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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

4. Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

Author

Wang, Hui, Chang, Timothy S, Dombroski, Beth A, Cheng, Po-Liang, Patil, Vishakha, Valiente-Banuet, Leopoldo, Farrell, Kurt, Mclean, Catriona, Molina-Porcel, Laura, Rajput, Alex, De Deyn, Peter Paul, Le Bastard, Nathalie, Gearing, Marla, Kaat, Laura Donker, Van Swieten, John C, Dopper, Elise, Ghetti, Bernardino F, Newell, Kathy L, Troakes, Claire, de Yébenes, Justo G, Rábano-Gutierrez, Alberto, Meller, Tina, Oertel, Wolfgang H, Respondek, Gesine, Stamelou, Maria, Arzberger, Thomas, Roeber, Sigrun, Müller, Ulrich, Hopfner, Franziska, Pastor, Pau, Brice, Alexis, Durr, Alexandra, Le Ber, Isabelle, Beach, Thomas G, Serrano, Geidy E, Hazrati, Lili-Naz, Litvan, Irene, Rademakers, Rosa, Ross, Owen A, Galasko, Douglas, Boxer, Adam L, Miller, Bruce L, Seeley, Willian W, Van Deerlin, Vivanna M, Lee, Edward B, White, Charles L, Morris, Huw, de Silva, Rohan, Crary, John F, Goate, Alison M, Friedman, Jeffrey S, Leung, Yuk Yee, Coppola, Giovanni, Naj, Adam C, Wang, Li-San, Dalgard, Clifton, Dickson, Dennis W, Höglinger, Günter U, Schellenberg, Gerard D, Geschwind, Daniel H, and Lee, Wan-Ping

Subjects
Biological Sciences, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Rare Diseases, Neurosciences, Dementia, Human Genome, Brain Disorders, Biotechnology, Aging, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease, 2.1 Biological and endogenous factors, Neurological, Progressive Supranuclear Palsy, Whole-Genome Sequencing, Genome-Wide Association Study, Structural Variants, Apolipoprotein E, P. S. P. genetics study group, Humans, Supranuclear Palsy, Progressive, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Female, Male, Whole Genome Sequencing, Clinical Sciences, Neurology & Neurosurgery, Biochemistry and cell biology
Abstract

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Published
2024

5. Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation

Author

Li, Junhao, Jaiswal, Manoj K, Chien, Jo-Fan, Kozlenkov, Alexey, Jung, Jinyoung, Zhou, Ping, Gardashli, Mahammad, Pregent, Luc J, Engelberg-Cook, Erica, Dickson, Dennis W, Belzil, Veronique V, Mukamel, Eran A, and Dracheva, Stella

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Genetics, Biological Sciences, Dementia, Neurodegenerative, Frontotemporal Dementia (FTD), Human Genome, Rare Diseases, ALS, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Alzheimer's Disease Related Dementias (ADRD), Acquired Cognitive Impairment, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Humans, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, C9orf72 Protein, Transcriptome, Epigenome, Mutation
Abstract

A repeat expansion in the C9orf72 (C9) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we investigate single nucleus transcriptomics (snRNA-seq) and epigenomics (snATAC-seq) in postmortem motor and frontal cortices from C9-ALS, C9-FTD, and control donors. C9-ALS donors present pervasive alterations of gene expression with concordant changes in chromatin accessibility and histone modifications. The greatest alterations occur in upper and deep layer excitatory neurons, as well as in astrocytes. In neurons, the changes imply an increase in proteostasis, metabolism, and protein expression pathways, alongside a decrease in neuronal function. In astrocytes, the alterations suggest activation and structural remodeling. Conversely, C9-FTD donors have fewer high-quality neuronal nuclei in the frontal cortex and numerous gene expression changes in glial cells. These findings highlight a context-dependent molecular disruption in C9-ALS and C9-FTD, indicating unique effects across cell types, brain regions, and diseases.

