Assessment of Associations Between a Molecule in the Blood, Behavior and Alzheimer’s Disease Related Changes Inside the Brain

Henrietta Nielsen, PhD
Stockholm University (Stockholm, Sweden)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2022
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2019446S
Award Type:
Standard
Award Region:
International
Henrietta Nielsen, PhD

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

Summary

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.

Details

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 underly 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.

About the Researcher

Dr Henrietta Nielsen received her PhD in medicine from Lund University, department of clinical sciences, Sweden, in 2007. Her doctoral studies aimed to assess the involvement of serine protease inhibitors, specifically alpha-1-antichymotrypsin, in neurodegenerative dementia disorders. She then moved on for postdoctoral studies at the VU Medical Center in Amsterdam, departments of neuropathology and clinical chemistry, the Netherlands, where she investigated the ability of primary human glial cells (astrocytes and microglia) isolated from autopsy-derived brain tissues, to ingest the amyloid-beta peptide in the presence/absence of various amyloid-associated proteins like apolipoproteins E and J. Dr Nielsen further got additional training as a postdoctoral fellow and assistant researcher at Lund University, Sweden, where she spear-headed fluid biomarker discovery efforts including cerebrospinal fluid and blood samples from patients with mild cognitive impairment, Alzheimer's and Parkinson's disease. Later, after working nearly four years at the Mayo Clinic, department of neuroscience, in Florida, USA, Dr Nielsen accepted a position as an assistant professor and principal investigator in neurochemistry at Stockholm University, Sweden. At Stockholm University she was recently given tenure as an associate professor in neurochemistry and she now splits her time between tenured positions at Stockholm University and Roskilde University, Denmark. Dr Nielsen's laboratory the 'Translational Neurodegeneration Group' has a major focus on investigating biological mechanisms promoting/leading to neurodegenerative dementia. As the strongest genetic risk factor for not only Alzheimer's disease but also dementia with Lewy bodies the Nielsen laboratory devotes a lot of time to better understand the biological processes linking APOE4 to the increased risk of neurodegenerative diseases. With nearly 12 years of reserach experience and extensive expertise in the field of neurodegenerative diseases Dr Nielsen serves as a senior editor for Molecular Neurodegeneration, an associate editor for the Journal of Alzheimer's Disease and an acadmic editor for Plos One.

Personal Story

I have always been inquisitive and a critical thinker by nature however it was merely chance or circumstances at the time that led me onto the path to become a scientist. Today I consider my line of work as a calling and I feel incredibly fortunate to have the opportunity to change the course of medicine with the potential to prevent or cure Alzheimer's disease. What in my view makes neurodegenerative disorders like Alzheimer's disease such devastating and terrible diseases not only to the patient her/himself but also the the family and friends of the patient, is the fact that the disease robs the patient of the core of their existence, their memories, their personality and in a sense their soul. Relatives and friends are forced to say goodbye to their loved one whilst they are in fact still present, there to see, there to love and there to hold. So many people around the world have to go through this painful process and me and my team work tirelessly to pave the way for an end to this suffering. The focus of my lab is to elucidate the biological processes that underly the dramatically increased risk of Alzheimer's disease in carriers of the APOE4 genotype. Unlike many other genetic risk factors, this is a very common gene variant which is present in 15-20% of the general population. The scientific community has known of the association between APOE4 and Alzheimer's disease for more than 25 years still we do not properly understand what the mechanism is that dictates which APOE4-carrier will develop Alzheimer's disease, since not all carriers do. Our project aims to assess a peripheral liver-associated phenotype as part of the processes that increase the risk of Alzheimer's disease in APOE4-carriers. Our approach is controversial and we are immensely grateful to the BrightFocus donors and the Foundation for their support that enables us to explore this new avenue relating to Alzheimer's disease. With our aims to investigate a peripheral, liver-associated phenotype as a potential mediator of the risk of Alzheimer's disease we hope to change the conventional thinking of neurodegenerative disease as a 'brain only' disease to a whole body disorder. Identification of specific processes that could be targeted in APOE4-carriers would enable the development of prevention strategies and overall in detail improve our understanding of Alzheimer's disease pathogenesis.

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