Browsing by Author "Ertekin-Taner, Nilüfer"

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    Blood-based gene and co-expression network levels are associated with AD/MCI diagnosis and cognitive phenotypes
    (Wiley, 2025-01-09) Chen, Xuan; Reddy, Joseph S.; Wang, Xue; Quicksall, Zachary; Nguyen, Thuy; Reyes, Denise A.; Graff-Radford, Jonathan; Jack, Clifford R., Jr.; Lowe, Val J.; Knopman, David S.; Petersen, Ronald C.; Kantarci, Kejal; Nho, Kwangsik; Allen, Mariet; Carrasquillo, Minerva M.; Saykin, Andrew J.; Ertekin-Taner, Nilüfer; Radiology and Imaging Sciences, School of Medicine
    Background: Alzheimer’s disease (AD) patients have decline in cognitive domains including memory, language, visuospatial, and/or executive function and brain pathology including amyloid‐β and tau deposition, neurodegeneration, and frequent vascular co‐pathologies detectable by neuroimaging and/or cerebrospinal fluid biomarkers. However, molecular disease mechanisms are complex and heterogeneous. It is necessary to develop cost‐effective blood‐based biomarkers reflecting brain molecular perturbations in AD. We identified blood‐based gene and co‐expression network level changes associated with AD/mild cognitive impairment (MCI) diagnosis and AD‐related phenotypes. Method: We performed differential gene expression and weighted gene co‐expression network analysis, followed by meta‐analysis, using blood transcriptome data of 391 participants from the Mayo Clinic Study of Aging and 654 participants from the Alzheimer's Disease Neuroimaging Initiative. The neuroimaging phenotypes include microhemorrhages, infarcts, amyloid burden, hippocampal volume, and white matter hyperintensities. The cognitive phenotypes include standardized cognitive subtest scores and composite scores for memory, language, visuospatial, and executive function. Result: Five out of 18 modules(M) are significantly associated with diagnosis or cognition (FDR‐adjusted p<0.05). M1 and M15 both positively associates with memory, M1 positively associated with language and M15 with visuospatial function. M1 and M15 are enriched in differentially expressed genes (DEGs) associated with language and executive function, respectively. M2 negatively associates with logical memory delayed recall scores(LMDR), memory, executive, and language functions and is enriched in DEGs for these phenotypes. M8 negatively associates with memory, language and executive functions and is enriched in DEGs for memory and language. M12 positively associates with LMDR. M1 and M15 are down‐regulated while M2 and M8 are up‐regulated in AD/MCI patients. Cell‐type enrichment analysis showed M2 is enriched in monocytes and neutrophils; M8 in monocytes; M15 in B cells (FDR <0.05). Gene ontology terms enriched in these modules indicated broad consistency with their cell types. Conclusion: We identified five modules significantly associated with AD/MCI or cognitive phenotypes using blood transcriptome data. These findings nominate blood transcriptome changes and their enriched biological processes as potential pathomechanisms in cognitive decline and AD/MCI development. We aim to investigate these blood transcripts as potential biomarkers for AD or AD‐related phenotypes and therapeutic targets through additional replication and experimental validation studies.
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    Cell-specific transcriptional signatures of vascular cells in Alzheimer’s disease: perspectives, pathways, and therapeutic directions
    (Springer Nature, 2025-01-29) Chaudhuri, Soumilee; Cho, Minyoung; Stumpff, Julia C.; Bice, Paula J; İş, Özkan; Ertekin-Taner, Nilüfer; Saykin, Andrew J.; Nho, Kwangsik
    Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that is marked by profound neurovascular dysfunction and significant cell-specific alterations in the brain vasculature. Recent advances in high throughput single-cell transcriptomics technology have enabled the study of the human brain vasculature at an unprecedented depth. Additionally, the understudied niche of cerebrovascular cells, such as endothelial and mural cells, and their subtypes have been scrutinized for understanding cellular and transcriptional heterogeneity in AD. Here, we provide an overview of rich transcriptional signatures derived from recent single-cell and single-nucleus transcriptomic studies of human brain vascular cells and their implications for targeted therapy for AD. We conducted an in-depth literature search using Medline and Covidence to identify pertinent AD studies that utilized single-cell technologies in human post-mortem brain tissue by focusing on understanding the transcriptional differences in cerebrovascular cell types and subtypes in AD and cognitively normal older adults. We also discuss impaired cellular crosstalk between vascular cells and neuroglial units, as well as astrocytes in AD. Additionally, we contextualize the findings from single-cell studies of distinct endothelial cells, smooth muscle cells, fibroblasts, and pericytes in the human AD brain and highlight pathways for potential therapeutic interventions as a concerted multi-omic effort with spatial transcriptomics technology, neuroimaging, and neuropathology. Overall, we provide a detailed account of the vascular cell-specific transcriptional signatures in AD and their crucial cellular crosstalk with the neuroglial unit.