Published
2023

6. 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

7. Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Author

Farrell, Kurt, Humphrey, Jack, Chang, Timothy, Zhao, Yi, Leung, Yuk Yee, Kuksa, Pavel P., Patil, Vishakha, Lee, Wan-Ping, Kuzma, Amanda B., Valladares, Otto, Cantwell, Laura B., Wang, Hui, Ravi, Ashvin, De Sanctis, Claudia, Han, Natalia, Christie, Thomas D., Afzal, Robina, Kandoi, Shrishtee, Whitney, Kristen, Krassner, Margaret M., Ressler, Hadley, Kim, SoongHo, Dangoor, Diana, Iida, Megan A., Casella, Alicia, Walker, Ruth H., Nirenberg, Melissa J., Renton, Alan E., Babrowicz, Bergan, Coppola, Giovanni, Raj, Towfique, Höglinger, Günter U., Müller, Ulrich, Golbe, Lawrence I., Morris, Huw R., Hardy, John, Revesz, Tamas, Warner, Tom T., Jaunmuktane, Zane, Mok, Kin Y., Rademakers, Rosa, Dickson, Dennis W., Ross, Owen A., Wang, Li-San, Goate, Alison, Schellenberg, Gerard, Geschwind, Daniel H., Crary, John F., and Naj, Adam

Published
2024
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9. Gliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood brain barrier dysfunction

Author

İş, Özkan, Wang, Xue, Reddy, Joseph S., Min, Yuhao, Yilmaz, Elanur, Bhattarai, Prabesh, Patel, Tulsi, Bergman, Jeremiah, Quicksall, Zachary, Heckman, Michael G., Tutor-New, Frederick Q., Can Demirdogen, Birsen, White, Launia, Koga, Shunsuke, Krause, Vincent, Inoue, Yasuteru, Kanekiyo, Takahisa, Cosacak, Mehmet Ilyas, Nelson, Nastasia, Lee, Annie J., Vardarajan, Badri, Mayeux, Richard, Kouri, Naomi, Deniz, Kaancan, Carnwath, Troy, Oatman, Stephanie R., Lewis-Tuffin, Laura J., Nguyen, Thuy, Carrasquillo, Minerva M., Graff-Radford, Jonathan, Petersen, Ronald C., Jr Jack, Clifford R., Kantarci, Kejal, Murray, Melissa E., Nho, Kwangsik, Saykin, Andrew J., Dickson, Dennis W., Kizil, Caghan, Allen, Mariet, and Ertekin-Taner, Nilüfer

Published
2024
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11. Influences of amyloid-β and tau on white matter neurite alterations in dementia with Lewy bodies

Author

Mak, Elijah, Reid, Robert I., Przybelski, Scott A., Lesnick, Timothy G., Schwarz, Christopher G., Senjem, Matthew L., Raghavan, Sheelakumari, Vemuri, Prashanthi, Jack, Jr, Clifford R., Min, Hoon Ki, Jain, Manoj K., Miyagawa, Toji, Forsberg, Leah K., Fields, Julie A., Savica, Rodolfo, Graff-Radford, Jonathan, Jones, David T., Botha, Hugo, St. Louis, Erik K., Knopman, David S., Ramanan, Vijay K., Dickson, Dennis W., Graff-Radford, Neill R., Ferman, Tanis J., Petersen, Ronald C., Lowe, Val J., Boeve, Bradley F., O’Brien, John T., and Kantarci, Kejal

Published
2024
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12. A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Author

