Search

Your search keyword '"Holtzman, David"' showing total 3,352 results
Start Over Author "Holtzman, David"
3,352 results on '"Holtzman, David"'

1. Symposium: What Does the Microbiome Tell Us about Prevention and Treatment of AD/ADRD?

Author

Capocchi, Joia K, Figueroa-Romero, Claudia, Dunham, Sage JB, Faraci, Gina, Rothman, Jason A, Whiteson, Katrine L, Seo, Dong-oh, Holtzman, David M, Grabrucker, Stefanie, Nolan, Yvonne M, Kaddurah-Daouk, Rima, and Jett, David A

Subjects
Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Neurosciences
Abstract

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRDs) are broad-impact multifactorial neurodegenerative diseases. Their complexity presents unique challenges for developing effective therapies. This review highlights research presented at the 2024 Society for Neuroscience meeting which emphasized the gut microbiome's role in AD pathogenesis by influencing brain function and neurodegeneration through the microbiota–gut–brain axis. This emerging evidence underscores the potential for targeting the gut microbiota to treat AD/ADRD.

Published
2024

2. Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference.

Author

Kloske, Courtney, Belloy, Michael, Blue, Elizabeth, Bowman, Gregory, Carrillo, Maria, Chen, Xiaoying, Chiba-Falek, Ornit, Davis, Albert, Paolo, Gilbert, Garretti, Francesca, Gate, David, Golden, Lesley, Heinecke, Jay, Herz, Joachim, Huang, Yadong, Iadecola, Costantino, Johnson, Lance, Kanekiyo, Takahisa, Karch, Celeste, Khvorova, Anastasia, Koppes-den Hertog, Sascha, Lamb, Bruce, Lawler, Paige, Guen, Yann, Litvinchuk, Alexandra, Liu, Chia-Chen, Mahinrad, Simin, Marcora, Edoardo, Marino, Claudia, Michaelson, Danny, Miller, Justin, Morganti, Josh, Narayan, Priyanka, Naslavsky, Michel, Oosthoek, Marlies, Ramachandran, Kapil, Ramakrishnan, Abhirami, Raulin, Ana-Caroline, Robert, Aiko, Saleh, Rasha, Sexton, Claire, Shah, Nilomi, Shue, Francis, Sible, Isabel, Soranno, Andrea, Strickland, Michael, Tcw, Julia, Thierry, Manon, Tsai, Li-Huei, Tuckey, Ryan, Ulrich, Jason, van der Kant, Rik, Wang, Na, Wellington, Cheryl, Weninger, Stacie, Yassine, Hussein, Zhao, Na, Bu, Guojun, Goate, Alison, and Holtzman, David

Subjects
APOE, Alzheimers disease, apolipoprotein E, conference proceedings, dementia, lipids, microglia, neuroinflammation, risk factor, therapeutics, vasculature, Humans, Apolipoproteins E, Alzheimer Disease, Congresses as Topic, Animals, Amyloid beta-Peptides, Dementia, Biomedical Research
Abstract

INTRODUCTION: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimers disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. METHODS: In 2023, the Alzheimers Association convened multidisciplinary researchers at the AAIC Advancements: APOE conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. RESULTS: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. DISCUSSION: Understanding apoEs multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. HIGHLIGHTS: APOE is a central player in the pathogenesis of Alzheimers disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.

Published
2024

5. Clinical validation of the PrecivityAD2 blood test: A mass spectrometry-based test with algorithm combining %p-tau217 and Aβ42/40 ratio to identify presence of brain amyloid.

Author

Meyer, Matthew, Kirmess, Kristopher, Eastwood, Stephanie, Wente-Roth, Traci, Irvin, Faith, Holubasch, Mary, Venkatesh, Venky, Fogelman, Ilana, Monane, Mark, Hanna, Lucy, Rabinovici, Gil, Siegel, Barry, Whitmer, Rachel, Apgar, Charles, Bateman, Randall, Holtzman, David, Irizarry, Michael, Verbel, David, Sachdev, Pallavi, Ito, Satoshi, Contois, John, Yarasheski, Kevin, Braunstein, Joel, Verghese, Philip, and West, Tim

Subjects
Alzheimers, amyloid beta, blood biomarker, clinical validity, diagnostic, p‐tau217, Humans, Amyloid beta-Peptides, Female, Male, tau Proteins, Alzheimer Disease, Aged, Algorithms, Positron-Emission Tomography, Peptide Fragments, Brain, Biomarkers, Mass Spectrometry, Middle Aged, Aged, 80 and over, ROC Curve
Abstract

BACKGROUND: With the availability of disease-modifying therapies for Alzheimers disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aβ)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.

Published
2024

7. Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner.

