Date of Award
Doctor of Philosophy
The main purpose of this dissertation project was to assess the behavioral and neural correlates of Episodic Memory as a function of the APOE genotype in a healthy young adult sample. To accomplish this, 98 subjects completed behavioral tasks assessing visual memory, working memory, episodic memory, and attention. Subjects also completed questionnaires evaluating IQ, years of education, drug use, personality, and emotional traits. These subjects were also genotyped for the APOE gene, resulting in 29 APOE-ε4 carriers (subjects who had at least one ε4 allele) and 69 Non APOE-ε4 carriers (having no ε4 alleles). No differences were found between genotypic groups on any demographic characteristics, behavioral measures, or personality traits. From this larger pool of 98 subjects, a subset of 22 subjects (10 APOE-ε4, 12 Non APOE-ε4) completed additional behavioral tasks while undergoing functional magnetic resonance imaging. While being scanned, subjects were asked to learn word pairs during an encoding phase, make metamemory evaluations on their ability to later remember each word pair during a judgment of learning (JOL) task, and try to discriminate between original and recombined word pairs during a final recognition phase. Interspersed between these tasks was a rest task meant to elicit activity within the Default Network. No differences in memory or metamemory performance were found on the behavioral tasks administered during imaging based on genotype. In contrast, marked differences in brain activation were found between APOE-ε4 carriers and Non APOE-ε4 carriers across the various imaging tasks. During encoding, APOE-ε4 carriers were found to have greater activation than Non APOE-ε4 carriers in the dorsal anterior portion of the left superior temporal gyrus, cingulate gyrus, and anterior middle frontal gyrus. This same pattern - greater APOE-ε4 carrier activation as compared to Non APOE-ε4 carriers - was present in the parahippocampal gyrus and posterior middle temporal gyrus during the judgment of learning metamemory task. During the recognition task, greater activation was found for Non APOE-ε4 carriers versus APOE-ε4 carriers in the left parahippocampal gyrus, SPL, and right anterior superior frontal gyrus. During the rest task, greater activation was seen in APOE-ε4 carriers versus Non APOE-ε4 carriers in the left inferior frontal gyrus, whereas the converse comparison resulted in medial anterior cingulate activation. The lack of behavioral differences suggests that in a healthy young adult sample, as was used in the present study, there are not yet detectable behavioral differences as a function of APOE genotype. The greater neural activity seen in APOE-ε4 carriers during the encoding and judgment of learning tasks is likely to reflect neural compensation: young adult APOE-ε4 carriers compensate for declines in cognitive efficiency with greater neural activity such that this greater neural activity improves behavioral performance, particularly in memory domains (Buckner, Andrews-Hanna, & Schacter, 2008; Han & Bondi, 2008; Levy et al., 2004; Trivedi et al., 2008). The relatively lower levels of activation in APOE-ε4 carriers during the recognition task may reflect stronger memory traces for studied items as a result of greater frontal and medial temporal lobe activity during the encoding and judgment of learning tasks in the APOE-ε4 carriers (Kirwan, Wixted, & Squire, 2008; Mondadoori et al., 2007; Squire, Wixted, & Clark, 2007). In the present sample, a lack of behavioral differences accompanied by neural disparity may signal the precursors of Alzheimer's disease, highlighting the progressive deteriorating influence of the APOE-ε4 allele. The aberrant pattern of default network activity seen in APOE-ε4 carriers underlies this influence as this genotype is proposed to preferentially contribute to the causes of Alzheimer's disease in areas common to the Default Network and Episodic Memory (Buckner et al., 2008). The present results strengthen previous findings illustrating a connection between the brain activity underlying memory processes, the default network, and the APOE genotype.
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