Swift, Imogen J., Rademakers, Rosa, Finch, NiCole, Baker, Matt, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, Rossi, Giacomina, Synofzik, Matthis, Wilke, Carlo, Mengel, David, Graff, Caroline, Takada, Leonel T., Sánchez-Valle, Raquel, Antonell, Anna, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Schreiber, Stefanie, Vielhaber, Stefan, Arndt, Philipp, Santana, Isabel, Almeida, Maria Rosario, Moreno, Fermín, Barandiaran, Myriam, Gabilondo, Alazne, Stubert, Johannes, Gómez-Tortosa, Estrella, Agüero, Pablo, Sainz, M. José, Gohda, Tomohito, Murakoshi, Maki, Kamei, Nozomu, Kittel-Schneider, Sarah, Reif, Andreas, Weigl, Johannes, Jian, Jinlong, Liu, Chuanju, Serrero, Ginette, Greither, Thomas, Theil, Gerit, Lohmann, Ebba, Gazzina, Stefano, Bagnoli, Silvia, Coppola, Giovanni, Bruni, Amalia, Quante, Mirja, Kiess, Wieland, Hiemisch, Andreas, Jurkutat, Anne, Block, Matthew S., Carlson, Aaron M., Bråthen, Geir, Sando, Sigrid Botne, Grøntvedt, Gøril Rolfseng, Lauridsen, Camilla, Heslegrave, Amanda, Heller, Carolin, Abel, Emily, Gómez-Núñez, Alba, Puey, Roger, Arighi, Andrea, Rotondo, Enmanuela, Jiskoot, Lize C., Meeter, Lieke H. H., Durães, João, Lima, Marisa, Tábuas-Pereira, Miguel, Lemos, João, Boeve, Bradley, Petersen, Ronald C., Dickson, Dennis W., Graff-Radford, Neill R., LeBer, Isabelle, Sellami, Leila, Lamari, Foudil, Clot, Fabienne, Borroni, Barbara, Cantoni, Valentina, Rivolta, Jasmine, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Illán-Gala, Ignacio, Andres-Cerezo, Lucie, Van Damme, Philip, Clarimon, Jordi, Steinacker, Petra, Feneberg, Emily, Otto, Markus, van der Ende, Emma L., van Swieten, John C., Seelaar, Harro, Zetterberg, Henrik, Sogorb-Esteve, Aitana, and Rohrer, Jonathan D.

Published
2024
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13. HDGFL2 cryptic proteins report presence of TDP-43 pathology in neurodegenerative diseases

Author

Calliari, Anna, Daughrity, Lillian M., Albagli, Ellen A., Castellanos Otero, Paula, Yue, Mei, Jansen-West, Karen, Islam, Naeyma N., Caulfield, Thomas, Rawlinson, Bailey, DeTure, Michael, Cook, Casey, Graff-Radford, Neill R., Day, Gregory S., Boeve, Bradley F., Knopman, David S., Petersen, Ronald C., Josephs, Keith A., Oskarsson, Björn, Gitler, Aaron D., Dickson, Dennis W., Gendron, Tania F., Prudencio, Mercedes, Ward, Michael E., Zhang, Yong-Jie, and Petrucelli, Leonard

Published
2024
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14. Impact of APOE on amyloid and tau accumulation in argyrophilic grain disease and Alzheimer’s disease

Author

Raulin, Ana-Caroline, Doss, Sydney V., Heckman, Michael G., Craver, Emily C., Li, Zonghua, Ikezu, Tadafumi C., Sekiya, Hiroaki, Liu, Chia-Chen, Martens, Yuka A., Rosenberg, Cassandra L., Kuchenbecker, Lindsey A., DeTure, Michael, Reichard, R. Ross, Nguyen, Aivi T., Constantopoulos, Eleni, Larsen, Rachel A., Kounaves, Emmaline K., Murray, Melissa E., Dickson, Dennis W., Petersen, Ronald C., Bu, Guojun, and Kanekiyo, Takahisa

Published
2024
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15. Letter to the editor on: Hornerin deposits in neuronal intranuclear inclusion disease: direct identification of proteins with compositionally biased regions in inclusions by Park et al. (2022)

Author

Luo, Huihui, Gustavsson, Emil K., Macpherson, Hannah, Dominik, Natalia, Zhelcheska, Kristina, Montgomery, Kylie, Anderson, Claire, Yau, Wai Yan, Efthymiou, Stephanie, Turner, Chris, DeTure, Michael, Dickson, Dennis W., Josephs, Keith A., Revesz, Tamas, Lashley, Tammaryn, Halliday, Glenda, Rowe, Dominic B., McCann, Emily, Blair, Ian, Lees, Andrew J., Tienari, Pentti J., Suomalainen, Anu, Molina-Porcel, Laura, Kovacs, Gabor G., Gelpi, Ellen, Hardy, John, Haltia, Matti J., Tucci, Arianna, Jaunmuktane, Zane, Ryten, Mina, Houlden, Henry, and Chen, Zhongbo

Published
2024
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16. Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion

