The principal activity of the Fisher Center Foundation is to provide funding to The Zachary and Elizabeth M. Fisher Center for Research on Alzheimer’s Disease (The Fisher Center Lab) at The Rockefeller University, one of the largest and most modern facilities in the world dedicated to solving the puzzle of Alzheimer’s disease and considered by many to be a prototype for Alzheimer’s research. The lab is currently being led by our newly appointed director, Dr. Nathaniel Heintz, the James and Marilyn Simons Professor at The Rockefeller University.

The Fisher Center has provided researchers around the globe with a conceptual framework for understanding the disease process and continues to be at the forefront of one day finding a cure for Alzheimer’s disease (AD).  The Fisher Center Lab is focused on identifying the precise molecular events that unfold in the very earliest stages of the disease before significant formation of AB plaques and Tau tangles. We believe that the key to effective intervention at this early stage is to identify the processes that are responsible for three key features of the disease. First, it is crucial to understand the nature of selective cellular vulnerability. As in all late onset human neurodegenerative diseases, very specific cell types are lost in the brains of Alzheimer’s patients in early phases of the disease whilst other cell types are resilient.

One key to intervention is to understand the molecular basis of this process, and to use this information to design an effective therapeutic strategy. A second and associated feature of Alzheimer’s disease is the nature of aging in each of the affected cell types. This, too, is a molecular problem and crucial to understand since the specific processes that unfold in the nervous system as cells age have been obscure until quite recently. A third key feature of the disease that we have discovered recently is that the regulation of APP, one of the important genes implicated in the disease, is different in each cell type. Defining the mechanisms that regulate APP (and perhaps other genes) in the vulnerable cell types in Alzheimer’s disease may provide a completely novel and potentially powerful avenue toward slowing or stopping progression of the disease.

Of course, discovery of the molecular details that underlie each of the processes outlined above is extremely challenging. Over the past several years, the Heintz laboratory has developed critical new technologies to enable these studies and has used them to characterize specific cell types in the human brain. This breakthrough is significant – each of the 500 – 1,000 discrete cell types in the human brain have unique molecular features that allow them to carry out their assigned roles in brain circuitry. It is understanding these differences, and leveraging how they are altered in the course of disease, that will provide the path to treatment.

Over the past year, The Fisher Center lab has developed new iterations of this powerful methodology to study the key cell types and circuits in Alzheimer’s disease. The data that emerged from this approach have shed new light on each of the three core features of the disease. Although analysis of cell types in samples from Alzheimer’s donors has begun and excitement is building, many more samples from control and AD donors for each of the affected brain circuits will be required to achieve the precision and accuracy needed to understand selective vulnerability, aging, and cell specific regulation as the disease unfolds.

It is important to note that these studies are at the very forefront of human disease research, and their execution requires teams of dedicated scientists whose skills are complementary. Human biology is extremely complicated – there are 12-14,000 expressed genes in each cell type, each with a specific function. Deciphering which of these is the lynchpin for the processes that unfold in human disease, and how to use this information to design therapies is the new frontier. The Fisher Center lab has the experimental acumen and the intellectual power to succeed in this endeavor.