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. The Fisher Center Lab is among the largest and most advanced facilities in the world dedicated to solving the mystery of Alzheimer’s disease and it is considered a prototype for Alzheimer’s research. The lab is currently led by our newly appointed director, Dr. Nathaniel Heintz, the James and Marilyn Simons Professor at The Rockefeller University.

The Fisher Center Lab has provided researchers around the globe with a conceptual framework for understanding disease process and continues to be at the forefront of one day finding a cure for Alzheimer’s. The lab is focused on identifying the precise molecular events that unfold in the very earliest stages of the disease, before significant formation of amyloid-beta plaques and tau tangles.

Dr. Heintz and his team believe that the key to effective intervention is to identify the processes that are responsible for three key features of Alzheimer’s disease:

• The first crucial feature to understand is 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, therefore, is to understand the molecular basis of this process and use this information to design an effective therapeutic strategy.
• The second and associated feature is the nature of aging in each of the cell types affected by Alzheimer’s disease. This, too, is a crucial molecular problem to understand, since the specific processes that unfold in the nervous system as cells age have remained obscure until quite recently.
• The third feature of the disease identified by the Fisher Center Lab is that the regulation of the APP gene, 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 cell types that are vulnerable to Alzheimer’s disease may provide a novel and powerful avenue toward slowing or stopping the 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, Dr. Heintz and his team have developed new technologies to enable these studies and have used them to characterize specific cell types in the human brain. This breakthrough is extremely 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. Understanding these differences, and leveraging how they are altered in the course of disease, will open up completely new paths 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 work 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 donors and Alzheimer’s donors for each of the affected brain circuits will be required in order 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 skillsets are complementary to one another. Human biology is extremely complicated—there are 12,000–14,000 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.