Author

Udine, Evan, DeJesus-Hernandez, Mariely, Tian, Shulan, das Neves, Sofia Pereira, Crook, Richard, Finch, NiCole A., Baker, Matthew C., Pottier, Cyril, Graff-Radford, Neill R., Boeve, Bradley F., Petersen, Ronald C., Knopman, David S., Josephs, Keith A., Oskarsson, Björn, Da Mesquita, Sandro, Petrucelli, Leonard, Gendron, Tania F., Dickson, Dennis W., Rademakers, Rosa, and van Blitterswijk, Marka

Published
2024
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17. Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease

Author

Bhattarai, Prabesh, Gunasekaran, Tamil Iniyan, Belloy, Michael E., Reyes-Dumeyer, Dolly, Jülich, Dörthe, Tayran, Hüseyin, Yilmaz, Elanur, Flaherty, Delaney, Turgutalp, Bengisu, Sukumar, Gauthaman, Alba, Camille, McGrath, Elisa Martinez, Hupalo, Daniel N., Bacikova, Dagmar, Le Guen, Yann, Lantigua, Rafael, Medrano, Martin, Rivera, Diones, Recio, Patricia, Nuriel, Tal, Ertekin-Taner, Nilüfer, Teich, Andrew F., Dickson, Dennis W., Holley, Scott, Greicius, Michael, Dalgard, Clifton L., Zody, Michael, Mayeux, Richard, Kizil, Caghan, and Vardarajan, Badri N.

Published
2024
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18. Role of GBA variants in Lewy body disease neuropathology

Author

Walton, Ronald L., Koga, Shunsuke, Beasley, Alexandra I., White, Launia J., Griesacker, Teresa, Murray, Melissa E., Kasanuki, Koji, Hou, Xu, Fiesel, Fabienne C., Springer, Wolfdieter, Uitti, Ryan J., Fields, Julie A., Botha, Hugo, Ramanan, Vijay K., Kantarci, Kejal, Lowe, Val J., Jack, Clifford R., Ertekin-Taner, Nilufer, Savica, Rodolfo, Graff-Radford, Jonathan, Petersen, Ronald C., Parisi, Joseph E., Reichard, R. Ross, Graff-Radford, Neill R., Ferman, Tanis J., Boeve, Bradley F., Wszolek, Zbigniew K., Dickson, Dennis W., Ross, Owen A., and Heckman, Michael G.

Published
2024
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19. Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer’s disease

Author

Agra Almeida Quadros, Ana Rita, Li, Zhaozhi, Wang, Xue, Ndayambaje, I. Sandra, Aryal, Sandeep, Ramesh, Nandini, Nolan, Matthew, Jayakumar, Rojashree, Han, Yi, Stillman, Hannah, Aguilar, Corey, Wheeler, Hayden J., Connors, Theresa, Lopez-Erauskin, Jone, Baughn, Michael W., Melamed, Ze’ev, Beccari, Melinda S., Olmedo Martínez, Laura, Canori, Michael, Lee, Chao-Zong, Moran, Laura, Draper, Isabelle, Kopin, Alan S., Oakley, Derek H., Dickson, Dennis W., Cleveland, Don W., Hyman, Bradley T., Das, Sudeshna, Ertekin-Taner, Nilüfer, and Lagier-Tourenne, Clotilde

Published
2024
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20. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author

Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L, Collins, Ryan L, Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Jerez, Pilar Alvarez, Malik, Laksh, Dawson, Ted M, Rosenthal, Liana S, Albert, Marilyn S, Pletnikova, Olga, Troncoso, Juan C, Masellis, Mario, Keith, Julia, Black, Sandra E, Ferrucci, Luigi, Resnick, Susan M, Tanaka, Toshiko, Soltis, Anthony R, Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Martinez, Elisa McGrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N, Adeleye, Adelani, Wilkerson, Matthew D, Pollard, Harvey B, Dalgard, Clifton L, Gan-Or, Ziv, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian G, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J, Troakes, Claire, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, and Gibbs, J Raphael

Subjects
Biological Sciences, Genetics, Brain Disorders, Dementia, ALS, Rare Diseases, Neurodegenerative, Neurosciences, Human Genome, Frontotemporal Dementia (FTD), Alzheimer's Disease, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aging, Aetiology, 2.1 Biological and endogenous factors, Neurological, American Genome Center, International LBD Genomics Consortium, International ALS/FTD Consortium, PROSPECT Consortium, Lewy body dementia, amyotrophic lateral sclerosis, case-control study, frontotemporal dementia, genome-wide association study, non–Alzheimer's dementia, resource, structural variant
Abstract

