where they go wrong, we can start to develop treatments that bring the system back into balance.”
This work was supported in part by the National Institutes of Health (NIH)/National
Institute on Aging, grant numbers U01AG046170, RF1AG054014, RF1AG057440, R01AG057907, U01AG052411, RF1AG064909, R01AG068030, RF1AG074010, R01NS145483, R01AG085182, UH2AG083258, R01DA051191, R01AG063819, R01DE029322, R01AG062355, R21AI149013, R01AG062661, R01AG082362, and R01AG083941.
The paper is titled “Multiscale Proteomic Modeling Reveals Interacting Neuronal and Glial Protein Networks Driving Alzheimer's Disease Pathogenesis.”
###
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,600 clinical residents and fellows training throughout the Health System. Its Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 560 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges. More than 4,500 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
-------------------------------------------------------
* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
END