Association of Head Injury with Multimodal Alzheimer's Disease Biomarkers and Genetics

Abstract

Alzheimer’s disease (AD) affects over 7 million Americans aged 65 and older and is the seventh-leading cause of death in the United States. AD represents a tremendous social and economic burden, but development of prevention and/or curative strategies has been slow. While much attention is focused on potential pharmacological therapies to stop and/or reverse disease progression, there is growing interest in lifestyle modifications that may lower risk for developing AD. One key lifestyle-related factor that is associated with elevated dementia risk, including AD is head injury (HI), also called concussion or traumatic brain injury (TBI). HI is extremely prevalent, with studies estimating as many as one in four Americans have experienced one. HI is even more prevalent in at-risk populations, including military service members and contact sport athletes. However, the mechanism(s) responsible for the link between HI and AD risk are largely unclear. While prior work has linked HI to elevated AD biomarkers, particularly amyloid-β (Aβ) and tau measured using positron emission tomography (PET) and via pathological investigation, the evidence is highly varied and its significance unclear. In this thesis, we utilize multimodal biomarker and genetic tools to investigate potential mechanisms involved in the association of HI with AD risk. Chapter One is a systematic literature review of published studies that assessed whether individuals with HI had higher levels of deposited Aβ and/or tau as indicated by PET scans. Chapter Two is an original research report investigating whether AD fluid biomarkers are altered in participants with HI from the Alzheimer’s Disease Neuroimaging Initiative. Chapter Three presents an original research investigation of tau deposition levels in participants with TBI from the National Alzheimer’s Coordinating Center cohort. Finally, Chapter Four is an exploration of whether genetic risk for AD is associated with more severe concussions and/or poorer concussion recovery in student athletes and military service academy students. The complex relationship between HI and dementia risk is not fully characterized, but this body of work elucidates unique and novel associations of AD biomarkers and genetics with HI.