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

Published
2023

21. LATE-NC staging in routine neuropathologic diagnosis: an update

Author

Nelson, Peter T, Lee, Edward B, Cykowski, Matthew D, Alafuzoff, Irina, Arfanakis, Konstantinos, Attems, Johannes, Brayne, Carol, Corrada, Maria M, Dugger, Brittany N, Flanagan, Margaret E, Ghetti, Bernardino, Grinberg, Lea T, Grossman, Murray, Grothe, Michel J, Halliday, Glenda M, Hasegawa, Masato, Hokkanen, Suvi RK, Hunter, Sally, Jellinger, Kurt, Kawas, Claudia H, Keene, C Dirk, Kouri, Naomi, Kovacs, Gabor G, Leverenz, James B, Latimer, Caitlin S, Mackenzie, Ian R, Mao, Qinwen, McAleese, Kirsty E, Merrick, Richard, Montine, Thomas J, Murray, Melissa E, Myllykangas, Liisa, Nag, Sukriti, Neltner, Janna H, Newell, Kathy L, Rissman, Robert A, Saito, Yuko, Sajjadi, S Ahmad, Schwetye, Katherine E, Teich, Andrew F, Thal, Dietmar R, Tomé, Sandra O, Troncoso, Juan C, Wang, Shih-Hsiu J, White, Charles L, Wisniewski, Thomas, Yang, Hyun-Sik, Schneider, Julie A, Dickson, Dennis W, and Neumann, Manuela

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Genetics, Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, Dementia, Rare Diseases, Neurological, Humans, Alzheimer Disease, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Processes, NCI, TDP-43, FTD, Stages, Hippocampal sclerosis, Neuroanatomy, Aging, Neurology & Neurosurgery
Abstract

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Published
2023

23. Proximity proteomics of C9orf72 dipeptide repeat proteins identifies molecular chaperones as modifiers of poly-GA aggregation

Author

Liu, Feilin, Morderer, Dmytro, Wren, Melissa C, Vettleson-Trutza, Sara A, Wang, Yanzhe, Rabichow, Benjamin E, Salemi, Michelle R, Phinney, Brett S, Oskarsson, Björn, Dickson, Dennis W, and Rossoll, Wilfried

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Neurosciences, Biotechnology, Brain Disorders, Dementia, ALS, Neurodegenerative, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, C9orf72 Protein, Dipeptides, Frontotemporal Dementia, HEK293 Cells, Humans, Molecular Chaperones, Protein Aggregation, Pathological, Proteomics, RNA, Repetitive Sequences, Nucleic Acid, C9orf72, Poly-GA, Proximity proteomics, Heat shock proteins, Clinical Sciences, Biochemistry and cell biology
Abstract

The most common inherited cause of two genetically and clinico-pathologically overlapping neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is the presence of expanded GGGGCC intronic hexanucleotide repeats in the C9orf72 gene. Aside from haploinsufficiency and toxic RNA foci, another non-exclusive disease mechanism is the non-canonical translation of the repeat RNA into five different dipeptide repeat proteins (DPRs), which form neuronal inclusions in affected patient brains. While evidence from cellular and animal models supports a toxic gain-of-function of pathologic poly-GA, poly-GR, and poly-PR aggregates in promoting deposition of TDP-43 pathology and neurodegeneration in affected brain areas, the relative contribution of DPRs to the disease process in c9FTD/ALS patients remains unclear. Here we have used the proximity-dependent biotin identification (BioID) proximity proteomics approach to investigate the formation and collective composition of DPR aggregates using cellular models. While interactomes of arginine rich poly-GR and poly-PR aggregates overlapped and were enriched for nucleolar and ribosomal proteins, poly-GA aggregates demonstrated a distinct association with proteasomal components, molecular chaperones (HSPA1A/HSP70, HSPA8/HSC70, VCP/p97), co-chaperones (BAG3, DNAJA1A) and other factors that regulate protein folding and degradation (SQSTM1/p62, CALR, CHIP/STUB1). Experiments in cellular models of poly-GA pathology show that molecular chaperones and co-chaperones are sequestered to the periphery of dense cytoplasmic aggregates, causing depletion from their typical cellular localization. Their involvement in the pathologic process is confirmed in autopsy brain tissue, where HSPA8, BAG3, VCP, and its adapter protein UBXN6 show a close association with poly-GA aggregates in the frontal cortex, temporal cortex, and hippocampus of c9FTLD and c9ALS cases. The association of heat shock proteins and co-chaperones with poly-GA led us to investigate their potential role in reducing its aggregation. We identified HSP40 co-chaperones of the DNAJB family as potent modifiers that increased the solubility of poly-GA, highlighting a possible novel therapeutic avenue and a central role of molecular chaperones in the pathogenesis of human C9orf72-linked diseases.

