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1. Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease

Author

Xicota, Laura, Cosentino, Stephanie, Vardarajan, Badri, Mayeux, Richard, Perls, Thomas T, Andersen, Stacy L, Zmuda, Joseph M, Thyagarajan, Bharat, Yashin, Anatoli, Wojczynski, Mary K, Krinsky‐McHale, Sharon, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark E, Schupf, Nicole, Lee, Joseph H, Barral, Sandra, Study, the Long‐Life Family, Abner, Erin, Adams, Perrie M, Aguirre, Alyssa, Albert, Marilyn S, Albin, Roger L, Allen, Mariet, Alvarez, Lisa, Andrews, Howard, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Ayres, Gayle, Barber, Robert C, Barnes, Lisa L, Bartlett, Jackie, Beach, Thomas G, Becker, James T, Beecham, Gary W, Benchek, Penelope, Bennett, David A, Bertelson, John, Biber, Sarah A, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Brewer, James B, Burke, James R, Burns, Jeffrey M, Bush, William S, Buxbaum, Joseph D, Byrd, Goldie, Cantwell, Laura B, Cao, Chuanhai, Carlsson, Cynthia M, Carrasquillo, Minerva M, Chan, Kwun C, Chasse, Scott, Chen, Yen‐Chi, Chesselet, Marie‐Francoise, Chin, Nathaniel A, Chui, Helena C, Chung, Jaeyoon, Craft, Suzanne, Crane, Paul K, Cranney, Marissa, Cruchaga, Carlos, Cuccaro, Michael L, Culhane, Jessica, Cullum, C Munro, Darby, Eveleen, Davis, Barbara, De Jager, Philip L, DeCarli, Charles, DeToledo, John C, Dickson, Dennis W, Dobbins, Nic, Duara, Ranjan, Ertekin‐Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fairchild, Thomas J, Fallin, Daniele, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Farrell, John, Farrer, Lindsay A, Fernandez‐Hernandez, Victoria, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gamboa, Adriana, Gauthreaux, Kathryn M, Gefen, Tamar, Geschwind, Daniel H, Ghetti, Bernardino, and Gilbert, John R

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, Dementia, Alzheimer's Disease, Human Genome, Biotechnology, Aging, Genetics, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Alzheimer Disease, Amyloid beta-Peptides, Genetic Predisposition to Disease, Genome-Wide Association Study, Microtubule-Associated Proteins, Polymorphism, Single Nucleotide, Sequence Analysis, genetic risk, late-onset Alzheimer's disease, microtubule protein, MTUS2 gene, whole genome sequence, Long‐Life Family Study, Alzheimer's Disease Genetic Consortium, Alzheimer's Biomarkers Consortium‐Down Syndrome, late‐onset Alzheimer's disease, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionLate-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.MethodsWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.ResultsWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DiscussionMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.HighlightsLong-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

Published
2024

2. LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry.

Author

Katsumata, Yuriko, Fardo, David W, Shade, Lincoln MP, Bowen, James D, Crane, Paul K, Jarvik, Gail P, Keene, C Dirk, Larson, Eric B, McCormick, Wayne C, McCurry, Susan M, Mukherjee, Shubhabrata, Kowall, Neil W, McKee, Ann C, Honig, Robert A, Lawrence, S, Vonsattel, Jean Paul, Williamson, Jennifer, Small, Scott, Burke, James R, Hulette, Christine M, Welsh-Bohmer, Kathleen A, Gearing, Marla, Lah, James J, Levey, Allan I, Wingo, Thomas S, Apostolova, Liana G, Farlow, Martin R, Ghetti, Bernardino, Saykin, Andrew J, Spina, Salvatore, Albert, Marilyn S, Lyketsos, Constantine G, Troncoso, Juan C, Frosch, Matthew P, Green, Robert C, Growdon, John H, Hyman, Bradley T, Tanzi, Rudolph E, Potter, Huntington, Dickson, Dennis W, Ertekin-Taner, Nilufer, Graff-Radford, Neill R, Parisi, Joseph E, Petersen, Ronald C, Duara, Ranjan, Buxbaum, Joseph D, Goate, Alison M, Sano, Mary, Masurkar, Arjun V, Wisniewski, Thomas, Bigio, Eileen H, Mesulam, Marsel, Weintraub, Sandra, Vassar, Robert, Kaye, Jeffrey A, Quinn, Joseph F, Woltjer, Randall L, Barnes, Lisa L, Bennett, David A, Schneider, Julie A, Yu, Lei, Henderson, Victor, Fallon, Kenneth B, Harrell, Lindy E, Marson, Daniel C, Roberson, Erik D, DeCarli, Charles, Jin, Lee-Way, Olichney, John M, Kim, Ronald, LaFerla, Frank M, Monuki, Edwin, Head, Elizabeth, Sultzer, David, Geschwind, Daniel H, Vinters, Harry V, Chesselet, Marie-Francoise, Galasko, Douglas R, Brewer, James B, Boxer, Adam, Karydas, Anna, Kramer, Joel H, Miller, Bruce L, Rosen, Howard J, Seeley, William W, Burns, Jeffrey M, Swerdlow, Russell H, Abner, Erin, Van Eldik, Linda J, Albin, Roger L, Lieberman, Andrew P, Paulson, Henry L, Arnold, Steven E, Trojanowski, John Q, Van Deerlin, Vivianna M, Hamilton, Ronald L, Kamboh, M Ilyas, Lopez, Oscar L, and Becker, James T

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Acquired Cognitive Impairment, Prevention, Aging, Minority Health, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Health Disparities, Genetics, 2.1 Biological and endogenous factors, Aetiology, Humans, Alleles, Polymorphism, Single Nucleotide, Alzheimer Disease, TDP-43 Proteinopathies, Progranulins, Membrane Proteins, Nerve Tissue Proteins, Sulfonylurea Receptors, Alzheimer’s Disease Genetics Consortium, KCNMB2, Diversity, Epidemiology, FTLD, Genome-Wide Association Studies, KATP, Neurology & Neurosurgery, Clinical sciences
Abstract

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Published
2023

3. Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping

Author

Ndayisaba, Alain, Pitaro, Ariana T., Willett, Andrew S., Jones, Kristie A., de Gusmao, Claudio Melo, Olsen, Abby L., Kim, Jisoo, Rissanen, Eero, Woods, Jared K., Srinivasan, Sharan R., Nagy, Anna, Nagy, Amanda, Mesidor, Merlyne, Cicero, Steven, Patel, Viharkumar, Oakley, Derek H., Tuncali, Idil, Taglieri-Noble, Katherine, Clark, Emily C., Paulson, Jordan, Krolewski, Richard C., Ho, Gary P., Hung, Albert Y., Wills, Anne-Marie, Hayes, Michael T., Macmore, Jason P., Warren, Luigi, Bower, Pamela G., Langer, Carol B., Kellerman, Lawrence R., Humphreys, Christopher W., Glanz, Bonnie I., Dielubanza, Elodi J., Frosch, Matthew P., Freeman, Roy L., Gibbons, Christopher H., Stefanova, Nadia, Chitnis, Tanuja, Weiner, Howard L., Scherzer, Clemens R., Scholz, Sonja W., Vuzman, Dana, Cox, Laura M., Wenning, Gregor, Schmahmann, Jeremy D., Gupta, Anoopum S., Novak, Peter, Young, Geoffrey S., Feany, Mel B., Singhal, Tarun, and Khurana, Vikram

Published
2024
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4. Landscape of brain myeloid cell transcriptome along the spatiotemporal progression of Alzheimer’s disease reveals distinct sequential responses to Aβ and tau

Author

Wachter, Astrid, Woodbury, Maya E., Lombardo, Sylvia, Abdourahman, Aicha, Wuest, Carolin, McGlame, Emily, Pastika, Timothy, Tamm, Joseph, Romanul, Nandini, Yanamandra, Kiran, Bennett, Rachel, Lin, Gen, Kwon, Taekyung, Liao, Fan, Klein, Corinna, Grinberg, Yelena, Jaisa-aad, Methasit, Li, Huan, Frosch, Matthew. P., Kummer, Markus P., Das, Sudeshna, Dellovade, Tammy, Karran, Eric H., Langlois, Xavier, Ried, Janina S., Serrano-Pozo, Alberto, Talanian, Robert V., Biber, Knut, and Hyman, Bradley T.

