Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article


Doctor of Philosophy




Hegele, Robert A.


Neurodegenerative diseases are progressive, incurable conditions characterized by neuronal degeneration and protein aggregation, resulting in cognitive decline and/or motor dysfunction. Over half a million Canadians are affected with these diseases, and the number of cases is expected to rise as the aging population grows and average lifespans continue to increase. There are currently no curative treatments, and only few therapeutics are available to target disease symptoms or slow disease progression. Further, diagnosis can be challenging, relying on clinical features that are often highly heterogeneous between patients. Gaining a greater understanding of the full spectrum of genetic factors contributing to these diseases may offer the opportunity to more accurately assess risk of disease development, improve diagnosis, and identify potential therapeutic targets. By leveraging the unique study design of the Ontario Neurodegenerative Disease Research Initiative (ONDRI) — a multi-platform study characterizing neurodegenerative diseases and cerebrovascular disease (CVD) — I have made significant progress in the elucidation of overlapping genetic determinants across neurodegenerative diagnoses. Using a targeted next-generation sequencing (NGS) approach, I comprehensively genetically characterized the ONDRI cohort (n = 519), including participants diagnosed with: 1) Alzheimer’s disease (AD); 2) amyotrophic lateral sclerosis (ALS); 3) frontotemporal dementia (FTD); 4) mild cognitive impairment (MCI); 5) Parkinson’s disease (PD); and 6) CVD. I identified associations between common genotypes or haplotypes of high phenotypic effect and neurodegenerative disease presentation and features. I also assessed novel gene-disease relationships and the potential genetic overlap between neurodegenerative and cerebrovascular diagnoses through the assessment of rare genetic variation captured by the targeted NGS panel and gold-standard Sanger sequencing methods. Finally, I identified a novel association between Notch receptor 3 (NOTCH3) rare variants and CVD burden in participants with PD. The work presented throughout this Dissertation highlights the complexity of neurodegenerative disease genetic risk factors by demonstrating a large amount of overlap between specific diagnoses. The findings contribute to the longstanding effort to fully understand the genetic architecture of neurodegenerative diseases and improve therapeutic development, diagnostic tools, and progression prediction.

Summary for Lay Audience

Neurodegenerative diseases are conditions characterized by progressive deterioration of brain cells resulting in memory loss, behavioural changes, and lack of muscle control. It was projected that more than 500,000 Canadians were affected with these diseases in 2016 — a number that will continue to rise in tandem with the aging population. Currently, neurodegenerative diseases lack treatment options with no ability to stop progression or even slow it to a manageable capacity, and accurate diagnosis can be difficult. To mitigate these issues, the Ontario Neurodegenerative Disease Research Initiative (ONDRI) study is aiming to gain a greater understanding of the risk factors and disease course of multiple neurodegenerative diseases including: 1) Alzheimer’s disease; 2) amyotrophic lateral sclerosis; 3) frontotemporal dementia; 4) mild cognitive impairment; and 5) Parkinson’s disease, as well as determining how cerebrovascular incidents, such as strokes, may influence neurodegeneration. Within this Dissertation, I present my work studying the DNA changes, or “genetic variants,” that may be increasing the participants’ risk of disease. To do this, I applied a DNA sequencing method to look for genetic changes within 80 genes that are known to contribute to the risk of neurodegenerative disease or stroke. In doing so, I determined that genetic risk for the various neurodegenerative diseases is complex, with some individuals carrying common variants that increase their disease risk and others carrying DNA variants that are much rarer. I also identified new associations between genetic variants in specific genes and individual neurodegenerative diseases. Finally, my results suggested that in addition to genetic variants that increase risk of disease, there may be genetic variants that cause individuals with the same diagnosis to present differently from one another. The application of my findings may provide further insight into what is causing neurodegenerative diseases on a molecular level and will allow for the development of new treatments and gene-sequencing-based early-diagnosis and risk-assessment tools.