UBC Theses and Dissertations
Investigating the pleiotropic effects of the apolipoprotein variant epsilon 4 allele on the schizophrenia syndrome Vila-Rodriguez, Fidel
Schizophrenia (SCZ) is a severe and complex disorder that presents in young adults and evolves to chronicity causing pervasive deterioration in personal, social, and professional functioning. SCZ is better conceptualized as a syndrome as the concrete underlying etiopathological mechanisms have not been identified. Nonetheless, there are reports of subtle abnormal post-mortem findings, moderate brain deficits, and severe neurocognitive impairments. Although the etiology of SCZ is unknown, evidence suggests a strong genetic contribution to the disorder. The apolipoprotein E gene (APOE) codifies for the apoE protein, which is involved in a wide range of functions from cholesterol metabolism to synaptic plasticity. One of the three main allele polymorphisms of APOE, APOE-ε4, is associated with increased risk of Alzheimer’s disease, decreased hippocampal volume, and neuropathological findings. However, data in youth indicates that it may also be associated with cognitive performance or brain development. Samples of post-mortem brain tissue from SCZ patients and healthy controls from Brodmann area 9 were used to quantify the amount of apoE, cholesterol, methylation of the promoter region of reelin, reelin mRNA, apoE receptor 2 (apoER2), and very-low density lipoprotein receptor (VLDLR). In addition, a sample of first-episode psychosis patients and healthy controls was recruited. Subjects underwent neurocognitive testing as well as brain imaging at baseline and 9 to 12 months after. Our data demonstrated higher levels of methylation of the reelin promoter region and decreased expression of apoER2 in SCZ samples, but there were no differences in apoE, cholesterol, reelin or VLDLR. In SCZ data suggested dysregulation of apoE and cholesterol in both grey and white matter. In FEP, there was severe impairment in verbal memory, but APOE-ε4 was associated with improved verbal memory over time in SCZ. APOE-ε4 status, but not memory capacity was associated with smaller hippocampal volume. APOE-ε4 is associated with different phenotypes of opposing effects in SCZ and may be associated with the syndromic expression of the disorder.
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