Unraveling Clusters of Influential and Sex-Specific Risk Factors in the Progression to Alzheimer's Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting cognition, daily functioning, and quality of life. Women are disproportionately affected by Alzheimer’s disease, with two-thirds of patients being female. Additionally, women have different disease trajectories and poorer prognoses upon diagnosis than men (Hebert, Weuve, Scherr, & Evans, 2013). Exact mechanisms for the disproportionate burden in females are not well understood. As there are no disease-modifying treatments for AD, early detection and diagnosis are imperative to maximizing quality of life. My dissertation study builds on the work of my three written comprehensive examinations. In my first comprehensive examination, “Identity and Perceptions of Quality of Life in Alzheimer’s Disease,” I utilized qualitative methods to explore the patient and caregiver perspectives on living with AD and optimizing quality of life. My results revealed a process by which 1) changes in activity occur in response to the diagnosis 2) dyads discover new ways in which to mutually adapt and cope and 3) the person with dementia remains meaningfully engaged in their lives with a generally positive perception of quality of life (Manson, Ciro, Williams, & Maliski, 2020). By taking a person-centered approach to care and accounting for individual levels of baseline engagement, healthcare providers will be able to better identify individual changes over time and positively impact the patient quality of life. This written examination was published in the journal, Applied Nursing Research. Consistent with national statistics, a greater proportion of participants in this first comprehensive examination study were female. Intrigued, I dug into the literature to see if there were any explanations for the disproportionate female burden. I read a call to action paper and discovered there was a large gap in the literature regarding sex and gender differences in AD. Thus, I decided to pursue this line of research for my next comprehensive exam. In my second comprehensive exam, “Does Sex Play a Role in Verbal Memory Performance Related to Alzheimer’s Disease? A Systematic Review,” I completed a systematic review of sex differences in verbal memory (VM) performance across the cognitive continuum. The role of VM is particularly interesting as a decline in VM is a hallmark of early AD and is a large factor in the detection and diagnosis of AD. It is well established in the literature that, across the lifespan, healthy women typically score higher than men on assessments of VM. Emerging evidence suggests that women may have a VM domain-specific form of cognitive reserve which may help explain why women are diagnosed later and their trajectory of disease is different than men’s. Results of the systematic review revealed that while research on the role of sex on VM in AD is in its infancy, there is an emerging pattern where mild cognitive impairment (MCI) is a critical stage when the impact of sex becomes accentuated (Manson, Dean, Williams, & Maliski, 2019). In my third comprehensive exam, “The Interplay of Sex and Verbal Memory Performance from Normal Cognition to Alzheimer’s Disease: An Intricate Story,” I utilized quantitative methods to further investigate the pattern of VM change between men and women across the cognitive continuum. I completed retrospective analyses on two cohorts of participants from the University of Kansas Alzheimer’s Disease Center’s clinical cohort, which is part of the National Alzheimer’s Coordinating Center Uniform Data Set. Results from analyses with each cohort were inconsistent, highlighting the heterogeneity of disease trajectories, the importance of biomarkers to better describe the clinical syndrome, and the need to better understand the various phenotypes leading to AD. My comprehensive examinations provided the foundational work leading to my dissertation. I learned that disease trajectories are quite heterogeneous and that additional work was needed to begin addressing the gap in the literature regarding sex differences in disease profiles. As such, I took a comprehensive approach to help better define phenotypes of amnestic MCI (aMCI), a transitional stage between normal cognition and AD. Using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, results from my dissertation study, “Unraveling Clusters of Influential and Sex-Specific Risk Factors in the Progression to Alzheimer’s Disease,” revealed four subtypes of aMCI-AD, only one of which was predominantly female. Each subtype had a unique profile, highlighting the heterogeneity within the clinical syndrome, as well as the differences in profiles between men and women. Overall, my results demonstrate that the aMCI-AD population has various subtypes and multiple indicators should be considered to better detect the clinical syndrome