Published
2024
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7. Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy.

Author

Hopfner, Franziska, Tietz, Anja, Ruf, Viktoria, Ross, Owen, Koga, Shunsuke, Dickson, Dennis, Aguzzi, Adriano, Attems, Johannes, Beach, Thomas, Beller, Allison, Cheshire, William, van Deerlin, Vivianna, Deuschl, Günther, Duyckaerts, Charles, Ellinghaus, David, Evsyukov, Valentin, Flanagan, Margaret, Franke, Andre, Frosch, Matthew, Gearing, Marla, Gelpi, Ellen, van Gerpen, Jay, Ghetti, Bernardino, Glass, Jonathan, Halliday, Glenda, Helbig, Ingo, Höllerhage, Matthias, Huitinga, Inge, Irwin, David, Keene, Dirk, Kovacs, Gabor, Lee, Edward, Levin, Johannes, Martí, Maria, Mackenzie, Ian, McKeith, Ian, Mclean, Catriona, Mollenhauer, Brit, Neumann, Manuela, Newell, Kathy, Pantelyat, Alex, Pendziwiat, Manuela, Peters, Annette, Molina Porcel, Laura, Rabano, Alberto, Matěj, Radoslav, Rajput, Alex, Rajput, Ali, Reimann, Regina, Scott, William, Selvackadunco, Sashika, Simuni, Tanya, Stadelmann, Christine, Svenningsson, Per, Thomas, Alan, Trenkwalder, Claudia, Troakes, Claire, Trojanowski, John, Uitti, Ryan, White, Charles, Wszolek, Zbigniew, Xie, Tao, Ximelis, Teresa, Yebenes, Justo, Müller, Ulrich, Schellenberg, Gerard, Herms, Jochen, Kuhlenbäumer, Gregor, Höglinger, Günter, Grinberg, Lea, Seeley, William, and Desplats, Paula

Subjects
ZIC1, ZIC4, autopsy-confirmed, genome-wide association study, multiple system atrophy, Autoantibodies, Autopsy, Genome-Wide Association Study, Humans, Multiple System Atrophy, Nerve Tissue Proteins, Olivopontocerebellar Atrophies, Striatonigral Degeneration, Transcription Factors, alpha-Synuclein
Abstract

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2022

8. Differential Vulnerability of Hippocampal Subfields in Primary Age-Related Tauopathy and Chronic Traumatic Encephalopathy.

Author

Farrell, Kurt, Iida, Megan A, Cherry, Jonathan D, Casella, Alicia, Stein, Thor D, Bieniek, Kevin F, Walker, Jamie M, Richardson, Timothy E, White, Charles L, Alvarez, Victor E, Huber, Bertrand R, Dickson, Dennis W, Insausti, Ricardo, Dams-O'Connor, Kristen, Vonsattel, Jean-Paul, Teich, Andy F, Gearing, Marla, Glass, Jonathan, Troncoso, Juan C, Frosch, Matthew P, Hyman, Bradley T, Murray, Melissa E, Attems, Johannes, Flanagan, Margaret E, Mao, Qinwen, Mesulam, M-Marsel, Weintraub, Sandra, Woltjer, Randy L, Pham, Thao, Kofler, Julia, Schneider, Julie A, Yu, Lei, Purohit, Dushyant P, Haroutunian, Vahram, Hof, Patrick R, Gandy, Sam, Sano, Mary, Beach, Thomas G, Poon, Wayne, Kawas, Claudia H, Corrada, María M, Rissman, Robert A, Metcalf, Jeff, Shuldberg, Sara, Salehi, Bahar, Nelson, Peter T, Trojanowski, John Q, Lee, Edward B, Wolk, David A, McMillan, Corey T, Keene, C Dirk, Latimer, Caitlin S, Montine, Thomas J, Kovacs, Gabor G, Lutz, Mirjam I, Fischer, Peter, Perrin, Richard J, Cairns, Nigel J, McKee, Ann C, and Crary, John F

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Frontotemporal Dementia (FTD), Acquired Cognitive Impairment, Aging, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Chronic Traumatic Encephalopathy, Hippocampus, Humans, Neurofibrillary Tangles, Tauopathies, tau Proteins, Chronic traumatic encephalopathy, Primary age-related tauopathy, Repetitive head impacts, Tauopathy, Part Working Group, Neurology & Neurosurgery, Clinical sciences
Abstract

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p

Published
2022

9. Correction to: Clinical trial-ready patient cohorts for multiple system atrophy: coupling biospecimen and iPSC banking to longitudinal deep-phenotyping

Author

Ndayisaba, Alain, Pitaro, Ariana T., Willett, Andrew S., Jones, Kristie A., de Gusmao, Claudio Melo, Olsen, Abby L., Kim, Jisoo, Rissanen, Eero, Woods, Jared K., Srinivasan, Sharan R., Nagy, Anna, Nagy, Amanda, Mesidor, Merlyne, Cicero, Steven, Patel, Viharkumar, Oakley, Derek H., Tuncali, Idil, Taglieri-Noble, Katherine, Clark, Emily C., Paulson, Jordan, Krolewski, Richard C., Ho, Gary P., Hung, Albert Y., Wills, Anne-Marie, Hayes, Michael T., Macmore, Jason P., Warren, Luigi, Bower, Pamela G., Langer, Carol B., Kellerman, Lawrence R., Humphreys, Christopher W., Glanz, Bonnie I., Dielubanza, Elodi J., Frosch, Matthew P., Freeman, Roy L., Gibbons, Christopher H., Stefanova, Nadia, Chitnis, Tanuja, Weiner, Howard L., Scherzer, Clemens R., Scholz, Sonja W., Vuzman, Dana, Cox, Laura M., Wenning, Gregor, Schmahmann, Jeremy D., Gupta, Anoopum S., Novak, Peter, Young, Geoffrey S., Feany, Mel B., Singhal, Tarun, and Khurana, Vikram

Published
2024
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10. MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study