Author

Bosch, Megan, Dodiya, Hemraj, Michalkiewicz, Julia, Lee, Choonghee, Shaik, Shabana, Weigle, Ian, Zhang, Can, Osborn, Jack, Nambiar, Aishwarya, Patel, Priyam, Parhizkar, Samira, Zhang, Xiaoqiong, Laury, Marie, Mondal, Prasenjit, Gomm, Ashley, Schipma, Matthew, Mallah, Dania, Butovsky, Oleg, Chang, Eugene, Tanzi, Rudolph, Gilbert, Jack, Holtzman, David, and Sisodia, Sangram

Subjects
Alzheimer’s disease, Microbiome, Microglia, Neuroinflammation, Sodium oligomannate, Humans, Mice, Male, Female, Animals, Alzheimer Disease, Gastrointestinal Microbiome, Microglia, Mice, Transgenic, Amyloidosis, Amyloid beta-Peptides, Plaque, Amyloid, Amyloid, Amyloidogenic Proteins, Disease Models, Animal
Abstract

It has recently become well-established that there is a connection between Alzheimers disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each others experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimers disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels.

Published
2024

8. Correction: Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner

Author

Bosch, Megan E., Dodiya, Hemraj B., Michalkiewicz, Julia, Lee, Choonghee, Shaik, Shabana M., Weigle, Ian Q., Zhang, Can, Osborn, Jack, Nambiar, Aishwarya, Patel, Priyam, Parhizkar, Samira, Zhang, Xiaoqiong, Laury, Marie L., Mondal, Prasenjit, Gomm, Ashley, Schipma, Matthew John, Mallah, Dania, Butovsky, Oleg, Chang, Eugene B., Tanzi, Rudolph E., Gilbert, Jack A., Holtzman, David M., and Sisodia, Sangram S.

Published
2024
Full Text
View/download PDF

9. Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center

Author

Fernandez, Maria Victoria, Liu, Menghan, Beric, Aleksandra, Johnson, Matt, Cetin, Arda, Patel, Maulik, Budde, John, Kohlfeld, Pat, Bergmann, Kristy, Lowery, Joseph, Flynn, Allison, Brock, William, Sanchez Montejo, Brenda, Gentsch, Jen, Sykora, Nicholas, Norton, Joanne, Gentsch, Jen, Valdez, Olga, Gorijala, Priyanka, Sanford, Jessie, Sun, Yichen, Wang, Ciyang, Western, Dan, Timsina, Jigyasha, Mangetti Goncalves, Tassia, Do, Anh N., Sung, Yun Ju, Zhao, Guoyan, Morris, John C., Moulder, Krista, Holtzman, David M., Bateman, Randall J., Karch, Celeste, Hassenstab, Jason, Xiong, Chengjie, Schindler, Suzanne E., Balls-Berry, Joyce (Joy), Benzinger, Tammie L. S., Perrin, Richard J., Denny, Andrea, Snider, B. Joy, Stark, Susan L., Ibanez, Laura, and Cruchaga, Carlos

Published
2024
Full Text
View/download PDF

10. Baseline levels and longitudinal changes in plasma Aβ42/40 among Black and white individuals

Author

Xiong, Chengjie, Luo, Jingqin, Wolk, David A., Shaw, Leslie M., Roberson, Erik D., Murchison, Charles F., Henson, Rachel L., Benzinger, Tammie L. S., Bui, Quoc, Agboola, Folasade, Grant, Elizabeth, Gremminger, Emily N., Moulder, Krista L., Geldmacher, David S., Clay, Olivio J., Babulal, Ganesh, Cruchaga, Carlos, Holtzman, David M., Bateman, Randall J., Morris, John C., and Schindler, Suzanne E.

Published
2024
Full Text
View/download PDF

11. Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease

Author

Xia, Zengjie, Prescott, Emily E., Urbanek, Agnieszka, Wareing, Hollie E., King, Marianne C., Olerinyova, Anna, Dakin, Helen, Leah, Tom, Barnes, Katy A., Matuszyk, Martyna M., Dimou, Eleni, Hidari, Eric, Zhang, Yu P., Lam, Jeff Y. L., Danial, John S. H., Strickland, Michael R., Jiang, Hong, Thornton, Peter, Crowther, Damian C., Ohtonen, Sohvi, Gómez-Budia, Mireia, Bell, Simon M., Ferraiuolo, Laura, Mortiboys, Heather, Higginbottom, Adrian, Wharton, Stephen B., Holtzman, David M., Malm, Tarja, Ranasinghe, Rohan T., Klenerman, David, and De, Suman

Published
2024
Full Text
View/download PDF

13. Disease staging of Alzheimer’s disease using a CSF-based biomarker model

Author

Salvadó, Gemma, Horie, Kanta, Barthélemy, Nicolas R., Vogel, Jacob W., Pichet Binette, Alexa, Chen, Charles D., Aschenbrenner, Andrew J., Gordon, Brian A., Benzinger, Tammie L. S., Holtzman, David M., Morris, John C., Palmqvist, Sebastian, Stomrud, Erik, Janelidze, Shorena, Ossenkoppele, Rik, Schindler, Suzanne E., Bateman, Randall J., and Hansson, Oskar

Published
2024
Full Text
View/download PDF

16. Author Correction: Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE

Author

Parhizkar, Samira, Arzberger, Thomas, Brendel, Matthias, Kleinberger, Gernot, Deussing, Maximilian, Focke, Carola, Nuscher, Brigitte, Xiong, Monica, Ghasemigharagoz, Alireza, Katzmarski, Natalie, Krasemann, Susanne, Lichtenthaler, Stefan F., Müller, Stephan A., Colombo, Alessio, Monasor, Laura Sebastian, Tahirovic, Sabina, Herms, Jochen, Willem, Michael, Pettkus, Nadine, Butovsky, Oleg, Bartenstein, Peter, Edbauer, Dieter, Rominger, Axel, Ertürk, Ali, Grathwohl, Stefan A., Neher, Jonas J., Holtzman, David M., Meyer-Luehmann, Melanie, and Haass, Christian

