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Ethnic Differences in Dementia Revealed by Multimodal Imaging

Description

Inflammatory genes are known to only show in African Americans and non-Hispanic Whites. The objective of this study was to observe the correlation from the obtained data of the prevalence of the APOE ε4 genotype. We examined cerebral free-water, a marker of neuroinflammation, hippocampal volume, and volume of white-matter hyperintensities…

Inflammatory genes are known to only show in African Americans and non-Hispanic Whites. The objective of this study was to observe the correlation from the obtained data of the prevalence of the APOE ε4 genotype. We examined cerebral free-water, a marker of neuroinflammation, hippocampal volume, and volume of white-matter hyperintensities in African Americans (AA) and non-Hispanic Whites who were categorized in groups based on whether they had APOE ε4 allele or not. AA had lower prevalence of APOE e4 genotype than non-Hispanic Whites. AA groups have a slightly higher hippocampal volume compared to the Non-Hispanic White (NHW) groups. African Americans also reported increased white-matter hyperintensities and cerebral free-water. Hippocampal atrophy is associated with Alzheimer's disease, this might suggest that the AA groups have a lower risk of Alzheimer's, although further research is needed to confirm this relationship. Lastly, our findings also suggest other potential socioeconomic factors that could contribute to increased incidence of dementia among AA and potential resilience factors early in the course of Alzheimer’s disease process.

ContributorsStephens, Sydney (Author) / Ofori, Edward (Thesis director) / Sklar, David (Committee member) / Barrett, The Honors College (Contributor)

Created2023-05

The prediction strength of APOE for Alzheimer’s Disease in the Latinx Population

Description

This project uses All of Us Data to analyze how well of a predictor APOE ε4 is in the Latinx community, a high grandparent care community. APOE is used as a predictor for Alzheimer’s disease, but it is unknown, due to the lack of studies, how strong of a predictor…

This project uses All of Us Data to analyze how well of a predictor APOE ε4 is in the Latinx community, a high grandparent care community. APOE is used as a predictor for Alzheimer’s disease, but it is unknown, due to the lack of studies, how strong of a predictor it will be for Latinx individuals. This project aims to understand if the increased risk of Alzheimer’s disease among Hispanics is associated with a different level of ε4 gene frequency.

ContributorsPerez, Julianna (Author) / Holechek, Susan (Thesis director) / Lopez, Gilberto (Committee member) / Barrett, The Honors College (Contributor) / Computer Science and Engineering Program (Contributor) / School of Life Sciences (Contributor)

Created2023-05

Investigating the Isoform-Specific Effects of Apolipoprotein E (APOE) in Modulating Alzheimer’s Disease-Related Phenotypes

Description

APOE encodes for a lipid transport protein and has three allelic variants-APOE ε2, ε3 and ε4 each of which differentially modulate the risk for Alzheimer’s disease (AD). The presence of the ε4 allele of APOE greatly increases AD risk compared to the presence of the more prevalent and risk neutral…

APOE encodes for a lipid transport protein and has three allelic variants-APOE ε2, ε3 and ε4 each of which differentially modulate the risk for Alzheimer’s disease (AD). The presence of the ε4 allele of APOE greatly increases AD risk compared to the presence of the more prevalent and risk neutral ε3 allele. An imbalance in the generation and clearance of amyloid beta (Aβ) peptides has been hypothesized to play a key role in driving the disease. APOE4 impacts several AD-relevant cellular processes. However, it is unclear whether these effects represent a gain of toxic function or a loss of function, specifically as it relates to modulating amyloid beta (Aβ) levels. Here, a set of APOE knockout (KO) and APOE4 isogenic human induced pluripotent stem cells (hiPSCs) were generated from a parental APOE3 hiPSC line with a highly penetrant familial AD (fAD) mutation to investigate this with respect to Aβ secretion in neural cultures and Aβ uptake in monocultures of microglia-like cells (iMGLs). Conversion of APOE3 to E4 as well as functionally knocking APOE out from the APOE3 parental line, result in elevated Aβ levels in neural cultures, likely through multiple mechanisms including the altered processing of the precursor protein to Aβ called amyloid precursor protein (APP). In pure neuronal cultures, a shift in the processing of APP was observed with the Aβ-generating amyloidogenic pathway being favored in both APOE3 as well as APOE4 neurons compared to APOE KO neurons, with APOE4 neurons exhibiting a greater shift. In iMGLs derived from the isogenic hiPSC lines, expression of APOE, regardless of the isoform, lowered the uptake of Aβ. Overall, APOE4 modulates Aβ levels through distinct loss of protective and gain of function effects. Dissecting these effects would contribute towards a better understanding of the design of potential APOE-targeted therapeutics in the future.

ContributorsRajaram Srinivasan, Gayathri (Author) / Brafman, David (Thesis advisor) / Plaisier, Christopher (Committee member) / Newbern, Jason (Committee member) / Stabenfeldt, Sarah (Committee member) / Wang, Xiao (Committee member) / Arizona State University (Publisher)

Created2024

Generation of isogenic pluripotent stem cell lines for study of APOE, an Alzheimer’s risk factor

Description

Alzheimer’s disease (AD), despite over a century of research, does not have a clearly defined pathogenesis for the sporadic form that makes up the majority of disease incidence. A variety of correlative risk factors have been identified, including the three isoforms of apolipoprotein E (ApoE), a cholesterol transport protein in…

Alzheimer’s disease (AD), despite over a century of research, does not have a clearly defined pathogenesis for the sporadic form that makes up the majority of disease incidence. A variety of correlative risk factors have been identified, including the three isoforms of apolipoprotein E (ApoE), a cholesterol transport protein in the central nervous system. ApoE ε3 is the wild-type variant with no effect on risk. ApoE ε2, the protective and most rare variant, reduces risk of developing AD by 40%. ApoE ε4, the risk variant, increases risk by 3.2-fold and 14.9-fold for heterozygous and homozygous representation respectively. Study of these isoforms has been historically complex, but the advent of human induced pluripotent stem cells (hiPSC) provides the means for highly controlled, longitudinal in vitro study. The effect of ApoE variants can be further elucidated using this platform by generating isogenic hiPSC lines through precise genetic modification, the objective of this research. As the difference between alleles is determined by two cytosine-thymine polymorphisms, a specialized CRISPR/Cas9 system for direct base conversion was able to be successfully employed. The base conversion method for transitioning from the ε3 to ε2 allele was first verified using the HEK293 cell line as a model with delivery via electroporation. Following this verification, the transfection method was optimized using two hiPSC lines derived from ε4/ε4 patients, with a lipofection technique ultimately resulting in successful base conversion at the same site verified in the HEK293 model. Additional research performed included characterization of the pre-modification genotype with respect to likely off-target sites and methods of isolating clonal variants.

ContributorsLakers, Mary Frances (Author) / Brafman, David (Thesis advisor) / Haynes, Karmella (Committee member) / Wang, Xiao (Committee member) / Arizona State University (Publisher)

Created2017