Published
2022

24. Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy

Author

Roemer, Shanu F, Grinberg, Lea T, Crary, John F, Seeley, William W, McKee, Ann C, Kovacs, Gabor G, Beach, Thomas G, Duyckaerts, Charles, Ferrer, Isidro A, Gelpi, Ellen, Lee, Edward B, Revesz, Tamas, White, Charles L, Yoshida, Mari, Pereira, Felipe L, Whitney, Kristen, Ghayal, Nikhil B, and Dickson, Dennis W

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Neurosciences, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Neurological, Humans, Neurofibrillary Tangles, Neuropathology, Reproducibility of Results, Supranuclear Palsy, Progressive, Tauopathies, tau Proteins, Autopsy cohort, Criteria, Human, Threads, Oligodendroglia, Phosphorylated tau, Progressive supranuclear palsy, Neurofibrillary tangles, Tufted astrocytes, Neurology & Neurosurgery
Abstract

Neuropathologic criteria for progressive supranuclear palsy (PSP) proposed by a National Institute of Neurological Disorders and Stroke (NINDS) working group were published in 1994 and based on the presence of neurofibrillary tangles in basal ganglia and brainstem. These criteria did not stipulate detection methods or incorporate glial tau pathology. In this study, a group of 14 expert neuropathologists scored digital slides from 10 brain regions stained with hematoxylin and eosin (H&E) and phosphorylated tau (AT8) immunohistochemistry. The cases included 15 typical and atypical PSP cases and 10 other tauopathies. Blinded to clinical and neuropathological information, raters provided a categorical diagnosis (PSP or not-PSP) based upon provisional criteria that required neurofibrillary tangles or pretangles in two of three regions (substantia nigra, subthalamic nucleus, globus pallidus) and tufted astrocytes in one of two regions (peri-Rolandic cortices, putamen). The criteria showed high sensitivity (0.97) and specificity (0.91), as well as almost perfect inter-rater reliability for diagnosing PSP and differentiating it from other tauopathies (Fleiss kappa 0.826). Most cases (17/25) had 100% agreement across all 14 raters. The Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of PSP feature a simplified diagnostic algorithm based on phosphorylated tau immunohistochemistry and incorporate tufted astrocytes as an essential diagnostic feature.

Published
2022

25. 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

26. Frequency of LATE neuropathologic change across the spectrum of Alzheimer’s disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts

Author

Nelson, Peter T, Brayne, Carol, Flanagan, Margaret E, Abner, Erin L, Agrawal, Sonal, Attems, Johannes, Castellani, Rudolph J, Corrada, Maria M, Cykowski, Matthew D, Di, Jing, Dickson, Dennis W, Dugger, Brittany N, Ervin, John F, Fleming, Jane, Graff-Radford, Jonathan, Grinberg, Lea T, Hokkanen, Suvi RK, Hunter, Sally, Kapasi, Alifiya, Kawas, Claudia H, Keage, Hannah AD, Keene, C Dirk, Kero, Mia, Knopman, David S, Kouri, Naomi, Kovacs, Gabor G, Labuzan, Sydney A, Larson, Eric B, Latimer, Caitlin S, Leite, Renata EP, Matchett, Billie J, Matthews, Fiona E, Merrick, Richard, Montine, Thomas J, Murray, Melissa E, Myllykangas, Liisa, Nag, Sukriti, Nelson, Ruth S, Neltner, Janna H, Nguyen, Aivi T, Petersen, Ronald C, Polvikoski, Tuomo, Reichard, R Ross, Rodriguez, Roberta D, Suemoto, Claudia K, Wang, Shih-Hsiu J, Wharton, Stephen B, White, Lon, and Schneider, Julie A