Published
2024
Full Text
View/download PDF

17. TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4.

Author

Gratuze, Maud, Schlachetzki, Johannes, DOliveira Albanus, Ricardo, Jain, Nimansha, Novotny, Brenna, Brase, Logan, Rodriguez, Lea, Mansel, Clayton, Kipnis, Michal, OBrien, Sydney, Pasillas, Martina, Lee, Choonghee, Manis, Melissa, Colonna, Marco, Harari, Oscar, Glass, Christopher, Ulrich, Jason, and Holtzman, David

Subjects
Alzheimer’s disease, ApoE4, TREM2, microgliosis, tau pathology, tau-mediated neurodegeneration, Mice, Animals, Apolipoprotein E4, Alzheimer Disease, Inflammation, Microglia, Disease Models, Animal, Membrane Glycoproteins, Receptors, Immunologic
Abstract

In addition to tau and Aβ pathologies, inflammation plays an important role in Alzheimers disease (AD). Variants in APOE and TREM2 increase AD risk. ApoE4 exacerbates tau-linked neurodegeneration and inflammation in P301S tau mice and removal of microglia blocks tau-dependent neurodegeneration. Microglia adopt a heterogeneous population of transcriptomic states in response to pathology, at least some of which are dependent on TREM2. Previously, we reported that knockout (KO) of TREM2 attenuated neurodegeneration in P301S mice that express mouse Apoe. Because of the possible common pathway of ApoE and TREM2 in AD, we tested whether TREM2 KO (T2KO) would block neurodegeneration in P301S Tau mice expressing ApoE4 (TE4), similar to that observed with microglial depletion. Surprisingly, we observed exacerbated neurodegeneration and tau pathology in TE4-T2KO versus TE4 mice, despite decreased TREM2-dependent microgliosis. Our results suggest that tau pathology-dependent microgliosis, that is, TREM2-independent microgliosis, facilitates tau-mediated neurodegeneration in the presence of ApoE4.

Published
2023

18. Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model

Author

Carling, Gillian K., Fan, Li, Foxe, Nessa R., Norman, Kendra, Wong, Man Ying, Zhu, Daphne, Corona, Carlo, Razzoli, Agnese, Yu, Fangmin, Yarahmady, Allan, Ye, Pearly, Chen, Hao, Huang, Yige, Amin, Sadaf, Sereda, Rebecca, Lopez-Lee, Chloe, Zacharioudakis, Emmanouil, Chen, Xiaoying, Xu, Jielin, Cheng, Feixiong, Gavathiotis, Evripidis, Cuervo, Ana Maria, Holtzman, David M., Mok, Sue-Ann, Sinha, Subhash C., Sidoli, Simone, Ratan, Rajiv R., Luo, Wenjie, Gong, Shiaoching, and Gan, Li

Published
2024
Full Text
View/download PDF

22. APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints

Author

Yin, Zhuoran, Rosenzweig, Neta, Kleemann, Kilian L., Zhang, Xiaoming, Brandão, Wesley, Margeta, Milica A., Schroeder, Caitlin, Sivanathan, Kisha N., Silveira, Sebastian, Gauthier, Christian, Mallah, Dania, Pitts, Kristen M., Durao, Ana, Herron, Shawn, Shorey, Hannah, Cheng, Yiran, Barry, Jen-Li, Krishnan, Rajesh K., Wakelin, Sam, Rhee, Jared, Yung, Anthony, Aronchik, Michael, Wang, Chao, Jain, Nimansha, Bao, Xin, Gerrits, Emma, Brouwer, Nieske, Deik, Amy, Tenen, Daniel G., Ikezu, Tsuneya, Santander, Nicolas G., McKinsey, Gabriel L., Baufeld, Caroline, Sheppard, Dean, Krasemann, Susanne, Nowarski, Roni, Eggen, Bart J. L., Clish, Clary, Tanzi, Rudolph E., Madore, Charlotte, Arnold, Thomas D., Holtzman, David M., and Butovsky, Oleg

