A pioneering investigation from the Icahn School of Medicine at Mount Sinai has illuminated one of the most comprehensive portraits yet of how brain cells communicate—and how that intricate dialogue deteriorates in Alzheimer’s disease. The research, published in Cell on 25 September, represents a major leap in understanding the cellular crosstalk underlying neurodegeneration. By mapping the complex web of protein interactions that govern communication between neurons and supporting cells, the team has revealed a systemic breakdown in this network that could explain why brain function collapses as the disease progresses. Notably, the study not only highlights how these failures occur but also identifies several potential therapeutic targets that may help restore healthy cellular communication and slow cognitive decline.
The Mount Sinai-led team analysed protein activity in post-mortem brain tissue samples from nearly two hundred individuals, both with and without Alzheimer’s disease. Using cutting-edge proteomics—the large-scale study of proteins—and advanced computational modelling, the researchers created an extensive “map” of how more than 12,000 proteins interact within the brain. This holistic approach allowed them to detect patterns of dysfunction that traditional methods, which tend to focus on single molecules such as amyloid or tau, often overlook. Their findings revealed that disruptions in communication between neurons and glial cells—particularly astrocytes and microglia—are central to the pathology of Alzheimer’s. These glial cells, which generally provide essential support, protection, and maintenance for neurons, appear to lose their regulatory balance in the disease, becoming hyperactive and contributing to inflammation and neural damage.
The study’s senior author, Bin Zhang, PhD, Willard T.C. Johnson Research Professor of Neurogenetics and Director of the Center for Transformative Disease Modeling, emphasised that Alzheimer’s must be understood as more than an accumulation of plaques or dying neurons. “Our work shows that the breakdown of communication within the brain’s ecosystem—between neurons and glial cells—is likely a key factor driving disease progression,” he explained. This interpretation challenges decades of Alzheimer’s research, which the amyloid hypothesis has dominated. While amyloid plaques and tau tangles are indeed hallmark features of the condition, targeting them directly has yielded only limited success in clinical trials. The Mount Sinai study suggests that a broader systems-level failure may be the actual cause, where the delicate equilibrium of cellular interactions is disrupted long before symptoms appear.
A particularly striking aspect of the research is the identification of a protein called AHNAK as a major driver of pathological changes in the Alzheimer’s brain. AHNAK, which is abundant in astrocytes, was found to increase significantly as the disease advanced. Its levels correlated with heightened concentrations of toxic proteins such as amyloid beta and tau. Laboratory experiments using human stem-cell-derived brain models confirmed that reducing AHNAK expression led to decreased tau accumulation and improved neuronal function. Co-senior author Dongming Cai, MD, PhD, of the University of Minnesota, noted that these results “suggest that AHNAK could be a promising therapeutic target. By lowering its activity, we saw both less toxicity and more neuronal vitality.” This discovery provides compelling evidence that modulating glial activity could help rebalance brain function, potentially reversing or slowing the degenerative process.
The study’s use of an “unsupervised” analytic framework was another major innovation. Co-senior author Junmin Peng, PhD, from St. Jude Children’s Research Hospital, explained that the approach allowed researchers to identify critical protein networks without bias. “By examining how thousands of proteins interact, rather than starting with assumptions about which ones matter, we gained an unprecedented view of the proteomic alterations underlying Alzheimer’s,” he said. This systems-biology perspective enabled the discovery of over three hundred previously underexplored proteins linked to the disease. These proteins may hold the key to understanding individual variations in disease onset and progression, offering new directions for both basic research and clinical investigation.
Another important insight from the study concerns how genetic and biological factors modulate these protein networks. Individuals carrying the APOE4 gene variant—a well-known risk factor for Alzheimer’s—showed markedly different patterns of network disruption compared with those without the gene. Similarly, the data suggested potential differences between men and women in how these cellular communication systems respond to stress and disease. Such findings underscore the importance of personalised medicine approaches in future Alzheimer’s research, recognising that therapeutic strategies may need to be tailored to a patient’s unique genetic and molecular background. The team has made their entire dataset publicly available, inviting scientists worldwide to explore these connections and accelerate progress across the field.
Ultimately, this study redefines Alzheimer’s as a disorder of broken communication rather than merely one of toxic buildup. By revealing how the interplay between neurons and glia governs the brain’s overall resilience, it opens a new conceptual framework for understanding neurodegeneration. As Dr Zhang eloquently summarised, “This research helps us see Alzheimer’s not as a static disease but as a dynamic failure of interaction. If we can understand where those conversations between brain cells go wrong, we can start finding ways to repair them.” The work thus marks a significant step towards developing therapies that target the root causes of cognitive decline—by restoring balance and harmony to the brain’s intricate network of cellular communication rather than simply clearing away its debris.
More information: Bin Zhang et al, Multiscale proteomic modeling reveals protein networks driving Alzheimer’s disease pathogenesis, Cell. DOI: 10.1016/j.cell.2025.08.038
Journal information: Cell Provided by The Mount Sinai Hospital / Mount Sinai School of Medicine
