Date of Award

Fall 12-15-2017

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)




Michael A. Robbins

Second Committee Member

Merrill F. Elias

Third Committee Member

Emily A. Haigh

Additional Committee Members

Craig A. Mason

Geoffrey L. Thorpe


Associations of cardiovascular risk factors, cognitive performance, and depressive symptoms have been well established. However, the directionality of these associations as well as the specificity of these associations with respect to executive function are less clear. Additionally few studies have determined whether genetic risk factors, such as apolipoprotein-E4 (APOE-E4) genotype, and age moderate the associations of cardiovascular risk factors such as homocysteine with changes in depressive symptoms and how these associations may be mediated by cognitive performance. The primary aim of this study was to analyze the bidirectional associations of a full range of cognitive domains and symptoms of depression over a period of 5 years and to determine the extent to which the conditional associations of homocysteine (moderated by age and APOE-E4 genotype) and changes in depressive symptoms are mediated by cognitive performance. Additionally, we aimed to determine the extent to which these associations are specific to executive function as compared with other domains of cognitive function. After exclusions for probable dementia, kidney dialysis, and acute stroke, 719 adult participants were available for analysis for the sixth and seventh waves of the Maine-Syracuse Longitudinal Study. We conducted cross-sectional multiple linear regression analyses and cross-lagged panel analyses (CLPD) to determine the strength and directionality of associations for cognitive function and symptoms of depression. Next, we conducted conditional mediation path analyses to explore the associations of homocysteine (moderated by age and APOE-E4) and changes in self-reported depressive symptoms as mediated by cognitive function. All models were adjusted for wave 6 demographic covariates (age, sex, education, ethnicity, and marital status), cardiovascular risk profile (Framingham Risk Score), and depressive symptoms. In fully adjusted cross-sectional models, depressive symptoms were inversely associated with executive function and several other cognitive domains. In CLPD, cognitive performance was a stronger and more consistent predictor of changes in depressive symptoms (Executive Function, Global performance, Scanning and Tracking, and Visual-Spatial Organization and Memory) than depressive symptoms were of changes in performance. Although cognitive performance largely did not mediate the associations of cardiovascular risk factors (homocysteine and Framingham Risk Score) and changes in depressive symptoms, we did observe direct associations of Framingham Risk Score and changes in symptoms as well as significant moderation by age and APOE-E4 for the associations of homocysteine and changes in depressive symptoms. For APOE-E4 non-carriers, higher homocysteine was associated with symptom increases for individuals ≥ 74.33 years of age and for APOE-E4 carriers, there were marginal risks for individuals ≤ 45 years of age. The findings of this study have important clinical implications in assessing risk for and prevention of depressive symptoms both via maintenance of cognitive function and CVD risk reduction. Better executive functioning and performance in other cognitive domains was associated with lower levels of depressive symptoms over five years. Lower levels of CVD risk, both for the well-established CVD risk factors indexed by the Framingham Risk Score and for homocysteine, were associated with lower levels of depressive symptoms over five years. Moderation of depressive symptoms may be afforded through interventions designed to maintain executive function and to reduce risk relating to modifiable CVD risk factors such as homocysteine. Clinical trials with patient populations are needed to determine whether modification of homocysteine via dietary or physical activity adjustments could provide effective prevention of depressive symptoms.