Published
2023
Full Text
View/download PDF

24. γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Author

Aguillon, David, Allegri, Ricardo F., Aschenbrenner, Andrew J., Baker, Bryce, Barthelemy, Nicolas, Bechara, Jacob A., Berman, Sarah B., Brooks, William S., Cash, David M., Chen, Allison, Chrem Mendez, Patricio, Courtney, Laura, Cruchaga, Carlos, Daniels, Alisha J., Fagan, Anne M., Flores, Shaney, Fox, Nick C., Franklin, Erin, Goate, Alison M., Graber-Sultan, Susanne, Graff-Radford, Neill R., Gremminger, Emily, Herries, Elizabeth, Hofmann, Anna, Holtzman, David M., Hornbeck, Russ, Huey, Edward D., Ibanez, Laura, Ikeuchi, Takeshi, Ikonomovic, Snezana, Jackson, Kelley, Jarman, Steve, Jerome, Gina, Johnson, Erik C.B, Kasuga, Kensaku, Keefe, Sarah, Koudelis, Deborah, Kuder-Buletta, Elke, Laske, Christoph, Leon, Yudy Milena, Levey, Allan I., Li, Yan, Llibre-Guerra, Jorge J., Lopera, Francisco, Lu, Ruijin, Marsh, Jacob, Martins, Ralph, Massoumzadeh, Parinaz, Masters, Colin, McCullough, Austin, McKay, Nicole, Minton, Matthew, Mori, Hiroshi, Morris, John C., Nadkarni, Neelesh K., Nicklaus, Joyce, Niimi, Yoshiki, Noble, James M., Obermueller, Ulrike, Picarello, Danielle M., Pulizos, Christine, Ramirez, Laura, Renton, Alan E., Ringman, John, Rizzo, Jacqueline, Roedenbeck, Yvonne, Roh, Jee Hoon, Rosa-Neto, Pedro, Ryan, Natalie S., Sabaredzovic, Edita, Salloway, Stephen, Sanchez-Valle, Raquel, Scott, Jalen, Seyfried, Nicholas T., Simmons, Ashlee, Smith, Jennifer, Smith, Hunter, Stauber, Jennifer, Stout, Sarah, Supnet-Bell, Charlene, Surace, Ezequiel, Vazquez, Silvia, Vöglein, Jonathan, Wang, Guoqiao, Wang, Qing, Xu, Xiong, Xu, Jinbin, Schultz, Stephanie A, Liu, Lei, Schultz, Aaron P, Fitzpatrick, Colleen D, Levin, Raina, Bellier, Jean-Pierre, Shirzadi, Zahra, Joseph-Mathurin, Nelly, Chen, Charles D, Benzinger, Tammie L S, Day, Gregory S, Farlow, Martin R, Gordon, Brian A, Hassenstab, Jason J, Jack, Clifford R, Jr, Jucker, Mathias, Karch, Celeste M, Lee, Jae-Hong, Levin, Johannes, Perrin, Richard J, Schofield, Peter R, Xiong, Chengjie, Johnson, Keith A, McDade, Eric, Bateman, Randall J, Sperling, Reisa A, Selkoe, Dennis J, and Chhatwal, Jasmeer P

Published
2024
Full Text
View/download PDF

25. Update on the diagnosis of tuberculosis

Author

Kontsevaya, Irina, Cabibbe, Andrea Maurizio, Cirillo, Daniela Maria, DiNardo, Andrew R., Frahm, Nicole, Gillespie, Stephen H., Holtzman, David, Meiwes, Lennard, Petruccioli, Elisa, Reimann, Maja, Ruhwald, Morten, Sabiiti, Wilber, Saluzzo, Francesca, Tagliani, Elisa, and Goletti, Delia

Published
2024
Full Text
View/download PDF

26. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia

Author

Tcw, Julia, Qian, Lu, Pipalia, Nina H, Chao, Michael J, Liang, Shuang A, Shi, Yang, Jain, Bharat R, Bertelsen, Sarah E, Kapoor, Manav, Marcora, Edoardo, Sikora, Elizabeth, Andrews, Elizabeth J, Martini, Alessandra C, Karch, Celeste M, Head, Elizabeth, Holtzman, David M, Zhang, Bin, Wang, Minghui, Maxfield, Frederick R, Poon, Wayne W, and Goate, Alison M

Subjects
Biochemistry and Cell Biology, Biological Sciences, Stem Cell Research, Neurodegenerative, Alzheimer's Disease, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Genetics, Aging, Neurosciences, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alzheimer Disease, Animals, Apolipoprotein E3, Apolipoprotein E4, Apolipoproteins E, Astrocytes, Cholesterol, Humans, Induced Pluripotent Stem Cells, Mice, Microglia, APOE, Alzheimer, astrocytes, cholesterol, genetic heterogeneity, haplotypes, iPSC disease modeling, inflammation, matrisome, microglia, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.

Published
2022

28. CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease

Author

Horie, Kanta, Salvadó, Gemma, Barthélemy, Nicolas R., Janelidze, Shorena, Li, Yan, He, Yingxin, Saef, Benjamin, Chen, Charles D., Jiang, Hong, Strandberg, Olof, Pichet Binette, Alexa, Palmqvist, Sebastian, Sato, Chihiro, Sachdev, Pallavi, Koyama, Akihiko, Gordon, Brian A., Benzinger, Tammie L. S., Holtzman, David M., Morris, John C., Mattsson-Carlgren, Niklas, Stomrud, Erik, Ossenkoppele, Rik, Schindler, Suzanne E., Hansson, Oskar, and Bateman, Randall J.