Author

Warner, Thomas T, Jaunmuktane, Zane, Boeve, Bradley F, Duara, Ranjan, Graff-Radford, Neill R, Josephs, Keith A, Knopman, David S, Koga, Shunsuke, Murray, Melissa E, Lyons, Kelly E, Pahwa, Rajesh, Petersen, Ronald C, Whitwell, Jennifer L, Grinberg, Lea T, Miller, Bruce, Schlereth, Athena, Spina, Salvatore, Grossman, Murray, Irwin, David J, Suh, EunRan, Trojanowski, John Q, Van Deerlin, Vivianna M, Wolk, David A, Connors, Theresa R, Dooley, Patrick M, Oakley, Derek H, Aldecoa, Iban, Balasa, Mircea, Gelpi, Ellen, Borrego-Écija, Sergi, Gascon-Bayarri, Jordi, Sánchez-Valle, Raquel, Sanz-Cartagena, Pilar, Piñol-Ripoll, Gerard, Bigio, Eileen H, Flanagan, Margaret E, Rogalski, Emily J, Weintraub, Sandra, Schneider, Julie A, Peng, Lihua, Zhu, Xiongwei, Chang, Koping, Troncoso, Juan C, Prokop, Stefan, Newell, Kathy L, Jones, Matthew, Richardson, Anna, Roncaroli, Federico, Snowden, Julie, Allinson, Kieren, Singh, Poonam, Serrano, Geidy E, Flowers, Xena E, Goldman, James E, Heaps, Allison C, Leskinen, Sandra P, Black, Sandra E, Masellis, Mario, King, Andrew, Al-Sarraj, Safa, Troakes, Claire, Hodges, John R, Kril, Jillian J, Kwok, John B, Piguet, Olivier, Roeber, Sigrun, Attems, Johannes, Thomas, Alan J, Evers, Bret M., Bieniek, Kevin F, Sieben, Anne A, Cras, Patrick P, De Vil, Bart B, Bird, Thomas, Castellani, Rudolph J, Chaffee, Ann, Franklin, Erin, Haroutunian, Vahram, Jacobsen, Max, Keene, Dirk, Latimer, Caitlin S, Metcalf, Jeff, Perrin, Richard J, Purohit, Dushyant P, Rissman, Robert A, Schantz, Aimee, Walker, Jamie, De Deyn, Peter P, Duyckaerts, Charles, Le Ber, Isabelle, Seilhean, Danielle, Turbant-Leclere, Sabrina, Ervin, John F, Nennesmo, Inger, Riehl, James, Nacmias, Benedetta, Finger, Elizabeth C, Blauwendraat, Cornelis, Nalls, Mike A, Singleton, Andrew B, Vitale, Dan, Cunha, Cristina, Wszolek, Zbigniew K, Valentino, Rebecca R, Scotton, William J, Roemer, Shanu F, Lashley, Tammaryn, Heckman, Michael G, Shoai, Maryam, Martinez-Carrasco, Alejandro, Tamvaka, Nicole, Walton, Ronald L, Baker, Matthew C, Macpherson, Hannah L, Real, Raquel, Soto-Beasley, Alexandra I, Mok, Kin, Revesz, Tamas, Christopher, Elizabeth A, DeTure, Michael, Seeley, William W, Lee, Edward B, Frosch, Matthew P, Molina-Porcel, Laura, Gefen, Tamar, Redding-Ochoa, Javier, Ghetti, Bernardino, Robinson, Andrew C, Kobylecki, Christopher, Rowe, James B, Beach, Thomas G, Teich, Andrew F, Keith, Julia L, Bodi, Istvan, Halliday, Glenda M, Gearing, Marla, Arzberger, Thomas, Morris, Christopher M, White, Charles L, 3rd, Mechawar, Naguib, Boluda, Susana, MacKenzie, Ian R, McLean, Catriona, Cykowski, Matthew D, Wang, Shih-Hsiu J, Graff, Caroline, Nagra, Rashed M, Kovacs, Gabor G, Giaccone, Giorgio, Neumann, Manuela, Ang, Lee-Cyn, Carvalho, Agostinho, Morris, Huw R, Rademakers, Rosa, Hardy, John A, Dickson, Dennis W, Rohrer, Jonathan D, and Ross, Owen A

Published
2024
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14. Demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy: an international cohort study and individual participant data meta-analysis

Author

Abdi, Zeinab, Agosta, Federica, Ahmed, Samrah, Alcolea, Daniel, Allen, Isabel Elaine, Allinson, Kieren S.J., Apostolova, Liana G., Arighi, Andrea, Balasa, Mircea, Barkhof, Frederik, Best, John, Boon, Baayla D., Brandt, Katherine D., Brosch, Jared, Burrell, James, Butler, Christopher R., Calandri, Ismael, Caminiti, Silvia Paola, Canu, Elisa, Carrillo, Maria C., Caso, Francesca, Chapleau, Marianne, Chrem Mendez, Patricio, Chu, Min, Crutch, Sebastian, Cordato, Nicholas, Costa, Ana Sofia, Cui, Yue, Dickerson, Bradford, Dickson, Dennis W., Duara, Ranjan, Dubois, Bruno, Eldaief, Mark, Farlow, Martin, Fenoglio, Chiara, Filippi, Massimo, Fliessbach, Klaus, Formaglio, Maïté, Fortea, Juan, Fox, Nick, Foxe, David, Tilikete, Caroline Froment, Frosch, Matthew P., Fumagalli, Giorgio Giulio, Galasko, Douglas, Galimberti, Daniela, Garat, Oscar, Giardinieri, Giulia, Graff-Radford, Jonathan, Graff-Radford, Neill R., Grinberg, Lea, Groot, Colin, Hake, Ann Marie, Hansson, Oskar, Headley, Alison, Hernandez, Micaela, Hochberg, Daisy, Hodges, John R., Hof, Patrick R., Holton, Janice, Hromas, Gabrielle, Gala, Ignacio Illán, Irwin, David J., Jaunmuktane, Zane, Jing, Donglai, Josephs, Keith, Kagerer, Sonja M., Kasuga, Kensaku, Kong, Yu, Kövari, Enikö, Lacombe-Thibault, Mégane, Lleó, Alberto, Laforce, Robert, La Joie, Renaud, Lashley, Tammaryn, Leger, Gabriel, Levin, Netta, Levy, Richard, Liu, Yang, Liu, Li, Lladó Plarrumaní, Albert, Lucente, Diane E., Machulda, Mary M., Magnani, Giuseppe, Magnin, Eloi, Malpetti, Maura, Matthews, Brandy, McGinnis, Scott, Mendez, Mario F., Mesulam, Marsel, Migliaccio, Raffaella, Miklitz, Carolin, Miller, Zachary A., Montembeault, Maxime, Murray, Melissa E., Mundada, Nidhi, Nemes, Sara, Nestor, Peter J., Ocal, Dilek, Ossenkoppele, Rik, Paterson, Ross, Pelak, Victoria, Perani, Daniela, Phillips, Jeffrey, Piguet, Olivier, Pijnenburg, Yolande, Putcha, Deepti, Quimby, Megan, Rabinovici, Gil D., Reetz, Kathrin, Rein, Netaniel, Revesz, Tamas, Rezaii, Neguine, Rodriguez-Porcel, Federico, Rogalski, Emily, Rowe, James B., Ryan, Natalie, Sanchez-Valle, Raquel, Sacchi, Luca, Santos-Santos, Miguel Ángel, Schott, Jonathan M., Seeley, William, Sherman, Janet, Spina, Salvatore, Stomrud, Erik, Sullivan, A. Campbell, Tanner, Jeremy, Tideman, Pontus, Tokutake, Takayoshi, Tondo, Giacomo, Touroutoglou, Alexandra, Tousi, Babak, Vandenberghe, Rik, van der Flier, Wiesje, Walker, Jamie M., Weintraub, Sandra, Whitwell, Jennifer L., Wolk, David A., Wong, Bonnie, Wu, Liyong, Xie, Kexin, Yong, Keir, Apostolova, Liana, Boon, Baayla D C, Grinberg, Lea T, Irwin, David J, Josephs, Keith A, Mendez, Mario F, Mendez, Patricio Chrem, Miller, Zachary A, Murray, Melissa E, Nemes, Sára, Schott, Jonathan M, Sullivan, A Campbell, Walker, Jamie, Whitwell, Jennifer L, Wolk, David A, and Rabinovici, Gil D

Published
2024
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15. Does Data-Independent Acquisition Data Contain Hidden Gems? A Case Study Related to Alzheimer’s Disease

Author

Hubbard, Evan E, Heil, Lilian R, Merrihew, Gennifer E, Chhatwal, Jasmeer P, Farlow, Martin R, McLean, Catriona A, Ghetti, Bernardino, Newell, Kathy L, Frosch, Matthew P, Bateman, Randall J, Larson, Eric B, Keene, C Dirk, Perrin, Richard J, Montine, Thomas J, MacCoss, Michael J, and Julian, Ryan R

Subjects
Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Brain Disorders, Acquired Cognitive Impairment, Aging, Neurodegenerative, Neurosciences, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Autophagy, Brain, Humans, Proteomics, tau Proteins, proteomics, age-related neurodegenerative disease, proteostasis, lysosome, aspartic acid, amyloid, neurofibrillary tangle, amyloid-beta, post-translational modification, hippocampus, Chemical Sciences, Biological Sciences, Biochemistry & Molecular Biology
Abstract

One of the potential benefits of using data-independent acquisition (DIA) proteomics protocols is that information not originally targeted by the study may be present and discovered by subsequent analysis. Herein, we reanalyzed DIA data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer's disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both autosomal dominant and sporadic AD samples. To explore potential mechanisms that might account for these observations, quantitative analysis of proteins related to isomerization repair and autophagy was performed. Differences consistent with reduced autophagic flux in AD-related samples relative to controls were found for numerous proteins, including most notably p62, a recognized indicator of autophagic inhibition. These results suggest, but do not conclusively demonstrate, that lower autophagic flux may be strongly associated with loss of function in AD brains. This study illustrates that DIA data may contain unforeseen results of interest and may be particularly useful for pilot studies investigating new research directions. In this case, a promising target for future investigations into the therapy and prevention of AD has been identified.

