Aging / Alzheimer's
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/30803
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Browsing Aging / Alzheimer's by Author "Barber, Robert C."
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Item Alzheimer's Disease Risk Allele Frequencies Differ Based on Ethnicity in HABLE Cohort(2022) Housini, Mohammad; Rao, Sumedha; Phillips, Nicole; O'Bryant, Sid; Barber, Robert C.Purpose: Alzheimer's Disease (AD) or other related dementias remain a significant burden on our aging population. Here we evaluate the top 10 AD risk alleles previously reported by Kunkle et al. (2018) in Mexican Americans and non-Hispanic whites enrolled in the Healthy Aging Brain in Latino Elders Study (HABLE) cohort to see if allele frequencies vary based on ethnicity. Methods: DNA was extracted from buffy coat samples (n = 1635) on the Hamilton robotic system with the Mag-Bind Blood & Tissue DNA HDQ 96 Kit. Genotyping was performed per manufacturer's protocol using the Illumina Infinium Global Screening Array (GSA) and analyzed with Genome Studio 2.0. Samples with call rates less than 98% were repeated or excluded. Allele and genotype frequencies were calculated using standard statistics by compiling the top ten AD risk alleles from Kunkle et al. (2018) and measuring their frequencies in the HABLE cohort. Results: Our data suggest varying degrees of allele and genotype frequencies among the top 10 risk conferring SNPs between Mexican Americans and Non-Hispanic Whites. In particular, we show some instances (BIN1, PTK2B) where the heterozygotes are in higher frequency than homozygotes. 8 of our evaluated SNPs show a difference greater than 5% between the two ethnicities. Conclusion: It may be beneficial to further study the top AD risk alleles among different ethnicities to determine if there are variable frequencies in those populations. We plan to expand and continue this work in other ethnicities and further elaborate on these differences to promote ethnicity targeted diagnostics and help reduce health disparities in medicine and science.Item Assessment of Mitochondrial DNA Damage in Cognitive Impairment via NGS: Health Disparities in Mexican Americans(2022) Reid, Danielle; Barber, Robert C.; Sun, Jie; Thorpe, Roland; Zhou, Zhengyang; Phillips, NicoleMexican Americans (MAs) are the fastest growing subpopulation in the US, and as age increases, this population will be disproportionately affected by age-related diseases such as Alzheimer's disease (AD). Diabetes, stroke, depression, and obesity are common risk factors for developing cognitive impairment (CI) and may be of particular relevance to MAs due to their increased prevalence. MtDNA damage has been implicated in AD, and since metabolic comorbidities are more common in MAs, mtDNA damage and mitochondrial dysfunction may be related to the increased burden and earlier age-of-onset among MAs. Mitochondrial dysfunction can induce oxidative damage to guanosine (8oxoG) and cause DNA deletions, both of which have been well-documented in AD. The mitochondrial genome is particularly vulnerable to DNA damage, and age-associated decline in mitochondrial function results in accumulating reactive oxygen species capable of damaging essential biomolecules. We hypothesize that MAs incur mtDNA damage at an elevated rate due to increased comorbidity burden altering mitochondrial function. MtDNA from buffy coat and plasma samples of participants enrolled in the Texas Alzheimer's Research Care and Consortium were amplified using the RepliG mtDNA Amplification kit and were sequenced via NexteraXT on Illumina NextSeq. Somatic variants indicative of oxidative DNA damage and the commonly observed 5kb deletion were quantified in both the buffy coat mtDNA and ccf-mtDNA. These data were analyzed for association with CI and T2D in both the NHW and MA populations. Further, haplogroup-associated risk for mtDNA damage and ccf-mtDNA status was assessed. Our preliminary findings suggest clinical implications of oxidative mtDNA damage as a risk factor for CI specifically in MA females. These data highlight ethnic/racial differences in oxidative burden which may elucidate sex-specific mechanisms contributing to the manifestation of age-related disease etiology as AD, and the results may ultimately inform precision-based approaches to design therapeutics for mitigating AD disparities in the MA population.Item Imputation Accuracy of Apolipoprotein E ε Alleles in Genome-wide arrays and real-time SNP Genotyping assays(2022) Subasinghe, Kumudu; Garlotte, Isabelle; O'Bryant, Sid E.; Barber, Robert C.; Phillips, NicolePurpose: The vast majority of the established genetic-based risk for late-onset Alzheimer's disease (AD) is attributable to variation within the apolipoprotein E (APOE) gene. This gene, which encodes a protein implicated in various aspects of AD pathology, is characterized by two single nucleotide polymorphisms (SNPs; rs429358 and rs7412) that result in three distinct isoforms (ε4, ε3 and ε2). Most population-based genome-wide association studies to date have identified the APOE ε4 and ε2 alleles as the strongest genetic-based risk and protective factors for AD, respectively. APOE genotype is not only critical for determining disease risk and diagnosis, but also for developing individualized therapeutic strategies. Genotyping via real-time quantitative PCR (qPCR) is the gold standard for APOE isoform determination; however, if genome wide SNP data is available, imputation of APOE (i.e., probabilistic genotyping through inference) may eliminate the need for qPCR genotyping. In this project, we evaluate the concordance of APOE genotypes obtained via qPCR and a genome-wide SNP chip in non-Hispanic White and Mexican American individuals from the Health & Aging Brain among Latino Elders (HABLE) cohort. Method: DNA was extracted from buffy coat samples (n = 1650) on the Hamilton robotic system with the Mag-Bind Blood & Tissue DNA HDQ 96 Kit. qPCR was then performed using the TaqMan Genotyping Kit as per manufacturer's protocol. Results produced via qPCR were then compared to those imputed for rs429358 and directly typed for rs7412 on the Illumina Infinium Global Screening Arrays (GSA) and analyzed with Genome Studio 2.0. Samples with call rates less than 98% were repeated