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Research, Alzheimer's Disease, Acquired Cognitive Impairment, Aging, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Alzheimer's Disease Related Dementias (ADRD), Dementia, Behavioral and Social Science, 2.1 Biological and endogenous factors, Aetiology, Neurological, Aged, 80 and over, Alzheimer Disease, Amyloid, Autopsy, DNA-Binding Proteins, Frontotemporal Dementia, Humans, Male, Nervous System Diseases, Plaque, Amyloid, ADRD, Tau, NFT, Nondemented, Oldest-old, Epidemiology, APOE, ROS-MAP, Vantaa 85+, HAAS, CFAS, CC75C, The 90+study, ACT, VITA, Nun study, Biobank for aging studies, Mayo clinic study of aging, The 90 + study, Vantaa 85 + , Clinical Sciences, Neurology & Neurosurgery
Abstract

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aβ phase = 0 (lacking detectable Aβ plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

Published
2022

28. Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

Author

Manzoni, Claudia, Kia, Demis A., Ferrari, Raffaele, Leonenko, Ganna, Costa, Beatrice, Saba, Valentina, Jabbari, Edwin, Tan, Manuela MX., Albani, Diego, Alvarez, Victoria, Alvarez, Ignacio, Andreassen, Ole A., Angiolillo, Antonella, Arighi, Andrea, Baker, Matt, Benussi, Luisa, Bessi, Valentina, Binetti, Giuliano, Blackburn, Daniel J., Boada, Merce, Boeve, Bradley F., Borrego-Ecija, Sergi, Borroni, Barbara, Bråthen, Geir, Brooks, William S., Bruni, Amalia C., Caroppo, Paola, Bandres-Ciga, Sara, Clarimon, Jordi, Colao, Rosanna, Cruchaga, Carlos, Danek, Adrian, de Boer, Sterre CM., de Rojas, Itziar, di Costanzo, Alfonso, Dickson, Dennis W., Diehl-Schmid, Janine, Dobson-Stone, Carol, Dols-Icardo, Oriol, Donizetti, Aldo, Dopper, Elise, Durante, Elisabetta, Ferrari, Camilla, Forloni, Gianluigi, Frangipane, Francesca, Fratiglioni, Laura, Kramberger, Milica G., Galimberti, Daniela, Gallucci, Maurizio, García-González, Pablo, Ghidoni, Roberta, Giaccone, Giorgio, Graff, Caroline, Graff-Radford, Neill R., Grafman, Jordan, Halliday, Glenda M., Hernandez, Dena G., Hjermind, Lena E., Hodges, John R., Holloway, Guy, Huey, Edward D., Illán-Gala, Ignacio, Josephs, Keith A., Knopman, David S., Kristiansen, Mark, Kwok, John B., Leber, Isabelle, Leonard, Hampton L., Libri, Ilenia, Lleo, Alberto, Mackenzie, Ian R., Madhan, Gaganjit K., Maletta, Raffaele, Marquié, Marta, Maver, Ales, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce L., Morris, Christopher M., Morris, Huw R., Nacmias, Benedetta, Newton, Judith, Nielsen, Jørgen E., Nilsson, Christer, Novelli, Valeria, Padovani, Alessandro, Pal, Suvankar, Pasquier, Florence, Pastor, Pau, Perneczky, Robert, Peterlin, Borut, Petersen, Ronald C., Piguet, Olivier, Pijnenburg, Yolande AL., Puca, Annibale A., Rademakers, Rosa, Rainero, Innocenzo, Reus, Lianne M., Richardson, Anna MT., Riemenschneider, Matthias, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rosen, Howard, Rossi, Giacomina, Rowe, James B., Rubino, Elisa, Ruiz, Agustin, Salvi, Erika, Sanchez-Valle, Raquel, Sando, Sigrid Botne, Santillo, Alexander F., Saxon, Jennifer A., Schlachetzki, Johannes CM., Scholz, Sonja W., Seelaar, Harro, Seeley, William W., Serpente, Maria, Sorbi, Sandro, Sordon, Sabrina, St George-Hyslop, Peter, