APOE4 dependent regulation of CSF Complement Pathway Activation in the development of Alzheimer's Disease

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Project Summary/Abstract Dementia is a common disorder that increases in frequency in the elderly. Dementia is a progressive loss of thinking and memory skills that eventually results in an inability to care for oneself and to live independently. The most common cause of dementia in older Americans is Alzheimer’s disease, which develops as a result of multiple lifestyle/environmental factors and inherited or familial causes. Many familial traits (such as the risk of developing Alzheimer’s disease are inherited genetically, through gene variants (sequences of a chemical code called DNA). The most common genetic variant that increases the risk of Alzheimer’s disease in older adults (ie above age 60) is called APOE4. Although we have known for over 25 years that inheriting an APOE4 genetic variant (also called an allele) increases Alzheimer’s disease risk, it is unclear how and why APOE4 increases this risk. Recent data has raised the possibility that APOE4 may act by increasing the activation of the complement pathway, a set of proteins that are used by immune cells to kill and eat bacteria, and that also play a role in “killing” and “eating” connections between nerve cells in the brain, known as synapses. In this project, we will examine whether people that carry the APOE4 allele (either 1 or 2 copies of this allele) have increased evidence of complement pathway activation in the fluid that bathes their brain and spinal cord, known as the cerebrospinal fluid (CSF). We will also determine whether CSF complement pathway activation in APOE4 allele carriers is associated with long term cognitive decline over a 7.5 year period. Finally, we will determine whether modulating APOE biology in vivo with a peptide that “mimics” the disease-resistant APOE2 allele. This work will be performed using an advanced method that can measure the levels of a large percentage of all proteins present in human CSF, and which can precisely measure the levels of proteins in the complement pathway. Overall, this work will help us understand how and why APOE4 changes the function of the brain, and how and why it contributes to AD risk. This work is an early step towards identifying proteins or pathways that could be targeted by drugs to prevent Alzheimer’s disease in people that carry an APOE4 allele.