The role of signaling factors that modulate immune and metabolic function in Alzheimer's disease

Makoto Ishii, MD, PhD Joan and Sanford I. Weill Medical College of Cornell University


Irreversible loss of brain cells and brain function may already exist by the time patients start developing memory loss due to Alzheimer’s disease. Therefore, it is imperative to identify the earliest changes occurring in Alzheimer’s disease, as they may yield new ways to intervene before irreversible brain damage has occurred. During the very early stages of Alzheimer’s disease when the memory remains relatively intact, there are significant changes in immune and metabolic function that contribute to Alzheimer’s disease; however, the underlying cause of these changes remain unclear. The goal of this project is to identify the circulating factors that affect immune and metabolic function early in Alzheimer’s disease before the memory loss and determine how they are involved in the overall disease process.

Project Details

The goal of this project is to identify whether signaling factors in the blood that control important immune and metabolic functions are altered early in Alzheimer’s disease and to determine how these factors are involved in the overall disease process. In the first part of this project, signaling factors that control metabolic and immune function are measured in the blood of individuals at the earliest stages of Alzheimer’s disease. These factors are analyzed to determine if they are significantly altered during the earliest stages of Alzheimer’s disease, and if so, are these changes associated with cognitive and memory function. Importantly, we are also examining whether blood levels of these factors can help predict those individuals who are at the highest risk for developing significant memory decline in the future. In parallel, for the second part of this project, we have taken one of the most promising signaling factors identified from our earlier pilot study and are developing a new mouse model to understand the role of this factor in Alzheimer’s disease. Specifically, we are evaluating whether reducing this factor in our mouse model can prevent the memory loss and halt the pathological processes leading to the development of Alzheimer’s disease. While circulating immune and metabolic factors have been previously studied in Alzheimer’s disease, these older studies have relied mostly on classifying individuals by clinical criteria without any supporting evidence from the newly developed molecular markers, which may have led to misdiagnosis of the individuals and misinterpretation of the results. Furthermore, we are complementing our human studies with mechanistic studies in a newly developed mouse model, specifically testing the role in Alzheimer’s disease for one of our most promising factors identified from our preliminary screen. Therefore, this research project is truly translational in nature and takes a “bedside-to-bench” approach to identify new factors in the blood that are contributing to the development of Alzheimer’s disease. Once this project is completed, the foreseeable benefits include providing new insights into the signaling factors that lead to the early metabolic and immune changes seen in Alzheimer’s disease, which could lead to the development of novel therapies based on agents acting on these signaling factors. Additionally, the identification of the factors in the blood that are altered at the earliest stages of Alzheimer’s disease could lead to the development of new blood biomarkers that would further enhance the ability to diagnose or risk-stratify patients during the earliest stage of Alzheimer’s disease.