Prodromal changes in subjects at genetic risk for Alzheimer's disease: Neuroimaging investigations

Alzheimer's disease (AD) is the most prominent form of dementia in adults, characterized by a relentless deterioration in memory systems. A wealth of evidence suggests that long before memory decline becomes severe enough to warrant a diagnosis of AD, there are substantial changes in brain structure and function.; This dissertation combines recent advances in the early detection of AD, including the genetic risk factor Apolipoprotein epsilon4 allele (APOE epsilon4), structural (MRI) and functional magnetic resonance imaging (fMRI), as well as novel neuroimaging analysis tools to identify early functional and structural deficits in a cognitively intact population.; Experiment 1 used fMRI to compare relative MR signal intensity during an attentional task of increasing difficulty between carriers of the APOE epsilon4 allele and non-carriers. The two genetic groups showed no difference in activation patterns, even at the most difficult task level.; Experiment 2 compared MR signal intensity during an episodic encoding task in APOE epsilon4 and APOE epsilon3 carriers during a follow-up scan to data acquired two years previously. At follow-up, APOE epsilon3 carriers demonstrated increased MR signal intensity in bilateral hippocampal regions and prefrontal cortical regions.; In Experiment 3, high-resolution fMRI was used to examine structural differences in APOE epsilon4 carriers compared to APOE epsilon3 carriers. APOE epsilon4 carriers showed decreased cortical thickness in entorhinal cortex and the subiculum.; Experiment 4 examined similar issues to those investigated in Experiment 3 but in a small subset of carriers of the APOE epsilon2 allele, a rare variant of the APOE gene. The changes in cortical thickness found in Experiment 3 in APOE epsilon4 carriers were not present in APOE epsilon2 carriers.; In Experiment 5, we evaluated subregional cortical thickness within the MTL in subjects suggested to be at-risk for frontotemporal dementia (FTD) as compared to subjects at-risk for AD (APOE epsilon4 subjects) and APOE epsilon3 carriers. Subjects at-risk for FTD showed decreased cortical thickness in neocortical regions but did not show differences within the hippocampas proper.; This dissertation supports the concept that cognitively intact subjects at-risk for AD demonstrate alterations in brain structure and function before the onset of clinical symptoms of dementia.