Date of Award
Doctor of Philosophy (PhD)
Alzheimer’s disease (AD) is a devastating neurodegenerative disease that slowly claims the memories and experiences that comprise the life experiences of individuals that suffer from the disease. Despite a continually accelerating pace of research and discovery, a viable therapeutic intervention for AD has yet to be realized. There are a multitude of factors that may contribute to this difficulty including the challenge of separating the overall disease of Alzheimer’s from the clinically recognizable memory loss that occurs in what is now known to be the end-stage of the disease. Efforts to treat AD have increasingly turned toward very early disease states, before clinical signs and symptoms become apparent, as a number of clinical trials have failed to meet cognitive endpoints over the last 5-10 years – potentially due to the sole recruitment of individuals already experiencing significant cognitive decline.
One important aspect of AD treatment is identification. It is now recognized that the disease begins more than a decade before the signature symptoms of cognitive impairment become apparent. Identifying individuals in this “preclinical” disease state has become a primary focus of many investigators who believe that AD must be targeted and fought well before the clinical manifestations of memory impairment appear.
Biomarkers, indicators of normal biological or pathological processes that may be studied as a means to give individuals a disease diagnosis, prognosis, or theragnosis – provided a treatment is available for the disease in question – are of paramount importance in many diseases. AD has proved a difficult target to nail down reliable, sensitive, and specific biomarkers. This is in part due to analytical difficulties in major, core biomarkers of disease and in part due to setbacks in clinical trials of promising therapeutic candidates.
The current work begins with an overview of biomarker modalities used in AD; however, the primary focus is on protein biomarkers in cerebrospinal fluid (CSF). CSF provides an intimate window to the central nervous system that, in the case of AD, has shown the ability to identify and monitor disease progress over time in cohorts of cognitively normal and demented individuals. In an effort to pinpoint AD before clinical signs and symptoms manifest, biomarker research in preclinical AD has become a robust area of investigation. CSF biomarkers of amyloid pathology, neuronal damage, and neuroinflammation are discussed in two independent cohorts: the Adult Children Study (ACS) from Washington University in St. Louis and the Alzheimer’s Disease Neuroimaging Initiative.
The ACS cohort is comprised of middle-aged, cognitively normal individuals recruited on a volunteer basis from community dwelling participants with and without a family history of AD. The ADNI cohort is comprised of older individuals also recruited on a volunteer basis from community dwelling participants, though participants are recruited with respect to clinical status and include cognitively normal individuals, individuals with mild cognitive impairment, and individuals with AD, in addition to being older than the ACS cohort.
In both cohorts, it was found that CSF markers of amyloid plaques – one of two required pathological hallmarks that indicate AD – changed earlier than those of tau tangles, the second required pathological hallmark.
Currently, examining biomarkers on a group-wide basis is the best way to get an accurate picture of biomarkers at baseline and followup lumbar punctures (LPs). As the goal is to be able to give individual people a diagnosis and prognosis of their disease, the behavior of biomarkers is particularly interesting because studies have found that CSF Aβ42 changes up to 15 or more years before cognitive signs and symptoms become apparent and, hopefully, beginning treatment in this period will be helpful not only for diagnosing for individuals with AD dementia, but also for individuals with very early disease.
Chair and Committee
Anne David M. Fagan Holtzman
Chengjie Xiong, John Cirrito, Paul Kotzbauer,
Sutphen, Courtney, "Longitudinal Cerebrospinal Fluid Biomarkers of Alzheimer Disease: Movement Toward the Diagnosis, Prognosis and Staging of Disease" (2017). Arts & Sciences Electronic Theses and Dissertations. 1198.