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.



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


CIRCUITS has its foundations in the Alzheimer’s Genome Project™ (AGP), headed by Rudy Tanzi, Ph.D., at Massachusetts General Hospital, and supported by Cure Alzheimer’s Fund since 2005. The AGP scanned the entire human genome from a large cohort of Alzheimer’s families for genes associated with risk for or protection against Alzheimer’s disease. The project identified dozens of risk genes, many of which currently are being investigated for therapeutic potential by CureAlz researchers.

“The AGP provided us with a wealth of genetic data,” explains Tanzi, “but to really understand how these genes are functioning in the disease, we need epigenetic data as well. That’s where CIRCUITS comes in.”


From Genetics to Epigenetics


Genes are sections of DNA that code for specific proteins. The APP gene, for instance, codes for the amyloid precursor protein. Mutations in these sections of code can lead to gain or loss of function as the mutated proteins perform differently than the typical version. Such changes can lead to dysfunction and disease in ways that, in many instances, scientists have been able to trace.

But recently, geneticists have found that genes themselves don’t tell the whole story. In addition to the genes in our DNA, there are vast sections of code that we are only just beginning to parse. Much of this DNA, which once was considered “junk,” is now thought to regulate whether and at what level genes are decoded into proteins.

“APP, APOE and other AD genes carry mutations that directly influence susceptibility to Alzheimer’s,” Tanzi explains, “but another section of DNA in the human genome might be responsible for regulating that gene. It’s just as important to understand this regulatory activity as it is to understand the gene defects themselves.”

These regulatory changes often take place through a process called DNA methylation. Molecules called methyl groups attach themselves to genes in DNA. The number and location of these groups will affect whether and how that section of DNA is made into proteins and used by the cell.

Epigenetics introduces new levels of complexity in our understanding of DNA, but also explains a great deal that our earlier concept of genetics could not. For instance, while an organism has the same DNA in each cell of its body, the location of methyl groups on the DNA can differ by cell type. This means that a neuron and a blood cell, for example, might have different patterns of methyl groups, and therefore identical genes produce different protein output in the different cell types. Additionally, evidence suggests that an organism’s life experience affects methylation, meaning how DNA is expressed can change over the course of an organism’s lifetime. As a result, two individuals born with the same gene variant impacting risk of disease still might face different levels of risk from that variant, depending on how their life experiences affect the methylation of that gene.

New Levels of Specificity

Manolis Kellis, Ph.D., of the Broad Institute and Massachusetts Institute of Technology (MIT), and Li-Huei Tsai, Ph.D., of MIT and a member of the Cure Alzheimer’s Fund Research Consortium, are leading a CIRCUITS project aimed at understanding these differences among cell types. “In the past, when researchers have looked at brain tissue for evidence of DNA changes linked to Alzheimer’s, they haven’t distinguished among cell types,” Kellis explains. “My project with Dr. Tsai will provide data specific to different cell types, so we’ll know whether the abnormal encoding is happening in neurons, glial cells or somewhere else.”

Other researchers are generating data from a variety of sources to build a comprehensive picture of changes seen in the disease. For example, Brad Hyman, M.D., Ph.D., of Harvard Medical School and Massachusetts General Hospital, will be comparing neurons grown from stem cells to actual brain tissue from the same patients. “With current stem cell technology,” explains Hyman, “we can take a patient’s skin cells, convert them back into stem cells, and then grow them into a new cell type, such as a neuron.” Hyman will be able to compare these lab-grown neurons with actual brain cells from the same patient upon autopsy. “No one has ever had the opportunity to compare stem cell models to brain cells from the very same individual,” says Hyman. “This experiment will be invaluable in telling us about possible limits of stem cell models, and if these newly generated cells differ from cells in tissue that has already lived many years.”

Analyzing and Disseminating Data


While researchers like Kellis, Tsai and Hyman are performing experiments to generate new data, other CIRCUITS researchers are working on ways to analyze that data. Winston Hide, Ph.D., of the University of Sheffield, brings his expertise as a computational biologist to the CIRCUITS team. Hide is working on the algorithms and database design needed to make sense of the volume and complexity of the experimental data produced by the other members of the consortium. Hide and Andreas Pfenning, Ph.D., of Carnegie Mellon, will employ “big data” computing and advanced biostatistics to reveal patterns and connections among the data inputs that would have gone unseen without such sophisticated tools. The end result will be a ranking of genes and epigenetic regulatory pathways based on their likely impact on Alzheimer’s disease, as well as their profile for potential drug intervention.

This data will be of vital importance to CureAlz researchers for future studies, but it also will be of great value to the Alzheimer’s field as a whole. “One of the primary goals of CIRCUITS,” Kellis explains, “is to generate data that can be widely distributed and used by any researcher. We don’t want to keep anything proprietary. We want this information to be used to get us to a cure as fast as possible.”