Published
2023
Full Text
View/download PDF

29. Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study

Author

Aizenstein, Howard J., Andrews, Howard F., Bell, Karen, Birn, Rasmus M., Bulova, Peter, Cheema, Amrita, Chen, Kewei, Clare, Isabel, Clark, Lorraine, Cohen, Ann D., Constantino, John N., Doran, Eric W., Feingold, Eleanor, Foroud, Tatiana M., Hartley, Sigan L., Hom, Christy, Honig, Lawrence, Ikonomovic, Milos D., Johnson, Sterling C., Jordan, Courtney, Kamboh, M. Ilyas, Keator, David, Klunk, William E., Kofler, Julia K., Kreisl, William C., Krinsky-McHale, Sharon J., Lao, Patrick, Laymon, Charles, Lott, Ira T., Lupson, Victoria, Mathis, Chester A., Minhas, Davneet S., Nadkarni, Neelesh, Pang, Deborah, Petersen, Melissa, Price, Julie C., Pulsifer, Margaret, Reiman, Eric, Rizvi, Batool, Sabbagh, Marwan N., Schupf, Nicole, Tudorascu, Dana L., Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A., Yassa, Michael A., Zaman, Shahid, Zhang, Fan, Bateman, Randall, Daniels, Alisha J., Courtney, Laura, McDade, Eric, Llibre-Guerra, Jorge J., Supnet-Bell, Charlene, Xiong, Chengie, Xu, Xiong, Lu, Ruijin, Wang, Guoqiao, Li, Yan, Gremminger, Emily, Perrin, Richard J., Franklin, Erin, Ibanez, Laura, Jerome, Gina, Herries, Elizabeth, Stauber, Jennifer, Baker, Bryce, Minton, Matthew, Cruchaga, Carlos, Goate, Alison M., Renton, Alan E., Picarello, Danielle M., Benzinger, Tammie, Gordon, Brian A., Hornbeck, Russall, Hassenstab, Jason, Smith, Jennifer, Stout, Sarah, Aschenbrenner, Andrew J., Karch, Celeste M., Marsh, Jacob, Morris, John C., Holtzman, David M., Barthelemy, Nicolas, Xu, Jinbin, Noble, James M., Berman, Sarah B., Ikonomovic, Snezana, Nadkarni, Neelesh K., Day, Gregory, Graff-Radford, Neill R., Farlow, Martin, Chhatwal, Jasmeer P., Ikeuchi, Takeshi, Kasuga, Kensaku, Niimi, Yoshiki, Huey, Edward D., Salloway, Stephen, Schofield, Peter R., Brooks, William S., Bechara, Jacob A., Martins, Ralph, Fox, Nick C., Cash, David M., Ryan, Natalie S., Jucker, Mathias, Laske, Christoph, Hofmann, Anna, Kuder-Buletta, Elke, Graber-Sultan, Susanne, Obermueller, Ulrike, Levin, Johannes, Roedenbeck, Yvonne, Vöglein, Jonathan, Lee, Jae-Hong, Roh, Jee Hoon, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Allegri, Ricardo F., Chrem Mendez, Patricio, Surace, Ezequiel, Vazquez, Silvia, Lopera, Francisco, Leon, Yudy Milena, Ramirez, Laura, Aguillon, David, Levey, Allan I., Johnson, Erik C.B, Seyfried, Nicholas T., Ringman, John, Mori, Hiroshi, Wisch, Julie K, McKay, Nicole S, Boerwinkle, Anna H, Kennedy, James, Flores, Shaney, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O’Bryant, Sid E, Price, Julie C, Laymon, Charles M, Krinsky-McHale, Sharon J, Lai, Florence, Rosas, H Diana, Hartley, Sigan L, Lott, Ira T, Tudorascu, Dana, Zammit, Matthew, Brickman, Adam M, Lee, Joseph H, Bird, Thomas D, Cohen, Annie, Chrem, Patricio, Daniels, Alisha, Chhatwal, Jasmeer P, Karch, Celeste M, Day, Gregory S, Llibre-Guerra, Jorge, Ringman, John M, van Dyck, Christopher H, Xiong, Chengjie, Morris, John C, Bateman, Randall J, Benzinger, Tammie L S, Gordon, Brian A, and Ances, Beau M

Published
2024
Full Text
View/download PDF

30. APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease

Author

Jackson, Rosemary J., Keiser, Megan S., Meltzer, Jonah C., Fykstra, Dustin P., Dierksmeier, Steven E., Hajizadeh, Soroush, Kreuzer, Johannes, Morris, Robert, Melloni, Alexandra, Nakajima, Tsuneo, Tecedor, Luis, Ranum, Paul T., Carrell, Ellie, Chen, YongHong, Nishtar, Maryam A., Holtzman, David M., Haas, Wilhelm, Davidson, Beverly L., and Hyman, Bradley T.

Published
2024
Full Text
View/download PDF

33. Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes

Author

Guo, Jing L., Braun, Dylan, Fitzgerald, Gabriel A., Hsieh, Yun-Ting, Rougé, Lionel, Litvinchuk, Alexandra, Steffek, Micah, Propson, Nicholas E., Heffner, Catherine M., Discenza, Claire, Han, Suk Ji, Rana, Anil, Skuja, Lukas L., Lin, Bi Qi, Sun, Elizabeth W., Davis, Sonnet S., Balasundar, Srijana, Becerra, Isabel, Dugas, Jason C., Ha, Connie, Hsiao-Nakamoto, Jennifer, Huang, Fen, Jain, Shourya, Kung, Jennifer E., Liau, Nicholas P.D., Mahon, Cathal S., Nguyen, Hoang N., Nguyen, Nathan, Samaddar, Madhuja, Shi, Yajuan, Tatarakis, David, Tian, Yuxi, Zhu, Yuda, Suh, Jung H., Sandmann, Thomas, Calvert, Meredith E.K., Arguello, Annie, Kane, Lesley A., Lewcock, Joseph W., Holtzman, David M., Koth, Christopher M., and Di Paolo, Gilbert