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    CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET
    (Springer Nature, 2024-09-20) Nho, Kwangsik; Risacher, Shannon L.; Apostolova, Liana G.; Bice, Paula J.; Brosch, Jared R.; Deardorff, Rachael; Faber, Kelley; Farlow, Martin R.; Foroud, Tatiana; Gao, Sujuan; Rosewood, Thea; Kim, Jun Pyo; Nudelman, Kelly; Yu, Meichen; Aisen, Paul; Sperling, Reisa; Hooli, Basavaraj; Shcherbinin, Sergey; Svaldi, Diana; Jack, Clifford R., Jr.; Jagust, William J.; Landau, Susan; Vasanthakumar, Aparna; Waring, Jeffrey F.; Doré, Vincent; Laws, Simon M.; Masters, Colin L.; Porter, Tenielle; Rowe, Christopher C.; Villemagne, Victor L.; Dumitrescu, Logan; Hohman, Timothy J.; Libby, Julia B.; Mormino, Elizabeth; Buckley, Rachel F.; Johnson, Keith; Yang, Hyun-Sik; Petersen, Ronald C.; Ramanan, Vijay K.; Ertekin-Taner, Nilüfer; Vemuri, Prashanthi; Cohen, Ann D.; Fan, Kang-Hsien; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Ali, Muhammad; Benzinger, Tammie; Cruchaga, Carlos; Hobbs, Diana; De Jager, Philip L.; Fujita, Masashi; Jadhav, Vaishnavi; Lamb, Bruce T.; Tsai, Andy P.; Castanho, Isabel; Mill, Jonathan; Weiner, Michael W.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI); Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN); Australian Imaging, Biomarker & Lifestyle Study (AIBL); Saykin, Andrew J.; Radiology and Imaging Sciences, School of Medicine
    Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.
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    Discovery of Genes Underlying Cognitive Resilience in Individuals Predisposed to Alzheimer's Disease Risk
    (Wiley, 2025-01-09) Tsai, Wei; McNiff, Caitlin E.; Reddy, Joseph S.; Wang, Xue; Quicksall, Zachary; Nho, Kwangsik; Dunn, Amy R.; Allen, Mariet; Heckman, Michael G.; Ren, Yingxue; Zhao, Na; Kantarci, Kejal; Mielke, Michelle M.; Petersen, Ronald C.; Kaczorowski, Catherine C.; Carrasquillo, Minerva M.; Saykin, Andrew J.; Ertekin-Taner, Nilüfer; Radiology and Imaging Sciences, School of Medicine
    Background: Two main risk factors of Alzheimer’s disease (AD) are aging and APOE‐ε4. However, some individuals remain cognitively normal despite having these risk factors. They are considered “cognitively resilient”. This study aimed to identify molecular factors that confer cognitive resilience in APOE‐ε4 carriers ≥ 80 years of age and may serve as biomarkers. Method: We applied weighted gene co‐expression network analysis (WGCNA) to generate consensus co‐expression networks from blood of participants in two antemortem cohorts, the Mayo Clinic Study of Aging (MCSA, n=105), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=91), using RNA‐sequencing and microarray data, respectively. We associated these networks with resilience (resilient vs non‐resilient), cognitive endophenotypes and hippocampal volume. Preservation between consensus networks from blood and those derived from postmortem brain tissues of AD and control donors from AMP‐AD (n=1174) was evaluated. We validated the human findings in four AD mouse models. Finally, machine learning models were utilized to discriminate cases (AD+mild cognitive impairment (MCI)) from controls in MCSA, ADNI and ANMerge antemortem cohorts. Result: Four consensus networks were significantly correlated with a memory phenotype (logical memory delayed recall=LMDR) and hippocampal volume in both MCSA and ADNI. Among these, blood expression module M3 was most preserved with the brain transcriptome. M3 was enriched with NDUF hub genes that are involved in the mitochondrial respiratory chain. Expression levels of M3 and many blood NDUFs had significant associations with better LMDR and hippocampal volume. In brain, NDUFs were upregulated in controls compared to AD, and their expression levels were associated with better global cognition and decreased AD neuropathology. Many NDUFs were significantly downregulated in the hippocampus or cortex of AD mice compared to wild‐types. Lastly, models that included blood NDUFs improved diagnostic accuracy of AD+MCI compared to models that only included demographic and risk variables (age, sex, APOE‐ε4) in MCSA, ADNI and ANMerge. In MCSA and ADNI, adding NDUFs’ expression to models that included established blood biomarkers (Aβ42/40, ptau181, NFL) further improved diagnostic accuracy. Conclusion: Our results suggest that mitochondrial NDUFs are centrally‐linked peripheral molecular signatures that may be resilience factors against AD and serve as both therapeutic targets and novel diagnostic biomarkers.
