The goal of the proposed research is to leverage genes associated with dyslipidemia and inflammation to systematically identify, validate and functionally characterize genes associated with Alzheimer’s neurodegeneration. I have a record of accomplishment in several domains of Alzheimer’s disease (AD) research. As an undergraduate student, my work identified false recognition and memory distortion in patients with AD. As a graduate student at Boston University and Massachusetts General Hospital, I developed an automated structural MRI-based parcellation atlas of the human cerebral cortex (now integrated into the FreeSurfer software package and used by major research groups worldwide). As a research fellow at Massachusetts General Hospital, I combined this cortical parcellation atlas with cerebrospinal fluid (CSF) biomarkers to identify individuals in the preclinical and very mildly symptomatic phases of the Alzheimer’s disease process. In my current position as research-track radiology resident and research fellow at the University of California, San Diego, I have expanded my research to study novel genes associated with AD risk. My current work involves leveraging known genetic associations from common diseases/phenotypes to discover and validate new genes associated with AD. Using this approach, I have identified a novel variant within the region as a susceptibility locus for AD, characterized the gene expression associated with this variant and shown a dose effect between this and longitudinal MRI-based atrophy of the medial temporal lobe. As a junior investigator, I am well positioned to execute and interpret studies that identify and validate genetic variants associated with Alzheimer’s disease and cardiovascular disease risk.
On February 17, 2017, I was diagnosed with amyotrophic lateral sclerosis, one of the very neurodegenerative diseases that has been the focus of my research for the past 17 years. ALS has completely destroyed my body; I can't speak, walk, use my hands or hold my head up. However, my mind and soul are strong. Using a hands-free setup, I am continuing my research with an entirely new perspective and a heightened sense of urgency. My team at the Laboratory for Precision Neuroimaging at UCSF is breaking new ground in understanding the genetic basis of the disease, in turn accelerating the development of individualized treatments. My vision is to help people like me who suffer from neurodegenerative diseases and for whom being alive is a daily struggle. We’ve always relied on scientists to tackle some of the toughest challenges of our time. Society needs scientists like us who can take tragedies and turn them into real innovation. Above all, we need your support to advance my team’s research and help ALS patients like me. What is the Laboratory for Precision Neuroimaging at UCSF? At the Laboratory for Precision Neuroimaging at UCSF, our mission is to integrate imaging with genetic, health, and behavioral data to understand, diagnose, and treat brain disease. We believe that brain disorders – from autism to schizophrenia and Alzheimer’s disease – have different underlying causes in different people. So our goal is to develop ways to identify these subgroups of people and target trials and treatments to their individual illness. What is the context of this research? Amyotrophic lateral sclerosis or ALS, popularly known as Lou Gehrig’s Disease, is a fatal neurodegenerative disorder characterized by progressive muscle paralysis that spreads rapidly leading to death from respiratory failure in 3-5 years. Although representing the second most common neurodegenerative disease in the Western world, the cause of ALS is poorly understood. Given the rapid disease progression and the absence of therapies, there is an urgent need to better understand ALS to expedite the development of therapeutic strategies. What is the significance of this project? For neurological illnesses like ALS and Alzheimer’s, identification of genetic risk factors has provided important insights into the mechanisms underlying the diseases. We have recently developed and validated genetic methods for discovering new genes associated with different diseases. In this project, we will use these tools along with data from 65 different traits acquired from over 3 million people worldwide to find new ALS genes. What are the goals of the project? The goal of this project is to help identify people who are at high genetic risk for ALS, and are developing heart disease or inflammation. Lowering cholesterol levels or inflammation in these people may hold the key to preventing ALS. We will exploit this large database to discover genes that are shared between ALS and modifiable risk factors such as high cholesterol and inflammation. We will then use cellular and molecular approaches to begin to define the role that these risk genes play in ALS-associated neurodegeneration. By unveiling the genetic basis of ALS, this work will improve our understanding of what causes ALS and identify new therapeutic targets.
Late-onset Alzheimer’s disease (AD), the most common form of dementia, places a large economic and financial burden on families and society and can be emotionally devastating to loved ones. While we know several things can affect AD, it is an incredibly complex disease, and there are likely other risk factors of AD that we still don’t understand. Over the past two decades cardiovascular disease (CVD) is being increasingly recognized as an important risk factor of AD. In this project, we are interested in seeing if there are specific changes to genes that are risk factors for CVD and risk factors for Alzheimer’s disease. If we can find genetic risk factors that overlap between CVD and AD, we could target these genes to prevent or delay the onset of Alzheimer’s disease. One way to identify the genetic risk factors for CVD that are also risk factors in AD is through large-scale genome-wide association studies (GWAS). In GWAS, human genomes – typically ones without a disease and ones with a disease – are compared to see if there are specific changes (or ‘genetic variants’) in the genomes of individuals with a specific disease. In this project, we plan to take GWAS a step further by using the genomes of patients with CVD to find new genetic risk factors for AD. By using this approach, we intend to identify a subset of genetic variants that are risk factors for dyslipidemia, inflammation (two CVD traits that can be treated and prevented) and AD. As a second step, to understand the role of these risk factors in AD, we will then investigate the relationship between each of these genes and known pathobiological markers of AD.1) Identify and validate genetic variants associated with AD and CVD traits. We plan to use GWAS to identify genetic variants that are common to traits of CVD (dyslipidemia and inflammation) and AD. 2) Determine the effect that these common genetic variants have on clinical and neuropathological measures of AD. We will determine the relationship between AD/CVD genetic risk variants and the presence of markers known to be elevated in AD.Late-onset Alzheimer’s disease (AD), the most common form of dementia, effects an estimated 30 million people worldwide, a number that is expected to quadruple in the next 40 years. In the brain (or ‘neuropathologically’), AD is characterized by the presence of amyloid-beta plaques and tau-associated neurofibrillary tangles. Since there are no current disease-modifying therapies and there has been an increasing awareness that symptoms of AD develop over many years, there is a strong need to develop effective strategies to prevent AD. If we could even delay the onset of dementia by a modest 2 years, we could potentially lower the worldwide prevalence of AD by more than 22 million cases over the next 40 years. Although previous studies have examined the association between AD and CVD traits, no study to date has fully identified the genetic and molecular basis of how dyslipidemia and inflammation influence AD. This project will provide us with a clearer understanding of how CVD and AD are related. Additionally, this study is the first step in research that is expected to lead to the development of novel strategies for preventing AD. Dyslipidemia and inflammation are effectively managed through current therapeutics; therefore, if we can identify an overlap between the genetic variants causing these CVD traits and AD, we could use drugs targeting dyslipidemia and inflammation to also treat, prevent, or delay AD.