| dc.description.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. | |
