An APOE-Linked Plasma Profile and Relevance to Behavior and Neurodegeneration

Alzheimer’s disease is a disease of the brain and for which the risk is determined by a heritable factor, the APOE4. We will investigate potential effects of a specific APOE4-linked bloodborne molecule on disease-related changes inside the brain. A successful discovery of a factor that can be targeted in the blood rather than the in brain, for the cure or prevention of Alzheimer’s disease, would facilitate the development of medication to prevent the disease.

The goal of our studies is to elucidate the role and potential impact of liver-derived apolipoprotein E in the blood on the risk and pathogenesis of Alzheimer’s disease. The APOE4 gene variant, present in approximately 15-20% of the general population, dramatically increases the risk of neurodegenerative diseases like Alzheimer’s disease and dementia with Lewy bodies. We have previously documented an APOE4-specific phenotype in plasma that appears to be important for processes in the brain. In the current project we will expand on those studies by developing a high-throughput laboratory assay based on mass-spectrometry for accurate and precise quantification of apolipoprotein E in body fluids and use this assay to examine the blood levels of apolipoprotein E in patients with sporadic and familial Alzheimer’s disease. Furthermore, we will in detail assess the effects of a human liver-generated plasma phenotype on pathological processes in the brain and behavioral outcome by use of an animal model with humanized livers. Our studies combine clinical and experimental approaches to elucidate processes that may underlie the increased risk of neurodegenerative diseases in carriers of the APOE4 gene variant. A potential role of the liver in the APOE4-associated risk and pathogenesis of neurodegenerative diseases has so far been grossly neglected and with our project we hope to pave the way for a paradigm shift in the research aiming to find a prevention or cure for Alzheimer’s disease.