Publication Date

2014-12-10

Availability

Embargoed

Embargo Period

2015-12-10

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Human Genetics and Genomics (Medicine)

Date of Defense

2014-06-23

First Committee Member

John R. Gilbert

Second Committee Member

Margaret A. Pericak-Vance

Third Committee Member

Gary W. Beecham

Fourth Committee Member

Deborah C. Mash

Fifth Committee Member

Derek M. Dykxhoorn

Abstract

Alzheimer disease (AD) is the most common form of dementia affecting approximately 13% of individuals 65 and older. Rare variants in the Amyloid precursor protein, Presenilin 1, or Presenilin 2 genes primarily cause Early-Onset Alzheimer disease and comprise 2% of AD cases. Conversely, Late-Onset Alzheimer disease (LOAD) is much more complex and accounts for greater than 90% of AD cases. Recent transcriptome studies have shed light on molecular functions altered in LOAD. Many of these studies have consistently observed alterations within several pathways: synaptic transmission, inflammation, energy metabolism, myelination, and signal transduction. While αβ plaques and neurofibrillary tangles (NFTs) are pathological hallmarks of Alzheimer disease, many clinical LOAD phenotypes are shared across other dementias, including cognitive decline and memory loss. Transcriptome studies have predominately compared Alzheimer samples to normal controls. Using this approach, it is often unclear if the observed disrupted processes in LOAD are specific to LOAD or are the result of non-specific general neurodegenerative effects. In this study, I deciphered the transcriptional and regulation changes observed in LOAD from those due to general neurodegeneration by using a disease control. In addition, two regulatory mechanisms that can influence transcription, ncRNAs and DNA methylation, were analyzed to determine their roles in the transcriptional changes specific to LOAD. This study revealed a wide disruption of transcription, splicing, and DNA methylation specific to LOAD and the general neurodegeneration process. In particular, LOAD specific changes were observed within cellular processes involved in myelination and the innate immune system. Further analysis revealed that strong LOAD specific disruptions of regulatory mechanisms of transcription (e.g. DNA methylation and ncRNAs) converged on cellular processes disrupted in LOAD, specifically processes involved in myelination. These results identified genes and processes specifically altered in LOAD, which could serve as potential avenues of treatment for LOAD. The use of additional types of neurodegenerative disease controls could allow the further honing in on genes specifically altered in LOAD and offers a very promising avenue for further investigations.

Keywords

Late-Onset Alzheimer's Disease; Transcriptome; Rna-seq; DNA methylation; Myelination

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