Browsing by Subject "APOE"

Now showing 1 - 9 of 9
  • Thumbnail Image
    Item
    Alzheimer's disease genetic risk variants beyond APOE ε4 predict mortality
    (Elsevier, 2017-08-24) Mez, Jesse; Marden, Jessica R.; Mukherjee, Shubhabrata; Walter, Stefan; Gibbons, Laura E.; Gross, Alden L.; Zahodne, Laura B.; Gilsanz, Paola; Brewster, Paul; Nho, Kwangsik; Crane, Paul K.; Larson, Eric B.; Glymour, M. Maria; Radiology and Imaging Sciences, School of Medicine
    • A genetic risk score from 21 non-APOE late-onset Alzheimer's disease risk variants predicts mortality. • The genetic risk score likely confers risk for mortality through its effect on dementia incidence. • Late-onset Alzheimer's disease risk loci effect estimates from genome-wide association unlikely suffer from selection bias.
  • Thumbnail Image
    Item
    APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer's Disease Risk in a Multiracial Sample
    (MDPI, 2019-08-16) Choi, Kyu Yeong; Lee, Jang Jae; Gunasekaran, Tamil Iniyan; Kang, Sarang; Lee, Wooje; Jeong, Jangho; Lim, Ho Jae; Zhang, Xiaoling; Zhu, Congcong; Won, So-Yoon; Choi, Yu Yong; Seo, Eun Hyun; Lee, Seok Cheol; Gim, Jungsoo; Chung, Ji Yeon; Chong, Ari; Byun, Min Soo; Seo, Sujin; Ko, Pan-Woo; Han, Ji-Won; McLean, Catriona; Farrell, John; Lunetta, Kathryn L.; Miyashita, Akinori; Hara, Norikazu; Won, Sungho; Choi, Seong-Min; Ha, Jung-Min; Jeong, Jee Hyang; Kuwano, Ryozo; Song, Min Kyung; An, Seong Soo A.; Lee, Young Min; Park, Kyung Won; Lee, Ho-Won; Choi, Seong Hye; Rhee, Sangmyung; Song, Woo Keun; Lee, Jung Sup; Mayeux, Richard; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Choo, IL Han; Nho, Kwangsik; Kim, Ki-Woong; Lee, Dong Young; Kim, SangYun; Kim, Byeong C.; Kim, Hoowon; Jun, Gyungah R.; Schellenberg, Gerard D.; Ikeuchi, Takeshi; Farrer, Lindsay A.; Lee, Kun Ho; Radiology and Imaging Sciences, School of Medicine
    Variants in the APOE gene region may explain ethnic differences in the association of Alzheimer's disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT: OR (odds ratio) = 27.02, p = 8.80 × 10-94; GT: OR = 15.87, p = 2.62 × 10-9) and EuroAs (TT: OR = 18.13, p = 2.69 × 10-108; GT: OR = 12.63, p = 3.44 × 10-64), and rs405509-T homozygotes had a younger onset and more severe cortical atrophy than those with G-allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes.
  • Thumbnail Image
    Item
    APOE, TOMM40, and Sex Interactions on Neural Network Connectivity
    (Elsevier, 2022) Li, Tianqi; Pappas, Colleen; Le, Scott T.; Wang, Qian; Klinedinst, Brandon S.; Larsen, Brittany; Pollpeter, Amy; Lee, Ling Yi; Lutz, Mike W.; Gottschalk, William K.; Swerdlow, Russell H.; Nho, Kwangsik; Willette, Auriel A.; Radiology and Imaging Sciences, School of Medicine
    The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer‟s disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 (‘650) G vs. A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE. We examined 21 orthogonal neural networks among 8,222 middle-aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 ‘650 genotypes, and if age and sex acted as moderators. APOE ε4 was associated with less strength in multiple networks, while ‘650 G vs. A carriage was related to more language comprehension network strength. In APOE ε4 carriers, ‘650 G-carriage led to less network strength with increasing age, while in non G-carriers this was only seen in women but not men. TOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.