or excluded. Results: Concordance between the APOE genotypes obtained from qPCR and Infinium GSA was 99.32%. Discordance was likely due to poor sample quality and low-frequency imputation errors of rs429358, which may be corrected with more conservative thresholding of the imputed genotype confidence statistics. Conclusion: Genotype imputation from SNPs commonly typed in the APOE region is an effective method for APOE isoform determination, even in Mexican Americans who are more genetically heterogenous due to ancestral admixture; this method may be effectively implemented in large population-based studies of aging and AD.Item Role of DNA Methylation in Risk for Cognitive Impairment and Type 2 Diabetes in a Mexican American Cohort(2022) Daniel, Ann Abraham; Silzer, Talisa K.; Hall, Courtney; Sun, Jie; Zhou, Zhengyang; Phillips, Nicole; Barber, Robert C.Purpose: Alzheimer's disease (AD) and type 2 diabetes (T2D) are among the leading causes of mortality among the aging Mexican American population (≥ 65 years old) in the US. This cohort is expected to be the largest aging ethnic minority group in the US by 2050. In comparison to their non-Hispanic white counterparts who are most likely to develop AD associated with inflammation, aging Mexican Americans have an earlier onset of AD and metabolism related predisposition for AD. Mild cognitive impairment (MCI) is a phenotype that often leads to AD and is also prevalent in this cohort. The presence of T2D is known to double the risk of developing MCI/AD. The risk for AD, MCI and T2D is multifactorial, involving genetics and epigenetics. Methylation is a form of epigenetic regulation whereby a methyl group is added to the cytosine base in DNA. Methylation patterns in DNA can be affected and possibly reversed by a variety of environmental factors such as lifestyle and diet. Targeting changes to methylation patterns through associated lifestyle changes could be a possible prevention method for AD, MCI and T2D in the future, particularly for minority groups affected by health disparities, such as the Mexican American population. We aim to establish an epigenetic association between cognitive impairment (identified here as AD and MCI), and T2D that is unique to the Mexican American population. Methods: For this project, 551 aging participants from the Texas Alzheimer's Research and Care Consortium (TARCC) were selected, following quality control. A cross phenotype study design will be used to assess differential methylation associated with cognitive impairment (CI) alone, T2D alone and then with both CI and T2D simultaneously. For the first stage of this project, 299 Mexican American and 252 non-Hispanic white participants were stratified into groups of individuals diagnosed with CI alone and controls without CI within each ethnic group. In the second stage, this cohort will be stratified into individuals with T2D alone and controls without T2D. The third stage will stratify participants into those with both CI and T2D versus normal healthy controls. Lastly, any differential methylation associated with each ethnic group will be compared and contrasted. Peripheral blood drawn from participants was used to obtain individual methylation profiles using the Illumina Infinium MethylationEPIC chip array. Differential methylation will be assessed using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R. The Beta MIxture Quantile dilation (BMIQ) method will be used for data normalization. Results: Gene set enrichment and pathway analysis tools will be used to analyze results. Conclusions: Identifying methylation sites associated with CI and T2D could contribute towards developing biomarkers that are ethnicity-specific for the Mexican American population and possibly lead towards more effective medical treatment in the future.Item Studying the Interplay Between Baseline Mental Health and Alzheimer's Disease Progression(2022) Rao, Sumedha; Housini, Mohammad; Royall, Donald; Palmer, Raymond; Barber, Robert C.Background: In aging adults, the most common form of dementia is Alzheimer's disease (AD). AD pathogenesis involves the accumulation of beta-amyloid (Aβ) protein aggregation in plaques and tau proteins in neurofibrillary tangles that are associated with a decreased number of synapses in the brain, altered neuronal function and cell death via neurotoxicity, as well as learning and memory deficits. Clinically, the presence and severity of neuropsychiatric symptoms that AD patients present with can be reliably measured by the Neuropsychiatric Inventory Questionnaire (NPIQ). This study aims to explore the association between baseline mental health and the severity of AD progression. Methods: To measure baseline mental health, NPIQ scores were used while the change in DeltaEq was used to represent the severity of AD progression within the TARCC cohort. DeltaEq is a homolog of Delta, a reliable latent dementia proxy that represents cognitive correlates of functional status and is specific for distinguishing cases with AD from other dementia-related presentations. Most crucially, the DeltaEq homolog has been adjusted for equivalence across ethnicities. Using stratified analysis and structured equation models, the association between baseline mental health and change in was investigated. Results: The first model exploring NPIQ and the change in DeltaEq was only adjusted for baseline eq; it showed NPIQ explaining 19% of the variance in delta DeltaEq and was statistically significant at p=0.016 for Non-Hispanic Whites. With the second model, age, sex, and education were adjusted for in addition to baseline eq. NPIQ was shown to explain 25% of the variance in delta DeltaEq while being statistically significant at p=0.037 for Non-Hispanic Whites. This model was replicated in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort; NPIQ was shown to be predictive for delta DeltaEq at p=0.013. Conclusion: In Non-Hispanic Whites, worse baseline mental health has been shown to predict increased severity and progression of AD. This makes it a clinical therapeutic target with the possible benefit of impacting the course of AD in patients. The fascinating interplay between mental health and its relationship to Alzheimer's disease should be studied further with an additional focus on ethnicity.