Published
2024
Full Text
View/download PDF

37. Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure

Author

Chen, Xianwei, Sun, Guoqiang, Tian, E, Zhang, Mingzi, Davtyan, Hayk, Beach, Thomas G, Reiman, Eric M, Blurton‐Jones, Mathew, Holtzman, David M, and Shi, Yanhong

Subjects
Biochemistry and Cell Biology, Biological Sciences, Stem Cell Research, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Alzheimer's Disease, Aging, Brain Disorders, Neurodegenerative, Stem Cell Research - Induced Pluripotent Stem Cell, Dementia, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Aetiology, Development of treatments and therapeutic interventions, Neurological, Good Health and Well Being, Alzheimer Disease, Brain, Humans, Induced Pluripotent Stem Cells, Organoids, brain organoids, disease modeling, induced pluripotent stem cells, serum exposure, sporadic Alzheimer's disease
Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. Huge efforts have been made to develop anti-AD drugs in the past decades. However, all drug development programs for disease-modifying therapies have failed. Possible reasons for the high failure rate include incomplete understanding of complex pathophysiology of AD, especially sporadic AD (sAD), and species difference between humans and animal models used in preclinical studies. In this study, sAD is modeled using human induced pluripotent stem cell (hiPSC)-derived 3D brain organoids. Because the blood-brain barrier (BBB) leakage is a well-known risk factor for AD, brain organoids are exposed to human serum to mimic the serum exposure consequence of BBB breakdown in AD patient brains. The serum-exposed brain organoids are able to recapitulate AD-like pathologies, including increased amyloid beta (Aβ) aggregates and phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, and impaired neural network. Serum exposure increases Aβ and p-Tau levels through inducing beta-secretase 1 (BACE) and glycogen synthase kinase-3 alpha / beta (GSK3α/β) levels, respectively. In addition, single-cell transcriptomic analysis of brain organoids reveals that serum exposure reduced synaptic function in both neurons and astrocytes and induced immune response in astrocytes. The human brain organoid-based sAD model established in this study can provide a powerful platform for both mechanistic study and therapeutic development in the future.

Published
2021

38. C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation

Author

Lall, Deepti, Lorenzini, Ileana, Mota, Thomas A, Bell, Shaughn, Mahan, Thomas E, Ulrich, Jason D, Davtyan, Hayk, Rexach, Jessica E, Muhammad, AKM Ghulam, Shelest, Oksana, Landeros, Jesse, Vazquez, Michael, Kim, Junwon, Ghaffari, Layla, O'Rourke, Jacqueline Gire, Geschwind, Daniel H, Blurton-Jones, Mathew, Holtzman, David M, Sattler, Rita, and Baloh, Robert H

Subjects
Genetics, Aging, Alzheimer's Disease, Frontotemporal Dementia (FTD), Alzheimer's Disease Related Dementias (ADRD), Brain Disorders, Neurodegenerative, Rare Diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, ALS, Neurosciences, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyloid, Animals, C9orf72 Protein, DNA Repeat Expansion, Disease Models, Animal, Lysosomes, Mice, Mice, Knockout, Microglia, Synapses, Alzheimer’s disease, C9orf72, amyotrophic lateral sclerosis, frontotemporal dementia, microglia, neurodegeneration, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer's disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microglia promote enhanced synapse loss and neuronal deficits in a mouse model of amyloid accumulation while paradoxically improving plaque clearance. These findings suggest that altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain-of-function toxicities.

Published
2021

41. Immigration in science

Author

Casanova, Jean-Laurent, Holtzman, David M, Kaech, Susan M, Lanier, Lewis L, Nathan, Carl F, Rudensky, Alexander Y, Tuveson, David, and Wolchok, Jedd D

Subjects
Biomedical and Clinical Sciences, Health Sciences, Emigrants and Immigrants, Emigration and Immigration, Humans, Laboratories, Leadership, Motivation, Research, Research Personnel, United States, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

The advance of science is dependent upon collaboration, which does not have a visa attached to it. Indeed, over 40% of all American-based Nobel Prize winners are immigrants, and data from the National Science Foundation show that 49% of postdocs and 29% of science and engineering faculty in the US are foreign-born. However, restrictive new immigration policies in the US have left many scientists deeply concerned about their future and many American-based laboratories worried about attracting the best talent. At JEM, we're celebrating immigration by sharing the experiences of immigrant and nonimmigrant scientists on our editorial board. Alexander Rudensky and Jean-Laurent Casanova give their firsthand perspective on immigrating to the US, while Jedd Wolchok, Carl Nathan, David Holtzman, Susan Kaech, Lewis Lanier, and David Tuveson reflect on how immigration has affected their laboratories.