Published
2022

16. Genome-wide association study and functional validation implicates JADE1 in tauopathy

Author

Farrell, Kurt, Kim, SoongHo, Han, Natalia, Iida, Megan A, Gonzalez, Elias M, Otero-Garcia, Marcos, Walker, Jamie M, Richardson, Timothy E, Renton, Alan E, Andrews, Shea J, Fulton-Howard, Brian, Humphrey, Jack, Vialle, Ricardo A, Bowles, Kathryn R, de Paiva Lopes, Katia, Whitney, Kristen, Dangoor, Diana K, Walsh, Hadley, Marcora, Edoardo, Hefti, Marco M, Casella, Alicia, Sissoko, Cheick T, Kapoor, Manav, Novikova, Gloriia, Udine, Evan, Wong, Garrett, Tang, Weijing, Bhangale, Tushar, Hunkapiller, Julie, Ayalon, Gai, Graham, Robert R, Cherry, Jonathan D, Cortes, Etty P, Borukov, Valeriy Y, McKee, Ann C, Stein, Thor D, Vonsattel, Jean-Paul, Teich, Andy F, Gearing, Marla, Glass, Jonathan, Troncoso, Juan C, Frosch, Matthew P, Hyman, Bradley T, Dickson, Dennis W, Murray, Melissa E, Attems, Johannes, Flanagan, Margaret E, Mao, Qinwen, Mesulam, M-Marsel, Weintraub, Sandra, Woltjer, Randy L, Pham, Thao, Kofler, Julia, Schneider, Julie A, Yu, Lei, Purohit, Dushyant P, Haroutunian, Vahram, Hof, Patrick R, Gandy, Sam, Sano, Mary, Beach, Thomas G, Poon, Wayne, Kawas, Claudia H, Corrada, María M, Rissman, Robert A, Metcalf, Jeff, Shuldberg, Sara, Salehi, Bahar, Nelson, Peter T, Trojanowski, John Q, Lee, Edward B, Wolk, David A, McMillan, Corey T, Keene, C Dirk, Latimer, Caitlin S, Montine, Thomas J, Kovacs, Gabor G, Lutz, Mirjam I, Fischer, Peter, Perrin, Richard J, Cairns, Nigel J, Franklin, Erin E, Cohen, Herbert T, Raj, Towfique, Cobos, Inma, Frost, Bess, Goate, Alison, White III, Charles L, and Crary, John F

Subjects
Biomedical and Clinical Sciences, Neurosciences, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Genetics, Dementia, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Aging, Alzheimer's Disease, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Animals, Cohort Studies, Drosophila, Female, Genome-Wide Association Study, Homeodomain Proteins, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Tauopathies, Tumor Suppressor Proteins, Clinical Sciences, Neurology & Neurosurgery
Abstract

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

Published
2022

17. Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis

Author

Nicks, Raymond, Clement, Nathan F., Alvarez, Victor E., Tripodis, Yorghos, Baucom, Zachery H., Huber, Bertrand R., Mez, Jesse, Alosco, Michael L., Aytan, Nurgul, Cherry, Jonathan D., Cormier, Kerry A., Kubilius, Carol, Mathias, Rebecca, Svirsky, Sarah E., Pothast, Morgan J., Hildebrandt, Audrey M., Chung, Jaeyoon, Han, Xudong, Crary, John F., McKee, Ann C., Frosch, Matthew P., and Stein, Thor D.

Published
2023
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19. Genome-wide association study and functional validation implicates JADE1 in tauopathy

Author

Farrell, Kurt, Kim, SoongHo, Han, Natalia, Iida, Megan A, Gonzalez, Elias, Otero-Garcia, Marcos, Walker, Jamie, Richardson, Tim, Renton, Alan E, Andrews, Shea J, Fulton-Howard, Brian, Humphrey, Jack, Vialle, Ricardo A, Bowles, Kathryn R, Whitney, Kristen, Dangoor, Diana K, Marcora, Edoardo, Hefti, Marco M, Casella, Alicia, Sissoko, Cheick, Kapoor, Manav, Novikova, Gloriia, Udine, Evan, Wong, Garrett, Tang, Weijing, Bhangale, Tushar, Hunkapiller, Julie, Ayalon, Gai, Graham, Rob, Cherry, Jonathan D, Cortes, Etty, Borukov, Valeriy, McKee, Ann C, Stein, Thor D, Vonsattel, Jean-Paul, Teich, Andy F, Gearing, Marla, Glass, Jonathan, Troncoso, Juan C, Frosch, Matthew P, Hyman, Bradley T, Dickson, Dennis W, Murray, Melissa E, Attems, Johannes, Flanagan, Margaret E, Mao, Qinwen, Mesulam, M-Marsel, Weintraub, Sandra, Woltjer, Randy, Pham, Thao, Kofler, Julia, Schneider, Julie A, Yu, Lei, Purohit, Dushyant P, Haroutunian, Vahram, Hof, Patrick R, Gandy, Sam, Sano, Mary, Beach, Thomas G, Poon, Wayne, Kawas, Claudia, Corrada, María, Rissman, Robert A, Metcalf, Jeff, Shuldberg, Sara, Salehi, Bahar, Nelson, Peter T, Trojanowski, John Q, Lee, Edward B, Wolk, David A, McMillan, Corey T, Keene, Dirk C, Montine, Thomas J, Kovacs, Gabor G, Lutz, Mirjam I, Fischer, Peter, Perrin, Richard J, Cairns, Nigel, Franklin, Erin E, Cohen, Herbert T, Sillero, Maria Inmaculada Cobos, Frost, Bess, Raj, Towfique, Goate, Alison, White, Charles L, and Crary, John F

Subjects
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Genetics, Dementia, Alzheimer's Disease, Frontotemporal Dementia (FTD), Brain Disorders, Neurosciences, Biotechnology, Neurodegenerative, Aging, Acquired Cognitive Impairment, Aetiology, 2.1 Biological and endogenous factors, Neurological
Abstract

AbstractPrimary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

Published
2021

20. Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis

Author

Mathewson, Nathan D, Ashenberg, Orr, Tirosh, Itay, Gritsch, Simon, Perez, Elizabeth M, Marx, Sascha, Jerby-Arnon, Livnat, Chanoch-Myers, Rony, Hara, Toshiro, Richman, Alyssa R, Ito, Yoshinaga, Pyrdol, Jason, Friedrich, Mirco, Schumann, Kathrin, Poitras, Michael J, Gokhale, Prafulla C, Gonzalez Castro, L Nicolas, Shore, Marni E, Hebert, Christine M, Shaw, Brian, Cahill, Heather L, Drummond, Matthew, Zhang, Wubing, Olawoyin, Olamide, Wakimoto, Hiroaki, Rozenblatt-Rosen, Orit, Brastianos, Priscilla K, Liu, X Shirley, Jones, Pamela S, Cahill, Daniel P, Frosch, Matthew P, Louis, David N, Freeman, Gordon J, Ligon, Keith L, Marson, Alexander, Chiocca, E Antonio, Reardon, David A, Regev, Aviv, Suvà, Mario L, and Wucherpfennig, Kai W

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Rare Diseases, Immunization, Cancer, Genetics, Vaccine Related, Brain Disorders, Stem Cell Research, Neurosciences, Brain Cancer, Human Genome, Stem Cell Research - Nonembryonic - Human, Animals, Antigens, Neoplasm, Disease Models, Animal, Gene Expression Profiling, Glioma, Killer Cells, Natural, Lectins, C-Type, Lymphocytes, Tumor-Infiltrating, Mice, NK Cell Lectin-Like Receptor Subfamily B, Receptors, Cell Surface, Single-Cell Analysis, T-Lymphocyte Subsets, T-Lymphocytes, Tumor Escape, CD161, IDH-mutant gliomas, T cells, glioblastoma, single-cell RNA-seq, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.

