Revealing New Genes and Pathways at the Intersection of Lipotoxic and Genetic Risk for Alzheimer’s Disease

Complex diseases, including Alzheimer’s disease (AD), are caused by an interaction of genetic and environmental risk factors. Emerging genetic studies of late-onset AD implicate neuroimmune mechanisms and the brain’s resident immune cells, called microglia, in AD pathogenesis. In many cases, genetic risk factors only are revealed by an environmental trigger. One particularly damaging instigator of disease is the overconsumption of dietary lipids, predominantly in the form of triglycerides, that leads to the accumulation of free fatty acids (FFAs) in many organs, including the brain. This byproduct of modern human diets rich in excess lipids causes a detrimental condition known as lipotoxicity.

Historically, studies involving FFAs were limited, because there was no technology available that allowed scientists to study the entire spectrum of dietary FFAs and how they contribute to disease progression. Having built this technology, we now can expose human-derived microglia from individuals with either high or low risk of Alzheimer’s disease to a comprehensive library of diverse FFAs. This unique gene by environment analysis will provide insights into mechanisms of disease and will reveal a new way to derive patient risk profiles that goes beyond genetics. This experimental approach uses human microglial-like cells differentiated from induced pluripotent stem cells (iMGL) that represent a rigorous model for assessing microglial states and function in human neurological diseases. We will use an array of modern tools such as transcriptomics, engulfment assays, CRISPR knockout screens and inflammation-profiling assays to gain insights into how human microglia respond to a lipotoxic environment. In summary, our work will investigate how excess lipids can affect the health of the brain by exacerbating the genetic risk for Alzheimer’s disease.