Published
2020

43. Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study

Author

Aizenstein, Howard J, Andrews, Howard F, Bell, Karen, Birn, Rasmus M, Bulova, Peter, Cheema, Amrita, Chen, Kewei, Clare, Isabel, Clark, Lorraine, Cohen, Ann D, Constantino, John N, Doran, Eric W, Feingold, Eleanor, Foroud, Tatiana M, Hartley, Sigan L, Hom, Christy, Honig, Lawrence, Ikonomovic, Milos D, Johnson, Sterling C, Jordan, Courtney, Kamboh, M Ilyas, Keator, David, Klunk MD, William E, Kofler, Julia K, Kreisl, William C, Krinsky- McHale, Sharon J, Lao, Patrick, Laymon, Charles, Lott, Ira T, Lupson, Victoria, Mathis, Chester A, Minhas, Davneet S, Nadkarni, Neelesh, Pang, Deborah, Petersen, Melissa, Price, Julie C, Pulsifer, Margaret, Reiman, Eric, Rizvi, Batool, Sabbagh, Marwan N, Schupf, Nicole, Tudorascu, Dana L, Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A, Yassa, Michael A, Zaman, Shahid, Zhang, Fan, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Mendez, Patricio C, Chua, Jasmin, Chui, Helena, Courtney, Laura, Day, Gregory, DeLaCruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Fox, Nick, Franklin, Erin, Joseph-Mathurin, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häslerc, Lisa, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Jucker, Mathias, Karch, Celeste, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martins, Ralph, Mason, Neal S, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, Mejia, Arlene, Morenas-Rodriguez, Estrella, Morris, John C, Mountz, James, Mummery, Catherine, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Obermüller, Ulricke, O'Connor, Antoinette, Patira, Riddhi, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nicholas T, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Xu, Jinbin, Xu, Xiong, Boerwinkle, Anna H, Gordon, Brian A, Wisch, Julie, Flores, Shaney, Henson, Rachel L, Butt, Omar H, McKay, Nicole, Chen, Charles D, Benzinger, Tammie L S, Fagan, Anne M, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O'Bryant, Sid, Lai, Florence, Rosas, H Diana, Lee, Joseph H, Silverman, Wayne, Brickman, Adam M, Chhatwal, Jasmeer P, Cruchaga, Carlos, Perrin, Richard J, Xiong, Chengjie, Hassenstab, Jason, McDade, Eric, Bateman, Randall J, and Ances, Beau M

Published
2023
Full Text
View/download PDF

44. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans

Author

Holth, Jerrah K, Fritschi, Sarah K, Wang, Chanung, Pedersen, Nigel P, Cirrito, John R, Mahan, Thomas E, Finn, Mary Beth, Manis, Melissa, Geerling, Joel C, Fuller, Patrick M, Lucey, Brendan P, and Holtzman, David M

Subjects
Biochemistry and Cell Biology, Biological Sciences, Sleep Research, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Basic Behavioral and Social Science, Dementia, Alzheimer's Disease, Brain Disorders, Acquired Cognitive Impairment, Neurodegenerative, Aging, Behavioral and Social Science, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Amyloid beta-Peptides, Animals, Brain, Circadian Rhythm, Extracellular Fluid, Female, Male, Mice, Mice, Transgenic, Sleep, Sleep Deprivation, Wakefulness, tau Proteins, General Science & Technology
Abstract

The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases Aβ plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ~90% during normal wakefulness versus sleep and ~100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

Published
2019

46. Predicting brain age from functional connectivity in symptomatic and preclinical Alzheimer disease

Author

Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bateman, Randall, Bechara, Jacob, Benzinger, Tammie, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William (Bill), Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Mendez, Patricio Chrem, Chua, Jasmin, Chui, Helena, Courtney, Laura, Cruchaga, Carlos, Day, Gregory S, DeLaCruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Fagan, Anne, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Flores, Shaney, Fox, Nick, Franklin, Erin, Joseph-Mathurin, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gordon, Brian, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häsler, Lisa, Hassenstab, Jason, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Jucker, Mathias, Karch, Celeste, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, McDade, Eric, Mejia, Arlene, Morenas-Rodriguez, Estrella, Morris, John, Mountz, James, Mummery, Cath, Nadkarni, N eelesh, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Obermüller, Ulricke, O'Connor, Antoinette, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nicholas T, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Xiong, Chengjie, Xu, Jinbin, Xu, Xiong, Millar, Peter R., Luckett, Patrick H., Gordon, Brian A., Benzinger, Tammie L.S., Schindler, Suzanne E., Fagan, Anne M., Bateman, Randall J., Lee, Jae-Hong, Mori, Hiroshi, Salloway, Stephen P, Yakushev, Igor, Morris, John C., and Ances, Beau M.

