University of Kentucky UKnowledge Theses and Dissertations--Gerontology College of Public Health 2014 A LIFE SPAN APPROACH TO THE RELATIONSHIP BETWEEN CHOLESTEROL, LATE ONSET ALZHEIMER’S DISEASE, AND COGNITIVE FUNCTIONING AMONG OLDER ADULTS Brian Downer University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Downer, Brian, "A LIFE SPAN APPROACH TO THE RELATIONSHIP BETWEEN CHOLESTEROL, LATE ONSET ALZHEIMER’S DISEASE, AND COGNITIVE FUNCTIONING AMONG OLDER ADULTS" (2014). Theses and Dissertations--Gerontology. 7. https://uknowledge.uky.edu/gerontol_etds/7 This Doctoral Dissertation is brought to you for free and open access by the College of Public Health at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Gerontology by an authorized administrator of UKnowledge. For more information, please contact [email protected]. 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Brian Downer, Student Dr. John Watkins, Major Professor Dr. John Watkins, Director of Graduate Studies A LIFE SPAN APPROACH TO THE RELATIONSHIP BETWEEN CHOLESTEROL, LATE ONSET ALZHEIMER’S DISEASE, AND COGNITIVE FUNCTIONING AMONG OLDER ADULTS _____________________________________ DISSERTATION _____________________________________ A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Gerontology at the University of Kentucky By Brian G. Downer Lexington, Kentucky Co-Directors: John F. Watkins, Professor of Gerontology and David W. Fardo, Assistant Professor of Biostatistics Copyright © Brian Gregory Downer, 2014 ABSTRACT OF DISSERTATION A LIFE SPAN APPROACH TO THE RELATIONSHIP BETWEEN CHOLESTEROL, LATE ONSET ALZHEIMER’S DISEASE, AND COGNITIVE FUNCTIONING AMONG OLDER ADULTS There is evidence that cholesterol presents an important risk factor for Alzheimer’s disease (AD), but the direction of this relationship is modified by age. High cholesterol during midlife and low cholesterol during late life are both associated with an increased risk for AD. This dissertation research engaged a life span approach to study the relationship between cholesterol, AD and cognitive functioning among older adults. The purpose of this research was to determine if trajectories of cholesterol from midlife through late life differ according to AD status and if these trajectories are associated with cognitive functioning during old age. This research employed a secondary analysis of cognitive, phenotypic and genetic data collected from subjects of the Framingham Heart Study (FHS) Original and Offspring Cohorts. Aim One involved creating three summary scores of the FHS neuropsychological battery. ROC analysis was used to determine which score best differentiated between cognitively normal, impaired and dementia subjects. Aim Two used generalized additive mixed models to examine trajectories of total, HDL and total/HDL cholesterol ratio according to AD status in the Original Cohort. Aim Three used mixed-effects models to examine the relationship between subject-specific trajectories of total cholesterol and cognition during old age. Aim One determined that a summary score that provided equal weight to each assessment in the FHS neuropsychological battery best differentiates between subjects classified as cognitively normal, cognitively impaired and dementia. The findings from Aim Two indicated that there are subtle differences in the longitudinal trajectories of total, HDL and total/HDL ratio according to AD status. The findings from Aim Three provide limited evidence for a relationship between subject-specific trajectories of total cholesterol and cognitive functioning later in life. Older adults in the highest quartile for cognitive functioning had lower total cholesterol at approximately 55 years of age, but there were no differences in the mean trajectories of total cholesterol according to cognitive functioning later in life. The findings from this research suggest that older adults with high cognitive functioning have lower total cholesterol during midlife, but life span cholesterol trajectories do not appear to be associated with AD status or cognitive function. KEYWORDS: Life span, Cholesterol, Alzheimer’s Disease, Cognition, Older Adults A LIFE SPAN APPROACH TO THE RELATIONSHIP BETWEEN CHOLESTEROL, LATE ONSET ALZHEIMER’S DISEASE, AND COGNITIVE FUNCTIONING AMONG OLDER ADULTS By Brian Gregory Downer David Fardo, PhD Co-Director of Dissertation John Watkins, PhD Co-Director of Dissertation John Watkins, PhD Director of Graduate Studies June 2, 2014 DEDICATION To My Grandparents ACKNOWLEDGMENTS This dissertation would not have been possible without the support and guidance of a countless number of individuals. I first want to thank my dissertation committee, Drs. John Watkins, David Fardo, Frederick Schmitt, Steven Estus, and Wayne Sanderson, as well as Dr. Glen Mays who served as outside examiner, for their mentorship throughout this entire process. I especially want to acknowledge the efforts of my dissertation co-chairs, Dr. Watkins and Dr. Fardo. First, John Watkins who challenged me intellectually and pushed my thinking to a level a never thought was possible. Second, David Fardo who patiently guided me throughout the duration of my research and who made himself available at a moments notice. I also want to thank Dr. Faika Zanjani who served as my primary advisor and mentor. Dr. Zanjani exemplifies what it means to be an advisor and mentor, and I will be forever grateful for the opportunities she provided me while a student in her lab. I also need to acknowledge the unending encouragement that I received from my friends and family. First, my girlfriend Paige Birkelbach, who supported me through all of the ups and downs of my research, and often times had more confidence in my abilities than I did. Next, my friend, Jared Neumann, who I could always count on too distract me from the stress of trying to complete my dissertation. Also, I need to recognize my classmates and colleagues who supported me in immeasurable ways throughout my time at the University of Kentucky. Finally, my parents, Jane and Greg Downer, and my brother, Ben, and sister, Lorraine, who gave me unconditional love and support through this entire process. iii TABLE OF CONTENTS Acknowledgements ........................................................................................................................ iii List of Tables ................................................................................................................................ vii List of Figures .............................................................................................................................. viii Chapter One: Introduction and Background ................................................................................... 1 Alzheimer’s Disease Research: A Brief Historical Review ............................................... 3 Understanding Plaques and Tangles ..................................................................... 7 Do Plaques and Tangles Cause Alzheimer’s Disease? ......................................... 8 An Increase in Public Awareness of Alzheimer’s Disease ................................. 10 The Future of Alzheimer’s Disease Research ...................................................... 14 Purpose and Objectives of Dissertation Research ............................................................ 17 Chapter Two: Review of the Literature ........................................................................................ 25 Background ...................................................................................................................... 25 Types of Cholesterol ........................................................................................... 26 Maintaining Cholesterol Homeostasis ................................................................ 26 Effects of Diet on Cholesterol Homeostasis .........................................