We have long known that advancing age and family history are the strongest risk factors for late-onset Alzheimer’s disease. What science has only recognized in the last two decades, however, is that the two interact—and their impact must be understood together. Although the genes we inherit from our parents—our genetics—do not change, and every cell carries the same DNA, the way and amounts that our DNA is translated into proteins—our epigenetics—is different in different cells, and can and does change with our life experience. Regulatory genes do not themselves encode proteins, but instead affect the expression of protein-encoding genes. CIRCUITS—the Collaboration to Infer Regulatory Circuits and Uncover Innovative Therapeutic Strategies—is investigating how the expression of regulatory genes differs in health and disease, at different stages of disease, and in different cell types and brain regions in these contexts.
The Alzheimer’s Genome Project™ (AGP), headed by Dr. Rudy Tanzi and funded by CureAlz, has identified many gene variants impacting either risk of Alzheimer’s or age of onset. Some of these variants—such as APOE4—are of genes that encode specific proteins; in that case, ApoE4. However, the majority of these risk variants are in regulatory genes. CIRCUITS is developing an extraordinary repository of information about how regulatory genes change gene expression over our lifespan in different cells and brain regions, how these changes differ in those who will or have developed Alzheimer’s disease, and how the risk variants identified by AGP relate to these changes. In a disease like Alzheimer’s, in which our risk increases as our bodies accumulate experience, and in which our genetics affects our risk but does not define it, understanding how epigenetic regulation ties experience to DNA is vital to understanding where and how to intervene.
CIRCUITS: FUNDED RESEARCHERS
Lars Bertram, M.D., University of Lübeck
Joseph R. Ecker, Ph.D., The Salk Institute
Winston Hide, Ph.D., Beth Israel Deaconess Medical Center
Bradley T. Hyman, M.D., Ph.D., Massachusetts General Hospital
Rudolf Jaenisch, M.D., Massachusetts Institute of Technology
*Manolis Kellis, Ph.D., Massachusetts Institute of Technology
Andreas Pfenning, Ph.D., Carnegie Mellon University
Rudy Tanzi, Ph.D., Massachusetts General Hospital
*Li-Huei Tsai, Ph.D., Massachusetts Institute of Technology