"The aging process is highly variable; some individuals develop cognitive deficits while others experience healthy aging. Cognitive deficits that emerge with aging can be anatomically linked to atrophy of specific brain areas. In particular, cognitive decline is associated with degeneration of the hippocampus. The hippocampus is important for spatial memory and spatial memory tasks are often used in research to assess the integrity of the hippocampus. However, when navigating in a new environment, multiple strategies can be used that depend on different memory systems. In particular, in young adults, the spatial strategy is associated with increased fMRI BOLD activity and grey matter in the hippocampus while the response strategy is associated with increased fMRI BOLD activity and grey matter in the caudate nucleus. There is an inverse relationship between the two memory systems, whereby increased use of one memory system is associated with decreased activity and grey matter in the other. In the current dissertation, we took a multimodal approach integrating genetics, behavior, anatomical MRI, and functional MRI in order to better understand factors associated with lower hippocampal grey matter and decreased hippocampal function using navigation strategies as a tool to assess the integrity of the hippocampus.In the first study, we compared fMRI BOLD activity in young and older adults during navigation. Older adults have decreased fMRI BOLD activity in the hippocampus and increased fMRI BOLD activity in the caudate nucleus. However, when we divided older adults based on whether they use a spatial or response strategy, we found that spatial strategy users have fMRI BOLD activity in the hippocampus similar to that of young adults. Only response strategy users have decreased fMRI BOLD activity in the hippocampus. In the second study, we built on these findings to assess whether in healthy older adults there are structural differences in the hippocampus between spatial and response strategy users. We found that older adults who use spatial strategies have more grey matter in the hippocampus compared to those who use response strategies. In the third study, we assessed the interaction between the APOE and BDNF genes and navigation strategies. We found that within APOE e4 allele carriers, spatial strategy users have fMRI BOLD activity in the hippocampus. In contrast, response strategy users have fMRI BOLD activity in the caudate nucleus and have decreased grey matter in the entorhinal cortex compared to those who use spatial strategies. When looking at BDNF, we found that met allele carriers have lower fMRI BOLD activity in the hippocampus. In the last study of this dissertation, we looked at the interaction between non-genetic factors and navigation strategies. We found that spatial strategy users have better general cognitive function compared to response strategy users. We also found that age negatively correlates with spatial memory ability. We additionally looked at plasma cholesterol levels and found that response strategies users have higher levels of total cholesterol and LDL-cholesterol compared to those who use spatial strategies. We also found that cholesterol-lowering medication modulates navigation strategy use, whereby there is a higher proportion of spatial strategy users within those who are taking cholesterol-lowering medication. In the current dissertation, by examining the interaction between various factors and navigation strategies, we are better able to discern possible contributors to low grey matter and function in the hippocampus. Furthermore, looking at navigation strategies may be a cost-effective method for assessing the integrity of the hippocampus. These findings also open avenues for future intervention studies allowing us to target specific individuals, such as response strategy uses who are APOE e4 allele carriers, who may benefit most from intervention programs." --