Published
2022
Full Text
View/download PDF

47. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study

Author

Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William (Bill), Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Chrem, Patricio, Chua, Jasmin, Chui, Helena, Cruchaga, Carlos, Day, Gregory S, De La Cruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Flores, Shaney, Fox, Nick, Franklin, Erin, Friedrichsen, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Häsler, Lisa, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William (Bill), Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Lopez, Oscar, Marsh, Jacob, Martinez, Rita, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, Mejia, Arlene, MountzMD, James, Mummery, Cath, Nadkarni, Neelesh, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, O'Connor, Antoinette, Obermüller, Ulricke, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nick, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Wang, Peter, Wang, Qing, Weamer, Elise, Xu, Jinbin, Xu, Xiong, Morenas-Rodríguez, Estrella, Li, Yan, Franzmeier, Nicolai, Xiong, Chengjie, Suárez-Calvet, Marc, Fagan, Anne M, Schultz, Stephanie, Gordon, Brian A, Benzinger, Tammie L S, Hassenstab, Jason, McDade, Eric, Feederle, Regina, Karch, Celeste M, Schlepckow, Kai, Morris, John C, Kleinberger, Gernot, Nellgard, Bengt, Vöglein, Jonathan, Blennow, Kaj, Zetterberg, Henrik, Ewers, Michael, Jucker, Mathias, Levin, Johannes, Bateman, Randall J, and Haass, Christian

Published
2022
Full Text
View/download PDF

48. Alzheimer's Disease‐Related Analytes Amyloid‐β and Tau in Perilymph: Correlation With Patient Age and Cognitive Score.

Author

Walia, Amit, Shew, Matthew A., Durakovic, Nedim, Herzog, Jacques A., Cirrito, John R., Yuede, Carla M., Wick, Cameron C., Manis, Melissa, Holtzman, David M., Buchman, Craig A., and Rutherford, Mark A.

Abstract

Objective: To describe the collection methods for perilymph fluid biopsy during cochlear implantation, detect levels of amyloid β 42 and 40 (Aβ42 and Aβ40), and total tau (tTau) analytes with a high‐precision assay, to compare these levels with patient age and Montreal Cognitive Assessment (MoCA) scores, and explore potential mechanisms and relationships with otic pathology. Study Design: Prospective study. Setting: Tertiary referral center. Methods: Perilymph was collected from 25 patients using polyimide tubing to avoid amyloid adherence to glass, and analyzed with a single‐molecule array advanced digital enzyme‐linked immunosorbent assay platform for Aβ40, Aβ42, and tTau. Cognition was assessed by MoCA. Results: Perilymph volumes ranged from ∼1 to 13 µL, with analyte concentrations spanning 2.67 to 1088.26 pg/mL. All samples had detectable levels of tTau, Aβ40, and Aβ42, with a significant positive correlation between Aβ42 and Aβ40 levels. Levels of Aβ42, Aβ40, and tTau were positively correlated with age, while MoCA scores were inversely correlated with age. tTau and Aβ42/Aβ40‐ratios were significantly correlated with MoCA scores. Conclusion: Alzheimer's disease‐associated peptides Aβ42, Aβ40, and tau analytes are detectable in human perilymph at levels approximately 10‐fold lower than those found in cerebrospinal fluid (CSF). These species increase with age and correlate with cognitive impairment indicators, suggesting their potential utility as biomarkers for cognitive impairment in patients undergoing cochlear implantation. Future research should investigate the origin of these analytes in the perilymph and their potential links to inner ear pathologies and hearing loss, as well as their relationships to CSF and plasma levels in individuals. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

49. Current insights into apolipoprotein E and the immune response in Alzheimer's disease.

Author

Lin, Peter Bor‐Chian and Holtzman, David M.

Subjects
*ALZHEIMER'S disease, *IMMUNOREGULATION, *NEUROLOGICAL disorders, *IMMUNE response, *OPEN-ended questions
Abstract

Summary: Alzheimer's disease (AD) is a progressive neurological disorder and the most common cause of dementia. Genetic analyses identified apolipoprotein E (APOE) as the strongest genetic risk for late‐onset AD. Studies have shown that ApoE modulates AD pathogenesis in part by influencing amyloid‐β (Aβ) deposition. However, ApoE also appears to regulate elements of AD via regulation of innate immune response, especially through microglial and astrocyte activation. In model systems, it also regulates changes in T‐cells. This review focuses on the key findings that have advanced our understanding of the role of ApoE in the pathogenesis of AD and the current view of innate immune response regulated by ApoE in AD, while discussing open questions and areas for future research. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

50. Insufficient evidence for an association between iatrogenic Alzheimer's disease and cadaveric pituitary‐derived growth hormone.

Author

Nath, Avi, Holtzman, David M., Miller, Bruce L., Grinberg, Lea T., and Leschek, Ellen Werber

Abstract

A Nature Medicine paper published in January 2024 describes eight cases of iatrogenic Alzheimer's disease in individuals who received cadaveric pituitary‐derived human growth hormone. The paper's conclusions argue for the transmissibility of Alzheimer's disease, which, if true, would create a significant public health crisis. For example, neurosurgical practices would require substantial revision, and many individuals who have undergone neurosurgical procedures would now be at considerable risk of Alzheimer's disease. A detailed review of the presented cases reveals that they do not have Alzheimer's disease, and there are alternative explanations for the cognitive decline described. In people with progressive cognitive decline, the diagnosis of Alzheimer's disease requires a demonstration of amyloid and tau pathology or amyloid and tau biomarkers. Extensive tau pathology is not demonstrated, and some also lack amyloid beta pathology. The cases described in this paper do not meet the criteria for dementia due to Alzheimer's disease by clinical and pathological standards. Highlights: Creutzfeldt‐Jakob disease has been transmitted by cadaveric growth hormone.There is no evidence for the transmission of Alzheimer's disease by cadaveric growth hormone.There is no evidence that Alzheimer's disease is transmissible. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results