Published
2021

21. Molecular and clinicopathologic characteristics of gliomas with EP300::BCOR fusions

Author

Wu, Zhichao, Rajan, Sharika, Chung, Hye-Jung, Raffeld, Mark, Panneer Selvam, Pavalan, Schweizer, Leonille, Perry, Arie, Samuel, David, Giannini, Caterina, Ragunathan, Aditya, Frosch, Matthew P., Marshall, Michael S., Boué, Daniel R., Donev, Kliment, Neill, Stewart G., Fernandes, Igor, Resnick, Adam, Rood, Brian, Cummings, Thomas J., Buckley, Anne F., Szymanski, Linda, Neto, Osorio Lopes Abath, Zach, Leor, Colman, Howard, Cheshier, Samuel, Ziskin, Jennifer, Tyagi, Manoj, Capper, David, Abdullaev, Zied, Cimino, Patrick J., Quezado, Martha, Pratt, Drew, and Aldape, Kenneth

Published
2022
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23. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study.

Author

Reiman, Eric M, Arboleda-Velasquez, Joseph F, Quiroz, Yakeel T, Huentelman, Matthew J, Beach, Thomas G, Caselli, Richard J, Chen, Yinghua, Su, Yi, Myers, Amanda J, Hardy, John, Paul Vonsattel, Jean, Younkin, Steven G, Bennett, David A, De Jager, Philip L, Larson, Eric B, Crane, Paul K, Keene, C Dirk, Kamboh, M Ilyas, Kofler, Julia K, Duque, Linda, Gilbert, John R, Gwirtsman, Harry E, Buxbaum, Joseph D, Dickson, Dennis W, Frosch, Matthew P, Ghetti, Bernardino F, Lunetta, Kathryn L, Wang, Li-San, Hyman, Bradley T, Kukull, Walter A, Foroud, Tatiana, Haines, Jonathan L, Mayeux, Richard P, Pericak-Vance, Margaret A, Schneider, Julie A, Trojanowski, John Q, Farrer, Lindsay A, Schellenberg, Gerard D, Beecham, Gary W, Montine, Thomas J, Jun, Gyungah R, and Alzheimer’s Disease Genetics Consortium

Subjects
Alzheimer’s Disease Genetics Consortium, Brain, Humans, Alzheimer Disease, Genetic Predisposition to Disease, Probability, Genotype, Homozygote, Alleles, Aged, Aged, 80 and over, Middle Aged, Female, Male, Apolipoprotein E2, Apolipoprotein E3, Apolipoprotein E4, Genetic Association Studies, Neuropathology, Aging, Brain Disorders, Acquired Cognitive Impairment, Dementia, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Genetics, Alzheimer's Disease, Prevention, Neurosciences, 2.1 Biological and endogenous factors, Neurological
Abstract

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.

Published
2020

24. MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study

Author

Valentino, Rebecca R, primary, Scotton, William J, additional, Roemer, Shanu F, additional, Lashley, Tammaryn, additional, Heckman, Michael G, additional, Shoai, Maryam, additional, Martinez-Carrasco, Alejandro, additional, Tamvaka, Nicole, additional, Walton, Ronald L, additional, Baker, Matthew C, additional, Macpherson, Hannah L, additional, Real, Raquel, additional, Soto-Beasley, Alexandra I, additional, Mok, Kin, additional, Revesz, Tamas, additional, Christopher, Elizabeth A, additional, DeTure, Michael, additional, Seeley, William W, additional, Lee, Edward B, additional, Frosch, Matthew P, additional, Molina-Porcel, Laura, additional, Gefen, Tamar, additional, Redding-Ochoa, Javier, additional, Ghetti, Bernardino, additional, Robinson, Andrew C, additional, Kobylecki, Christopher, additional, Rowe, James B, additional, Beach, Thomas G, additional, Teich, Andrew F, additional, Keith, Julia L, additional, Bodi, Istvan, additional, Halliday, Glenda M, additional, Gearing, Marla, additional, Arzberger, Thomas, additional, Morris, Christopher M, additional, White, Charles L, additional, Mechawar, Naguib, additional, Boluda, Susana, additional, MacKenzie, Ian R, additional, McLean, Catriona, additional, Cykowski, Matthew D, additional, Wang, Shih-Hsiu J, additional, Graff, Caroline, additional, Nagra, Rashed M, additional, Kovacs, Gabor G, additional, Giaccone, Giorgio, additional, Neumann, Manuela, additional, Ang, Lee-Cyn, additional, Carvalho, Agostinho, additional, Morris, Huw R, additional, Rademakers, Rosa, additional, Hardy, John A, additional, Dickson, Dennis W, additional, Rohrer, Jonathan D, additional, Ross, Owen A, additional, Warner, Thomas T, additional, Jaunmuktane, Zane, additional, Boeve, Bradley F, additional, Duara, Ranjan, additional, Graff-Radford, Neill R, additional, Josephs, Keith A, additional, Knopman, David S, additional, Koga, Shunsuke, additional, Murray, Melissa E, additional, Lyons, Kelly E, additional, Pahwa, Rajesh, additional, Petersen, Ronald C, additional, Whitwell, Jennifer L, additional, Grinberg, Lea T, additional, Miller, Bruce, additional, Schlereth, Athena, additional, Spina, Salvatore, additional, Grossman, Murray, additional, Irwin, David J, additional, Suh, EunRan, additional, Trojanowski, John Q, additional, Van Deerlin, Vivianna M, additional, Wolk, David A, additional, Connors, Theresa R, additional, Dooley, Patrick M, additional, Oakley, Derek H, additional, Aldecoa, Iban, additional, Balasa, Mircea, additional, Gelpi, Ellen, additional, Borrego-Écija, Sergi, additional, Gascon-Bayarri, Jordi, additional, Sánchez-Valle, Raquel, additional, Sanz-Cartagena, Pilar, additional, Piñol-Ripoll, Gerard, additional, Bigio, Eileen H, additional, Flanagan, Margaret E, additional, Rogalski, Emily J, additional, Weintraub, Sandra, additional, Schneider, Julie A, additional, Peng, Lihua, additional, Zhu, Xiongwei, additional, Chang, Koping, additional, Troncoso, Juan C, additional, Prokop, Stefan, additional, Newell, Kathy L, additional, Jones, Matthew, additional, Richardson, Anna, additional, Roncaroli, Federico, additional, Snowden, Julie, additional, Allinson, Kieren, additional, Singh, Poonam, additional, Serrano, Geidy E, additional, Flowers, Xena E, additional, Goldman, James E, additional, Heaps, Allison C, additional, Leskinen, Sandra P, additional, Black, Sandra E, additional, Masellis, Mario, additional, King, Andrew, additional, Al-Sarraj, Safa, additional, Troakes, Claire, additional, Hodges, John R, additional, Kril, Jillian J, additional, Kwok, John B, additional, Piguet, Olivier, additional, Roeber, Sigrun, additional, Attems, Johannes, additional, Thomas, Alan J, additional, Evers, Bret M., additional, Bieniek, Kevin F, additional, Sieben, Anne A, additional, Cras, Patrick P, additional, De Vil, Bart B, additional, Bird, Thomas, additional, Castellani, Rudolph J, additional, Chaffee, Ann, additional, Franklin, Erin, additional, Haroutunian, Vahram, additional, Jacobsen, Max, additional, Keene, Dirk, additional, Latimer, Caitlin S, additional, Metcalf, Jeff, additional, Perrin, Richard J, additional, Purohit, Dushyant P, additional, Rissman, Robert A, additional, Schantz, Aimee, additional, Walker, Jamie, additional, De Deyn, Peter P, additional, Duyckaerts, Charles, additional, Le Ber, Isabelle, additional, Seilhean, Danielle, additional, Turbant-Leclere, Sabrina, additional, Ervin, John F, additional, Nennesmo, Inger, additional, Riehl, James, additional, Nacmias, Benedetta, additional, Finger, Elizabeth C, additional, Blauwendraat, Cornelis, additional, Nalls, Mike A, additional, Singleton, Andrew B, additional, Vitale, Dan, additional, Cunha, Cristina, additional, and Wszolek, Zbigniew K, additional

