Abstract

Prior work suggests females may develop Alzheimer disease (AD) dementia at a higher rate than males, and that this effect may interact with apolipoprotein (APOE) ε4 genotype. However, this work has often been limited by imprecise clinical diagnoses and a lack of AD biomarkers. In addition to the frequency of dementia, there are mixed reports on whether sex impacts rates of cognitive decline. Further, females consistently exhibit greater accumulation of AD pathological biomarkers, particularly tau, than males. It has been theorized that females initially demonstrate resilience to AD pathology, maintaining cognitive functioning longer than males, but experiencing a steeper cognitive decline as the disease progresses. To understand the role sex plays in AD we conducted two studies. The first Study (Study 1) investigated the influence of sex and APOE ε4 status on risk of AD, as well as the effects of sex on cross-sectional and longitudinal cognition. The second Study (Study 2) explored sex differences in the relationships between AD pathology levels and cognition cross-sectionally and longitudinally. Participants were selected from the Charles F. and Joanne Knight Alzheimer Disease Research Center. In Study 1, we characterized cognition in two ways. Dementia severity was assessed using Clinical Dementia Rating (CDR) scores and cognitive performance was assessed using neuropsychological tests combined into a Preclinical Alzheimer Cognitive Composite (PACC). Based upon the epidemiological literature we were interested in whether sex impacted the incidence rate of developing dementia. Dementia was defined using three approaches to mirror different standards in the field. First, all-cause dementia, or any sign of decline, provided insight into sex differences in dementia risk within general populations. Second, restricting analyses to clinically diagnosed AD accounted for clinician-based identification of the disease. Finally, defining AD using biomarker-confirmed amyloid-beta (Aβ) status, alongside cognitive impairment, aligned with the biological framework of AD. For risk analyses, only participants who were cognitively normal at baseline (CDR = 0) were included. Cox proportional Hazards were used to estimate risk of developing dementia. As expected, overtime, APOE ε4 carriers had a significantly higher risk of all cause dementia compared to non-carriers with an 84.5% increased risk (HR = 1.85 [1.50–2.27], p < 0.0001), a 97% increased risk of clinical AD dementia (HR = 1.97 [1.55–2.51], p < 0.0001), and a 276.3% increased risk of dementia in individuals with biomarker-confirmed Aβ, (HR = 3.76 [2.38–5.94], p < 0.0001). There were no significant differences between males and females in the likelihood of developing all-cause dementia (HR = 0.93 [0.76-1.14], p = 0.5), clinical AD dementia (HR = 0.95 [0.75-1.2], p = 0.6), or dementia in Aβ-positive participants (HR = 1.1 [0.70-1.7], p = 0.7). Additionally, APOE ε4 status did not differ by sex in predicting dementia risk (HR = 0.96 [0.6-1.4] p = 0.8, HR = 0.99 [0.6-1.6] p = 1.0, HR = 0.85 [0.3-2.1] p = 0.7, respectively). As a compliment to analyzing overt dementia in Study 1, we analyzed continuous cognitive performance using a neuropsychological composite. To assess sex differences, we stratified the cohort into cognitively unimpaired individuals and a combined group of unimpaired and impaired individuals. We then further restricted our analysis to Aβ-positive participants. This allowed us to examine sex differences in normative cognition and determine whether cognitively impaired females experience faster decline than impaired males. By focusing on Aβ-positive individuals, we assessed sex differences and cognitive decline in individuals on an AD pathological trajectory. Cross-sectional analyses utilized linear regression models and longitudinal analyses employed linear mixed effects models. Females demonstrated superior cognitive performance at baseline in the unimpaired subgroup (β = 0.12, t = 4.7, p < 0.0001), Aβ-positive unimpaired subgroup (β = 0.15, t = 4.5, p < 0.0001), unimpaired and impaired subgroup (β = 0.14, t = 