Antidepressant Use and Risk of Dementia and Cognitive Decline

Thesis (Ph.D.)--University of Washington, 2016-06

The causes of late-onset dementia and cognitive decline are not fully understood, and are likely the result of a complex interplay between genetics, environment, and health and lifestyle factors. In light of the devastating personal and economic burden of dementia, targeting midlife factors that contribute to these diseases could lead to important interventions to ameliorate risk and/or delay onset. Depression, a common condition among older adults, has been linked to dementia outcomes in multiple studies. It is unknown whether pharmacological treatment can alter this risk. Treating depression may benefit those at risk of dementia and Alzheimer’s disease (AD) by virtue of neurogenic properties, or by altering the pathobiological pathway between depression and dementia. Additionally, non-modifiable genetic risk factors may influence disease outcomes, either directly or through gene x environment interactions. The ɛ4 variant of the apolipoprotein E (APOE) gene is the most-studied and well-established genetic risk factor for dementia, and may interact with depression and/or antidepressant medications to influence risk of dementia and cognitive decline. In the following chapters we present an interdisciplinary dissertation project that seeks greater understanding of the epidemiology of pharmaceutical depression management, genetics, and dementia risk in an aging population, as well as ethical considerations for future studies. The first chapter describes a pharmacoepidemiology study, which measured associations between antidepressant use and dementia and the rate of cognitive decline using a large longitudinal cohort of older adults with biannual cognitive testing and detailed pharmacy records. The second chapter examines the complex interactions between a known genetic risk variant, the ɛ4 variant of the apolipoprotein E (APOE) gene, and depression and antidepressant use in this population. Finally, the last chapter built on the results of the first two chapters to discuss the ethical considerations of genotype-driven recruitment strategies in the context of a research study testing an intervention on individuals with a known risk-conferring gene variant, APOE ɛ4.