Published
2024
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26. LATE to the PART-y

Author

Josephs, Keith A, Mackenzie, Ian, Frosch, Matthew P, Bigio, Eileen H, Neumann, Manuela, Arai, Tetsuaki, Dugger, Brittany N, Ghetti, Bernardino, Grossman, Murray, Hasegawa, Masato, Herrup, Karl, Holton, Janice, Jellinger, Kurt, Lashley, Tammaryn, McAleese, Kirsty E, Parisi, Joseph E, Revesz, Tamas, Saito, Yuko, Vonsattel, Jean Paul, Whitwell, Jennifer L, Wisniewski, Thomas, and Hu, William

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Consensus, DNA-Binding Proteins, Humans, Limbic Encephalitis, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Published
2019

27. Protection of tissue physicochemical properties using polyfunctional crosslinkers

Author

Park, Young-Gyun, Sohn, Chang Ho, Chen, Ritchie, McCue, Margaret, Yun, Dae Hee, Drummond, Gabrielle T, Ku, Taeyun, Evans, Nicholas B, Oak, Hayeon Caitlyn, Trieu, Wendy, Choi, Heejin, Jin, Xin, Lilascharoen, Varoth, Wang, Ji, Truttmann, Matthias C, Qi, Helena W, Ploegh, Hidde L, Golub, Todd R, Chen, Shih-Chi, Frosch, Matthew P, Kulik, Heather J, Lim, Byung Kook, and Chung, Kwanghun

Subjects
Agricultural, Veterinary and Food Sciences, Engineering, Biomedical Engineering
Abstract

Understanding complex biological systems requires the system-wide characterization of both molecular and cellular features. Existing methods for spatial mapping of biomolecules in intact tissues suffer from information loss caused by degradation and tissue damage. We report a tissue transformation strategy named stabilization under harsh conditions via intramolecular epoxide linkages to prevent degradation (SHIELD), which uses a flexible polyepoxide to form controlled intra- and intermolecular cross-link with biomolecules. SHIELD preserves protein fluorescence and antigenicity, transcripts and tissue architecture under a wide range of harsh conditions. We applied SHIELD to interrogate system-level wiring, synaptic architecture, and molecular features of virally labeled neurons and their targets in mouse at single-cell resolution. We also demonstrated rapid three-dimensional phenotyping of core needle biopsies and human brain cells. SHIELD enables rapid, multiscale, integrated molecular phenotyping of both animal and clinical tissues.

Published
2019

28. The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI–neuropathology diagnostic accuracy study

Author

Charidimou, Andreas, Boulouis, Gregoire, Frosch, Matthew P, Baron, Jean-Claude, Pasi, Marco, Albucher, Jean Francois, Banerjee, Gargi, Barbato, Carmen, Bonneville, Fabrice, Brandner, Sebastian, Calviere, Lionel, Caparros, François, Casolla, Barbara, Cordonnier, Charlotte, Delisle, Marie-Bernadette, Deramecourt, Vincent, Dichgans, Martin, Gokcal, Elif, Herms, Jochen, Hernandez-Guillamon, Mar, Jäger, Hans Rolf, Jaunmuktane, Zane, Linn, Jennifer, Martinez-Ramirez, Sergi, Martínez-Sáez, Elena, Mawrin, Christian, Montaner, Joan, Moulin, Solene, Olivot, Jean-Marc, Piazza, Fabrizio, Puy, Laurent, Raposo, Nicolas, Rodrigues, Mark A, Roeber, Sigrun, Romero, Jose Rafael, Samarasekera, Neshika, Schneider, Julie A, Schreiber, Stefanie, Schreiber, Frank, Schwall, Corentin, Smith, Colin, Szalardy, Levente, Varlet, Pascale, Viguier, Alain, Wardlaw, Joanna M, Warren, Andrew, Wollenweber, Frank A, Zedde, Marialuisa, van Buchem, Mark A, Gurol, M Edip, Viswanathan, Anand, Al-Shahi Salman, Rustam, Smith, Eric E, Werring, David J, and Greenberg, Steven M

Published
2022
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29. Somatic genomic changes in single Alzheimer’s disease neurons

Author

Miller, Michael B., Huang, August Yue, Kim, Junho, Zhou, Zinan, Kirkham, Samantha L., Maury, Eduardo A., Ziegenfuss, Jennifer S., Reed, Hannah C., Neil, Jennifer E., Rento, Lariza, Ryu, Steven C., Ma, Chanthia C., Luquette, Lovelace J., Ames, Heather M., Oakley, Derek H., Frosch, Matthew P., Hyman, Bradley T., Lodato, Michael A., Lee, Eunjung Alice, and Walsh, Christopher A.

Published
2022
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37. Author Response: Machine learning of dissection photographs and surface scanning for quantitative 3D neuropathology

Author

Gazula, Harshvardhan, primary, Tregidgo, Henry F. J., additional, Billot, Benjamin, additional, Balbastre, Yael, additional, William-Ramirez, Jonathan, additional, Herisse, Rogeny, additional, Deden-Binder, Lucas J, additional, Casamitjana, Adrià, additional, Melief, Erica J., additional, Latimer, Caitlin S., additional, Kilgore, Mitchell D., additional, Montine, Mark, additional, Robinson, Eleanor, additional, Blackburn, Emily, additional, Marshall, Michael S., additional, Connors, Theresa R., additional, Oakley, Derek H., additional, Frosch, Matthew P., additional, Young, Sean I., additional, Leemput, Koen Van, additional, Dalca, Adrian V., additional, Fischl, Bruce, additional, Mac Donald, Christine L., additional, Keene, C. Dirk, additional, Hyman, Bradley T., additional, and Iglesias, Juan Eugenio, additional

Published
2024
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38. Machine learning of dissection photographs and surface scanning for quantitative 3D neuropathology

Author

Gazula, Harshvardhan, primary, Tregidgo, Henry F. J., additional, Billot, Benjamin, additional, Balbastre, Yael, additional, William-Ramirez, Jonathan, additional, Herisse, Rogeny, additional, Deden-Binder, Lucas J, additional, Casamitjana, Adrià, additional, Melief, Erica J., additional, Latimer, Caitlin S., additional, Kilgore, Mitchell D., additional, Montine, Mark, additional, Robinson, Eleanor, additional, Blackburn, Emily, additional, Marshall, Michael S., additional, Connors, Theresa R., additional, Oakley, Derek H., additional, Frosch, Matthew P., additional, Young, Sean I., additional, Leemput, Koen Van, additional, Dalca, Adrian V., additional, Fischl, Bruce, additional, Mac Donald, Christine L., additional, Keene, C. Dirk, additional, Hyman, Bradley T., additional, and Iglesias, Juan Eugenio, additional

Published
2024
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39. Demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy: an international cohort study and individual participant data meta-analysis

Author

Chapleau, Marianne, primary, La Joie, Renaud, additional, Yong, Keir, additional, Agosta, Federica, additional, Allen, Isabel Elaine, additional, Apostolova, Liana, additional, Best, John, additional, Boon, Baayla D C, additional, Crutch, Sebastian, additional, Filippi, Massimo, additional, Fumagalli, Giorgio Giulio, additional, Galimberti, Daniela, additional, Graff-Radford, Jonathan, additional, Grinberg, Lea T, additional, Irwin, David J, additional, Josephs, Keith A, additional, Mendez, Mario F, additional, Mendez, Patricio Chrem, additional, Migliaccio, Raffaella, additional, Miller, Zachary A, additional, Montembeault, Maxime, additional, Murray, Melissa E, additional, Nemes, Sára, additional, Pelak, Victoria, additional, Perani, Daniela, additional, Phillips, Jeffrey, additional, Pijnenburg, Yolande, additional, Rogalski, Emily, additional, Schott, Jonathan M, additional, Seeley, William, additional, Sullivan, A Campbell, additional, Spina, Salvatore, additional, Tanner, Jeremy, additional, Walker, Jamie, additional, Whitwell, Jennifer L, additional, Wolk, David A, additional, Ossenkoppele, Rik, additional, Rabinovici, Gil D, additional, Abdi, Zeinab, additional, Ahmed, Samrah, additional, Alcolea, Daniel, additional, Allinson, Kieren S.J., additional, Arighi, Andrea, additional, Balasa, Mircea, additional, Barkhof, Frederik, additional, Brandt, Katherine D., additional, Brosch, Jared, additional, Burrell, James, additional, Butler, Christopher R., additional, Calandri, Ismael, additional, Caminiti, Silvia Paola, additional, Canu, Elisa, additional, Carrillo, Maria C., additional, Caso, Francesca, additional, Chu, Min, additional, Cordato, Nicholas, additional, Costa, Ana Sofia, additional, Cui, Yue, additional, Dickerson, Bradford, additional, Dickson, Dennis W., additional, Duara, Ranjan, additional, Dubois, Bruno, additional, Eldaief, Mark, additional, Farlow, Martin, additional, Feneglio, Chiara, additional, Fliessbach, Klaus, additional, Formaglio, Maïté, additional, Fortea, Juan, additional, Fox, Nick, additional, Foxe, David, additional, Tilikete, Caroline Froment, additional, Frosch, Matthew P., additional, Galasko, Douglas, additional, Garat, Oscar, additional, Giardinieri, Giulia, additional, Graff-Radford, Neill R., additional, Groot, Colin, additional, Hake, Ann Marie, additional, Hansson, Oskar, additional, Headley, Alison, additional, Hernandez, Micaela, additional, Hochberg, Daisy, additional, Hodges, John R., additional, Hof, Patrick R., additional, Holton, Janice, additional, Hromas, Gabrielle, additional, Illán Gala, Ignacio, additional, Jaunmuktane, Zane, additional, Jing, Donglai, additional, Kagerer, Sonja M., additional, Kasuga, Kensaku, additional, Kong, Yu, additional, Kövari, Enikö, additional, Lacombe-Thibault, Mégane, additional, Lleó Plarrumaní, Alberto, additional, Lucente, Diane E., additional, Machulda, Mary M., additional, Magnani, Giuseppe, additional, Magnin, Eloi, additional, Malpetti, Maura, additional, Matthews, Brandy, additional, McGinnis, Scott, additional, Mesulam, Marsel, additional, Miklitz, Carolin, additional, Mundada, Nidhi, additional, Nestor, Peter J., additional, Ocal, Dilek, additional, Paterson, Ross, additional, Piguet, Olivier, additional, Putcha, Deepti, additional, Quimby, Megan, additional, Reetz, Kathrin, additional, Rein, Netaniel, additional, Revesz, Tamas, additional, Rezaii, Neguine, additional, Rodriguez-Porcel, Federico, additional, Rowe, James B., additional, Ryan, Natalie, additional, Sanchez-Valle, Raquel, additional, Sacchi, Luca, additional, Santos-Santos, Miguel Ángel, additional, Sherman, Janet, additional, Stomrud, Erik, additional, Tideman, Pontus, additional, Tokutake, Takayoshi, additional, Tondo, Giacomo, additional, Touroutoglou, Alexandra, additional, Tousi, Babak, additional, Vandenberghe, Rik, additional, van der Flier, Wiesje, additional, Weintraub, Sandra, additional, Wong, Bonnie, additional, Wu, Liyong, additional, and Xie, Kexin, additional

Published
2024
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41. Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation

Author

Amaral, Ana Claudia, Perez-Nievas, Beatriz G., Siao Tick Chong, Michael, Gonzalez-Martinez, Alicia, Argente-Escrig, Herminia, Rubio-Guerra, Sara, Commins, Caitlin, Muftu, Serra, Eftekharzadeh, Bahareh, Hudry, Eloise, Fan, Zhanyun, Ramanan, Prianca, Takeda, Shuko, Frosch, Matthew P., Wegmann, Susanne, and Gomez-Isla, Teresa

Published
2021
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42. Transethnic genome‐wide scan identifies novel Alzheimer's disease loci

Author

Jun, Gyungah R, Chung, Jaeyoon, Mez, Jesse, Barber, Robert, Beecham, Gary W, Bennett, David A, Buxbaum, Joseph D, Byrd, Goldie S, Carrasquillo, Minerva M, Crane, Paul K, Cruchaga, Carlos, De Jager, Philip, Ertekin‐Taner, Nilufer, Evans, Denis, Fallin, M Danielle, Foroud, Tatiana M, Friedland, Robert P, Goate, Alison M, Graff‐Radford, Neill R, Hendrie, Hugh, Hall, Kathleen S, Hamilton‐Nelson, Kara L, Inzelberg, Rivka, Kamboh, M Ilyas, Kauwe, John SK, Kukull, Walter A, Kunkle, Brian W, Kuwano, Ryozo, Larson, Eric B, Logue, Mark W, Manly, Jennifer J, Martin, Eden R, Montine, Thomas J, Mukherjee, Shubhabrata, Naj, Adam, Reiman, Eric M, Reitz, Christiane, Sherva, Richard, St. George‐Hyslop, Peter H, Thornton, Timothy, Younkin, Steven G, Vardarajan, Badri N, Wang, Li‐San, Wendlund, Jens R, Winslow, Ashley R, Adams, Perrie M, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Barmada, Michjael M, Barnes, Lisa L, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, De Jager, Philip L, DeCarli, Charles, DeKosky, Steven T, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Doody, Rachelle S, Duara, Ranjan, Faber, Kelley M, Fairchild, Thomas J, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Glass, Jonathan D, Green, Robert C, and Growdon, John H

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Genetics, Dementia, Alzheimer's Disease, Aging, Prevention, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Apolipoprotein E4, GTPase-Activating Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Heparin-binding EGF-like Growth Factor, Humans, Membrane Glycoproteins, Molecular Chaperones, NFI Transcription Factors, Peroxisomal Bifunctional Enzyme, Polymorphism, Single Nucleotide, Receptors, GABA, Alzheimer's Disease Genetics Consortium, APOE interaction, Alzheimer's disease, Genome-wide association, Transethnic, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionGenetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.MethodsWe conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.ResultsGenome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P

Published
2017

43. Entorhinal vessel density correlates with phosphorylated tau and TDP‐43 pathology.

Author

Llamas Rodríguez, Josué, van der Kouwe, André J. W., Oltmer, Jan, Rosenblum, Emma, Mercaldo, Nathaniel, Fischl, Bruce, Marshall, Michael, Frosch, Matthew P., and Augustinack, Jean C.

Abstract

INTRODUCTION: The entorhinal cortex (EC) and perirhinal cortex (PC) are vulnerable to Alzheimer's disease. A triggering factor may be the interaction of vascular dysfunction and tau pathology. METHODS: We imaged post mortem human tissue at 100 μm3 with 7 T magnetic resonance imaging and manually labeled individual blood vessels (mean = 270 slices/case). Vessel density was quantified and compared per EC subfield, between EC and PC, and in relation to tau and TAR DNA‐binding protein 43 (TDP‐43) semiquantitative scores. RESULTS: PC was more vascularized than EC and vessel densities were higher in posterior EC subfields. Tau and TDP‐43 strongly correlated with vasculature density and subregions with severe tau at the preclinical stage had significantly greater vessel density than those with low tau burden. DISCUSSION: These data impact cerebrovascular maps, quantification of subfield vasculature, and correlation of vasculature and pathology at early stages. The ordered association of vessel density, and tau or TDP‐43 pathology, may be exploited in a predictive context. Highlights: Vessel density correlates with phosphorylated tau (p‐tau) burden in entorhinal and perirhinal cortices.Perirhinal area 35 and posterior entorhinal cortex showed greatest p‐tau burden but also the highest vessel density in the preclinical phase of Alzheimer's disease.We combined an ex vivo magnetic resonance imaging model and histopathology to demonstrate the 3D reconstruction of intracortical vessels and its spatial relationship to the pathology. [ABSTRACT FROM AUTHOR]

Published
2024
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44. Machine learning of dissection photographs and surface scanning for quantitative 3D neuropathology.