  • Thumbnail Image
    Item
    Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction
    (bioRxiv, 2024-03-13) Onos, Kristen; Lin, Peter B.; Pandey, Ravi S.; Persohn, Scott A.; Burton, Charles P.; Miner, Ethan W.; Eldridge, Kierra; Nyandu Kanyinda, Jonathan; Foley, Kate E.; Carter, Gregory W.; Howell, Gareth R.; Territo, Paul R.; Neurology, School of Medicine
    Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein ε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. Results: All hAPOE strains showed AD phenotype progression by 8 mo, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 mo, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. Discussion: This work highlights APOEε4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.
  • Thumbnail Image
    Item
    Genome-Wide Association Analysis across Endophenotypes in Alzheimer's Disease: Main Effects and Disease Stage-Specific Interactions
    (MDPI, 2023-10-27) Rosewood, Thea J.; Nho, Kwangsik; Risacher, Shannon L.; Gao, Sujuan; Shen, Li; Foroud, Tatiana; Saykin, Andrew J.; Alzheimer’s Disease Neuroimaging Initiative; Medical and Molecular Genetics, School of Medicine
    The underlying genetic susceptibility for Alzheimer's disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD endophenotypes based on amyloid-β, tau, and neurodegeneration (A/T/N) biomarkers and cognitive performance were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). A genome-wide association study (GWAS) of quantitative phenotypes was performed using an SNP main effect and an SNP by Diagnosis interaction (SNP × DX) model to identify disease stage-specific genetic effects. Nine loci were identified as study-wide significant with one or more A/T/N endophenotypes in the main effect model, as well as additional findings significantly associated with cognitive measures. These nine loci include SNPs in or near the genes APOE, SRSF10, HLA-DQB1, XKR3, and KIAA1671. The SNP × DX model identified three study-wide significant genetic loci (BACH2, EP300, and PACRG-AS1) with a neuroprotective effect in later AD stage endophenotypes. An endophenotype approach identified novel genetic associations and provided insight into the molecular mechanisms underlying the genetic associations that may otherwise be missed using conventional case-control study designs.
  • Thumbnail Image
    Item
    Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's disease related proteins
    (BMC, 2023-01-07) Oatman, Stephanie R.; Reddy, Joseph S.; Quicksall, Zachary; Carrasquillo, Minerva M.; Wang, Xue; Liu, Chia‑Chen; Yamazaki, Yu; Nguyen, Thuy T.; Malphrus, Kimberly; Heckman, Michael; Biswas, Kristi; Nho, Kwangsik; Baker, Matthew; Martens, Yuka A.; Zhao, Na; Kim, Jun Pyo; Risacher, Shannon L.; Rademakers, Rosa; Saykin, Andrew J.; DeTure, Michael; Murray, Melissa E.; Kanekiyo, Takahisa; Alzheimer’s Disease Neuroimaging Initiative; Dickson, Dennis W.; Bu, Guojun; Allen, Mariet; Ertekin‑Taner, Nilüfer; Radiology and Imaging Sciences, School of Medicine
    Background: Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aβ40, Aβ42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis. Methods: Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency. Temporal cortex levels of five AD-related proteins from three fractions, buffer-soluble (TBS), detergent-soluble (Triton-X = TX), and insoluble (Formic acid = FA), were available for these same individuals. Variants were tested for association with each quantitative biochemical measure using linear regression, and GSA-SNP2 was used to identify enriched Gene Ontology (GO) terms. Implicated variants and genes were further assessed for association with other relevant variables. Results: We identified genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Conclusions: Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.
  • Thumbnail Image
    Item
    Nuclear receptor agonist-driven modification of inflammation and amyloid pathology enhances and sustains cognitive improvements in a mouse model of Alzheimer's disease
    (BioMed Central, 2018-02-15) Casali, Brad T.; Reed-Geaghan, Erin G.; Landreth, Gary E.; Neurology, School of Medicine
    BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder characterized by pathological hallmarks of beta-amyloid plaque deposits, tau pathology, inflammation, and cognitive decline. Treatment remains a clinical obstacle due to lack of effective therapeutics. Agonists targeting nuclear receptors, such as bexarotene, reversed cognitive deficits regardless of treatment duration and age in murine models of AD. While bexarotene demonstrated marked efficacy in decreasing plaque levels following short-term treatment, prolonged treatment did not modulate plaque burden. This suggested that plaques might reform in mice treated chronically with bexarotene and that cessation of bexarotene treatment before plaques reform might alter amyloid pathology, inflammation, and cognition in AD mice. METHODS: We utilized one-year-old APP/PS1 mice that were divided into two groups. We treated one group of mice for 2 weeks with bexarotene. The other group of mice was treated for 2 weeks with bexarotene followed by withdrawal of drug treatment for an additional 2 weeks. Cognition was evaluated using the novel-object recognition test either at the end of bexarotene treatment or the end of the withdrawal period. We then analyzed amyloid pathology and microgliosis at the conclusion of the study in both groups. RESULTS: Bexarotene treatment enhanced cognition in APP/PS1 mice similar to previous findings. Strikingly, we observed sustained cognitive improvements in mice in which bexarotene treatment was discontinued for 2 weeks. We observed a sustained reduction in microgliosis and plaque burden following drug withdrawal exclusively in the hippocampus. CONCLUSIONS: Our findings demonstrate that bexarotene selectively modifies aspects of neuroinflammation in a region-specific manner to reverse hippocampal-dependent cognitive deficits in AD mice and may provide insight to inform future studies with nuclear receptor agonists.
  • Thumbnail Image
    Item
    Telomere length associations with cognition depend on Alzheimer's disease biomarkers
    (Elsevier, 2019-01-01) Mahoney, Emily R.; Dumitrescu, Logan; Seto, Mabel; Nudelman, Kelly N.H.; Buckley, Rachel F.; Gifford, Katie A.; Saykin, Andrew J.; Jefferson, Angela J.; Hohman, Timothy J.; Medical and Molecular Genetics, School of Medicine
    Introduction While telomere shortening, a marker of cellular aging, may impact the progression of age‐related neurodegenerative diseases, its association with cognition is unclear, particularly in the context of Alzheimer's disease (AD) pathology. Methods Telomere, cognitive, and CSF data from 482 participants in the AD Neuroimaging Initiative (148 cognitively normal, 283 mild cognitive impairment, 51 AD) was leveraged to assess telomere length associations with cognition (measured by memory and executive function) and interactions with CSF amyloid‐β, tau, and APOE‐ε4. Secondary analyses assessed brain volume and thickness outcomes. Results Longer telomeres at baseline were associated with faster executive function decline. Amyloid‐β and tau interacted with telomere length on cognition, with longer telomeres related to faster decline among biomarker‐positive individuals. Discussion Telomere associations with cognition shift with AD progression, with longer telomeres related to worse outcomes as pathology increases, highlighting the need for further investigation of telomere length along the AD neuropathological cascade.
  • Thumbnail Image
    Item
    Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans
    (Elsevier, 2017-02) Mez, Jesse; Chung, Jaeyoon; Jun, Gyungah; Kriegel, Joshua; Bourlas, Alexandra P.; Sherva, Richard; Logue, Mark W.; Barnes, Lisa L.; Bennett, David A.; Buxbaum, Joseph D.; Byrd, Goldie S.; Crane, Paul K.; Ertekin-Taner, Nilüfer; Evans, Denis; Fallin, M. Daniele; Foroud, Tatiana; Goate, Alison; Graff-Radford, Neill R.; Hall, Kathleen S.; Kamboh, M. Ilyas; Kukull, Walter A.; Larson, Eric B.; Manly, Jennifer J.; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Lunetta, Kathryn L.; Farrer, Lindsay A.; Department of Medical & Molecular Genetics, IU School of Medicine
    INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.