UCSF

Despite the tremendous burden of Alzheimer’s disease and related dementias (ADRD on patients, their families, and the public health system, there are still no effective treatments for the disease. Seeking a better understanding of important disease-subgroup-specific associations in a highly heterogeneous patient population, like those diagnosed with ADRD, can help facilitate the development of new therapeutics by enhancing clinical trial design. This thesis focuses on elucidating the genetic and transcriptomic underpinnings of the heterogeneities in ADRD and where these subgroups mechanistically converge.Chapter 1 focuses on features driving sex differences in AD progression to help reveal what protects some individuals and what makes others more vulnerable, ultimately informing the development of personalized therapeutics that benefit both sexes. Chapter 2 presents a meta-analysis of Alzheimer's disease genetics across multiple ancestries and highlights the current lack of diversity in neurodegenerative disease genetic research, suggesting a need for more inclusive studies. Chapter 3 links peripheral immune changes to familial tauopathy and early-onset Alzheimer's, showing altered monocytes in tauopathies and increased interferon-responsive T cells in EOAD. This chapter highlights the importance of the immune system in ADRD.