Author

Gazula, Harshvardhan, Tregidgo, Henry F. J., Billot, Benjamin, Balbastre, Yael, Williams-Ramirez, Jonathan, Herisse, Rogeny, Deden-Binder, Lucas J., Casamitjana, Adria, Melief, Erica J., Latimer, Caitlin S., Kilgore, Mitchell D., Montine, Mark, Robinson, Eleanor, Blackburn, Emily, Marshall, Michael S., Connors, Theresa R., Oakley, Derek H., Frosch, Matthew P., Young, Sean I., and Van Leemput, Koen

Published
2024
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45. Gerstmann‐Sträussler‐Scheinker Disease Presenting as Late‐Onset Slowly Progressive Spinocerebellar Ataxia, and Comparative Case Series with Neuropathology

Author

Stephen, Christopher D., primary, de Gusmao, Claudio Melo, additional, Srinivasan, Sharan R., additional, Olsen, Abby, additional, Freua, Fernando, additional, Kok, Fernando, additional, Montes Garcia Barbosa, Renata, additional, Chen, Jin Yun (Helen), additional, Appleby, Brian S., additional, Prior, Thomas, additional, Frosch, Matthew P., additional, and Schmahmann, Jeremy D., additional

Published
2024
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46. ABCA7 frameshift deletion associated with Alzheimer disease in African Americans

Author

Cukier, Holly N, Kunkle, Brian W, Vardarajan, Badri N, Rolati, Sophie, Hamilton-Nelson, Kara L, Kohli, Martin A, Whitehead, Patrice L, Dombroski, Beth A, Van Booven, Derek, Lang, Rosalyn, Dykxhoorn, Derek M, Farrer, Lindsay A, Cuccaro, Michael L, Vance, Jeffery M, Gilbert, John R, Beecham, Gary W, Martin, Eden R, Carney, Regina M, Mayeux, Richard, Schellenberg, Gerard D, Byrd, Goldie S, Haines, Jonathan L, Pericak-Vance, Margaret A, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barmada, M Michael, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cai, Guiqing, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlsson, Cynthia M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, Cruchaga, Carlos, De Jager, Philip L, DeCarli, Charles, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Duara, Ranjan, Ertekin-Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fallin, M Daniele, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Go, Rodney CP, Goate, Alison M, Graff-Radford, Neill R, Green, Robert C, Griffith, Patrick, Growdon, John H, Hakonarson, Hakon, Hamilton, Ronald L, Haroutunian, Vahram, Harrell, Lindy E, Honig, Lawrence S, Huebinger, Ryan M, Hulette, Christine M, Hyman, Bradley T, Jicha, Gregory A, and Jin, Lee-Way

Subjects
Biological Sciences, Genetics, Human Genome, Neurodegenerative, Neurosciences, Dementia, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Alzheimer's Disease, Clinical Research, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Alzheimer's Disease Genetics Consortium, Clinical sciences
Abstract

ObjectiveTo identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.MethodsCustom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.ResultsA 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42-3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12-2.44]), and joint analysis increased the significance (p = 1.414 × 10(-5), OR = 1.81 [95% CI: 1.38-2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function.ConclusionsThis common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

Published
2016

47. Assessment of the genetic variance of late-onset Alzheimer's disease

Author

Ridge, Perry G, Hoyt, Kaitlyn B, Boehme, Kevin, Mukherjee, Shubhabrata, Crane, Paul K, Haines, Jonathan L, Mayeux, Richard, Farrer, Lindsay A, Pericak-Vance, Margaret A, Schellenberg, Gerard D, Kauwe, John SK, Consortium, Alzheimer's Disease Genetics, Adams, Perrie M, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barber, Robert C, Barmada, Michael M, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Beecham, Gary W, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, Cruchaga, Carlos, De Jager, Philip L, DeCarli, Charles, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Doody, Rachelle S, Duara, Ranjan, Ertekin-Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fairchild, Thomas J, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Goate, Alison M, Graff-Radford, Neill R, Green, Robert C, Growdon, John H, Hakonarson, Hakon, Hamilton, Ronald L, Hamilton-Nelson, Kara L, Hardy, John, Harrell, Lindy E, Honig, Lawrence S, Huebinger, Ryan M, Huentelman, Matthew J, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Jicha, Gregory A, Jin, Lee-Way, Jun, Gyungah, Kamboh, M Ilyas, Karydas, Anna, Katz, Mindy J, Kaye, Jeffrey A, Kim, Ronald, and Kowall, Neil W

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Genetics, Acquired Cognitive Impairment, Aging, Human Genome, Dementia, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Protein Precursor, Datasets as Topic, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Membrane Glycoproteins, Netrin Receptors, Polymorphism, Single Nucleotide, Receptors, Cell Surface, Receptors, Immunologic, Risk, Alzheimer's Disease Genetics Consortium, Alzheimer's disease, Genetic variance, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.

Published
2016

48. Multisite assessment of NIA‐AA guidelines for the neuropathologic evaluation of Alzheimer's disease

Author

Montine, Thomas J, Monsell, Sarah E, Beach, Thomas G, Bigio, Eileen H, Bu, Yunqi, Cairns, Nigel J, Frosch, Matthew, Henriksen, Jonathan, Kofler, Julia, Kukull, Walter A, Lee, Edward B, Nelson, Peter T, Schantz, Aimee M, Schneider, Julie A, Sonnen, Joshua A, Trojanowski, John Q, Vinters, Harry V, Zhou, Xiao‐Hua, and Hyman, Bradley T

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Acquired Cognitive Impairment, Dementia, Brain Disorders, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Neurological, Alzheimer Disease, Brain, Humans, National Institute on Aging (U.S.), Neuropathology, Practice Guidelines as Topic, United States, Voluntary Health Agencies, Alzheimer's disease, Methods, Whole-slide imaging, Multisite, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionNeuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used.MethodsFifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change.ResultsCurrent practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77-0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable.DiscussionAD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements.

Published
2016

49. Machine learning of dissection photographs and surface scanning for quantitative 3D neuropathology

Author

Gazula, Harshvardhan, primary, Tregidgo, Henry F. J., additional, Billot, Benjamin, additional, Balbastre, Yael, additional, William-Ramirez, Jonathan, additional, Herisse, Rogeny, additional, Deden-Binder, Lucas J, additional, Casamitjana, Adrià, additional, Melief, Erica J., additional, Latimer, Caitlin S., additional, Kilgore, Mitchell D., additional, Montine, Mark, additional, Robinson, Eleanor, additional, Blackburn, Emily, additional, Marshall, Michael S., additional, Connors, Theresa R., additional, Oakley, Derek H., additional, Frosch, Matthew P., additional, Young, Sean I., additional, Van Leemput, Koen, additional, Dalca, Adrian V., additional, Fischl, Bruce, additional, Mac Donald, Christine L., additional, Keene, C. Dirk, additional, Hyman, Bradley T., additional, and Iglesias, Juan Eugenio, additional

Published
2023
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50. Tau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease

Author

Taddei, Raquel N., primary, Perbet, Romain, additional, Mate de Gerando, Anastasie, additional, Wiedmer, Anne E., additional, Sanchez-Mico, Maria, additional, Connors Stewart, Theresa, additional, Gaona, Angelica, additional, Melloni, Alexandra, additional, Amaral, Ana C., additional, Duff, Karen, additional, Frosch, Matthew P., additional, and Gómez-Isla, Teresa, additional

Published
2023
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