4.5, p < 0.0001) and Aβ-positive unimpaired and impaired subgroup (β = 0.2, t = 4.7, p < 0.0001). There was no evidence to suggest sex-based differences in cognitive decline over time in the unimpaired subgroup (β = -0.002, t = -0.6, p = 0.5) or the Aβ-positive unimpaired subgroup (β = -0.001, t = -0.3, p = 0.8). Additionally, there were no significant differences in PACC slopes between males and females in the unimpaired subgroup (t = -1.03, p = 0.3) or in the Aβ-positive unimpaired subgroup (t = 0.3, p = 0.7). In both the unimpaired and impaired subgroup (β = -0.003, t = -0.6, p = 0.6) and the Aβ-positive unimpaired and impaired subgroup (β = 0.003, t = 0.3, p = 0.8), impaired females did not exhibit a faster rate of cognitive decline than impaired males. Further, the effect of sex on PACC slopes did not significantly differ across CDR groups in both the unimpaired and impaired subgroup (F=1.6, p=0.2) and the Aβ-positive unimpaired and impaired subgroup (F=1.6, p=0.2). In Study 2, we examined whether there was any evidence that sex infers an inherent resistance or vulnerability to AD pathology. To test this question, we tested if sex alters the relationship between levels of baseline AD pathology and both cross-sectional and longitudinal cognition. First, we studied the relationship between tau and cognition using the PACC neuropsychological composite. We then studied the relationship between Aβ pathology and cognition. We also further restricted our analysis to Aβ-positive participants to examine effects in individuals on an AD pathological trajectory. Cross-sectional analyses utilized linear regression models and longitudinal analyses employed linear mixed effects models. Greater baseline tau was associated with worse PACC scores at baseline in the full group (β = -1.1, t = - 6.2, p < 0.001) and in the Aβ-positive subgroup (β = -1.3, t = -5.3, p < 0.001). Longitudinally, greater baseline tau was associated with steeper rate of decline on PACC scores in the full group (β = -0.2, t = -3.2, p = 0.001) and in the Aβ-positive subgroup (β = -0.3, t = -2.7, p = 0.007). The adverse effect of baseline tau on baseline cognition was more pronounced in females compared to males in the full group (β = -0.48, t = -2.0, p = 0.04) and Aβ-positive subgroup (β = -0.84, t = -2.5, p = 0.01). Compared to males, females demonstrated slower longitudinal slopes relative to baseline tau, indicative of greater cognitive resilience to similar levels of baseline tau pathology over time in both the full cohort (β = 0.3, t = 3.3, p = 0.0009) and the Aβ-positive subgroup (β = 0.5, t = 3.5, p = 0.0005). This pattern aligns with the hypothesis that females may maintain better cognitive functioning than males despite the presence of AD pathology. Greater baseline Aβ was also associated with worse baseline PACC scores in both the full group (β = -0.006, t = -6.9, p < 0.001) and the Aβ-positive subgroup (β = -0.0081, t = -5.0, p < 0.0001). Longitudinally, greater baseline Aβ was associated with a steeper decline in PACC scores, but this relationship was not statistically significant in either the full cohort (β = -0.0004, t = -1.9, p = 0.06) or the Aβ-positive subgroup (β = -0.0004, t = -0.9, p = 0.4). No sex differences were observed in baseline PACC performance in relation to baseline Aβ pathology in either the full group (β = 0.002, t = 1.5, p = 0.1) or the Aβ-positive subgroup (β = 0.004, t = 1.7, p = 0.09). Males and females showed similar longitudinal slopes relative to baseline Aβ in both the full cohort (β = 0.0002, t = 0.7, p =0.5) and the Aβ-positive subgroup (β = 0.0005, t = 0.8, p = 0.4), indicating no significant sex differences in the effect of baseline Aβ burden on PACC decline over time.

Committee Chair

Brian A. Gordon, PhD

Committee Members

Ryan Bodgan, PhD Denise Head, PhD

Degree

Master of Arts (AM/MA)

Author's Department

Philosophy/Neuroscience, and Psychology

Author's School

Graduate School of Arts and Sciences

Document Type

Thesis

Date of Award

Summer 8-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0002-6398-0726

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