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    Gene-based GWAS and -biological pathway analysis of the resilience of executive functioning
    (Springer US, 2014-03) Mukherjee, Shubhabrata; Kim, Sungeun; Ramanan, Vijay K.; Gibbons, Laura E.; Nho, Kwangsik; Glymour, M. Maria; Ertekin-Taner, Nilüfer; Montine, Thomas J.; Saykin, Andrew J.; Crane, Paul K.; Alzheimer’s Disease Neuroimaging Initiative; Department of Radiology and Imaging Sciences, School of Medicine
    Resilience in executive functioning (EF) is characterized by high EF measured by neuropsychological test performance despite structural brain damage from neurodegenerative conditions. We previously reported single nucleotide polymorphism (SNP) genome-wide association study (GWAS) results for EF resilience. Here, we report gene- and pathway-based analyses of the same resilience phenotype, using an optimal SNP-set (Sequence) Kernel Association Test (SKAT) for gene-based analyses (conservative threshold for genome-wide significance = 0.05/18,123=2.8×10−6) and the gene-set enrichment package GSA-SNP for biological pathway analyses (False discovery rate (FDR) < 0.05). Gene-based analyses found a genome-wide significant association between RNASE13 and EF resilience (p=1.33×10−7). Genetic pathways involved with dendritic/neuron spine, presynaptic membrane, postsynaptic density etc. were enriched with association to EF resilience. Although replication of these results is necessary, our findings indicate the potential value of gene- and pathway-based analyses in research on determinants of cognitive resilience.
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    Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy
    (Nature Publishing Group, 2015-06-16) Kouri, Naomi; Ross, Owen A.; Dombroski, Beth; Younkin, Curtis S.; Serie, Daniel J.; Soto-Ortolaza, Alexandra; Baker, Matthew; Finch, Ni Cole A.; Yoon, Hyejin; Kim, Jungsu; Fujioka, Shinsuke; McLean, Catriona A.; Ghetti, Bernardino; Spina, Salvatore; Cantwell, Laura B.; Farlow, Martin R.; Grafman, Jordan; Huey, Edward D.; Ryung Han, Mi; Beecher, Sherry; Geller, Evan T.; Kretzschmar, Hans A.; Roeber, Sigrun; Gearing, Marla; Juncos, Jorge L.; Vonsattel, Jean Paul G.; Van Deerlin, Vivianna M.; Grossman, Murray; Hurtig, Howard I.; Gross, Rachel G.; Arnold, Steven E.; Trojanowski, John Q.; Lee, Virginia M.; Wenning, Gregor K.; White, Charles L.; Höglinger, Günter U.; Müller, Ulrich; Devlin, Bernie; Golbe, Lawrence I.; Crook, Julia; Parisi, Joseph E.; Boeve, Bradley F.; Josephs, Keith A.; Wszolek, Zbigniew K.; Uitti, Ryan J.; Graff-Radford, Neill R.; Litvan, Irene; Younkin, Steven G.; Wang, Li-San; Ertekin-Taner, Nilüfer; Rademakers, Rosa; Hakonarsen, Hakon; Schellenberg, Gerard D.; Dickson, Dennis W.; Department of Pathology & Laboratory Medicine, IU School of Medicine
    Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10−7) and MAPT H1c (17q21; rs242557; P=7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
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    Genome-wide transcriptome analysis identifies novel dysregulated genes implicated in Alzheimer's pathology
    (Wiley, 2020-08-05) Nho, Kwangsik; Nudelman, Kelly; Allen, Mariet; Hodges, Angela; Kim, Sungeun; Risacher, Shannon L.; Apostolova, Liana G.; Lin, Kuang; Lunnon, Katie; Wang, Xue; Burgess, Jeremy D.; Ertekin-Taner, Nilüfer; Petersen, Ronald C.; Wang, Lisu; Qi, Zhenhao; He, Aiqing; Neuhaus, Isaac; Patel, Vishal; Foroud, Tatiana; Faber, Kelley M.; Lovestone, Simon; Simmons, Andrew; Weiner, Michael W.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of Medicine
    INTRODUCTION: Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer’s disease (LOAD). METHODS: We performed transcriptome-wide meta-analysis (N=1,440) of blood-based microarray gene expression profiles as well as neuroimaging and CSF endophenotype analysis. RESULTS: We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid-β accumulation, especially in the entorhinal cortex region. cis-eQTL mapping analysis of CREB5 detected five significant associations (p<5x10−8), where rs56388170 (most significant) was also significantly associated with global cortical amyloid-β (Aβ) deposition measured by [18F]Florbetapir PET and CSF Aβ1-42. DISCUSSION: RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to AD. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity and learning and memory.
