Sex Differences in the Genetic Architecture of Cognition Among Older Adults Spanning the Alzheimer’s Disease Clinical Spectrum

Abstract

Females comprise two-thirds of Alzheimer’s disease (AD) cases, and females have a twofold increased lifetime risk for AD as compared to males. Furthermore, females have a higher AD neuropathologic burden (i.e., amyloid and tau), driven by an increased tau tangle burden, a later stage hallmark pathology of AD. Neuropathology in females is more likely to present as AD dementia, and every unit of neuropathology harbors a 22-fold increased AD risk in females as compared to a 3-fold increased risk in males. Additionally, the literature shows robust sex/gender differences in cognition over time. Throughout life, clinically healthy women show cognitive advantages in episodic memory and verbal fluency, whereas clinically healthy men show advantages in nonverbal memory and visuospatial ability. However, in disease (i.e., AD), women tend to lose their cognitive advantages to men, declining more rapidly than their male counterparts. In addition, twin studies have shown AD to be 60-80% heritable, and genetic studies have identified a number of risk and protective loci associated with AD-related cognitive endophenotypes (i.e., measurable cognitive metrics). However, despite known sex/gender differences in AD risk and progression, genetic studies on AD cognitive endophenotypes have mainly been sex-agnostic, masking any sex-specific genetic effects. Thus, the overall goal of this dissertation is to characterize sex differences in the genetic architecture of Alzheimer’s diseaserelated cognitive trajectories and cognitive resilience (e.g., cognition accounting for pathology). We accomplish this goal through identifying sex-specific variant and gene associations with cognition (Aim 1), exploring X-chromosome associations with cognition (Aim 2), and finding shared genetic architecture between cognition and complex traits in each sex (Aim 3). Through these research aims, we identify sex-specific candidate genes conferring risk or resilience to ADrelated decline, sex-specific pathways of vulnerability to decline, and cross-trait associations revealing shared genetic architecture between cognition and relevant comorbid traits. Taken together, this dissertation provides the largest and most comprehensive exploration of sex-specific genetic drivers of cognition in older adults to date. This dissertation suggests that in the quest to identify the right treatment for an individual with AD, biological sex and genetic context may play an important and synergistic role.