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    Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction
    (Springer Nature, 2024-06-20) İş, Özkan; Wang, Xue; Reddy, Joseph S.; Min, Yuhao; Yilmaz, Elanur; Bhattarai, Prabesh; Patel, Tulsi; Bergman, Jeremiah; Quicksall, Zachary; Heckman, Michael G.; Tutor-New, Frederick Q.; Demirdogen, Birsen Can; White, Launia; Koga, Shunsuke; Krause, Vincent; Inoue, Yasuteru; Kanekiyo, Takahisa; Cosacak, Mehmet Ilyas; Nelson, Nastasia; Lee, Annie J.; Vardarajan, Badri; Mayeux, Richard; Kouri, Naomi; Deniz, Kaancan; Carnwath, Troy; Oatman, Stephanie R.; Lewis-Tuffin, Laura J.; Nguyen, Thuy; Alzheimer’s Disease Neuroimaging Initiative; Carrasquillo, Minerva M.; Graff-Radford, Jonathan; Petersen, Ronald C.; Jack, Clifford R., Jr.; Kantarci, Kejal; Murray, Melissa E.; Nho, Kwangsik; Saykin, Andrew J.; Dickson, Dennis W.; Kizil, Caghan; Allen, Mariet; Ertekin-Taner, Nilüfer; Radiology and Imaging Sciences, School of Medicine
    To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer’s disease, we performed single nucleus RNA sequencing in 24 Alzheimer’s disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer’s disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer’s disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer’s disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer’s disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3-astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer’s disease.
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    Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease
    (medRxiv, 2024-01-24) Arnold, Matthias; Buyukozkan, Mustafa; Doraiswamy, P. Murali; Nho, Kwangsik; Wu, Tong; Gudnason, Vilmundur; Launer, Lenore J.; Wang-Sattler, Rui; Adamski, Jerzy; The Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Metabolomics Consortium; De Jager, Philip L.; Ertekin-Taner, Nilüfer; Bennett, David A.; Saykin, Andrew J.; Peters, Annette; Suhre, Karsten; Kaddurah-Daouk, Rima; Kastenmüller, Gabi; Krumsiek, Jan; Radiology and Imaging Sciences, School of Medicine
    Impaired glucose uptake in the brain is one of the earliest presymptomatic manifestations of Alzheimer's disease (AD). The absence of symptoms for extended periods of time suggests that compensatory metabolic mechanisms can provide resilience. Here, we introduce the concept of a systemic 'bioenergetic capacity' as the innate ability to maintain energy homeostasis under pathological conditions, potentially serving as such a compensatory mechanism. We argue that fasting blood acylcarnitine profiles provide an approximate peripheral measure for this capacity that mirrors bioenergetic dysregulation in the brain. Using unsupervised subgroup identification, we show that fasting serum acylcarnitine profiles of participants from the AD Neuroimaging Initiative yields bioenergetically distinct subgroups with significant differences in AD biomarker profiles and cognitive function. To assess the potential clinical relevance of this finding, we examined factors that may offer diagnostic and therapeutic opportunities. First, we identified a genotype affecting the bioenergetic capacity which was linked to succinylcarnitine metabolism and significantly modulated the rate of future cognitive decline. Second, a potentially modifiable influence of beta-oxidation efficiency seemed to decelerate bioenergetic aging and disease progression. Our findings, which are supported by data from more than 9,000 individuals, suggest that interventions tailored to enhance energetic health and to slow bioenergetic aging could mitigate the risk of symptomatic AD, especially in individuals with specific mitochondrial genotypes.
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    Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease
    (Springer Nature, 2025-02-24) Arnold, Matthias; Buyukozkan, Mustafa; Doraiswamy, P. Murali; Nho, Kwangsik; Wu, Tong; Gudnason, Vilmundur; Launer, Lenore J.; Wang-Sattler, Rui; Adamski, Jerzy; The Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Metabolomics Consortium; De Jager, Philip L.; Ertekin-Taner, Nilüfer; Bennett, David A.; Saykin, Andrew J.; Peters, Annette; Suhre, Karsten; Kaddurah-Daouk, Rima; Kastenmüller, Gabi; Krumsiek, Jan; Radiology and Imaging Sciences, School of Medicine
    Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.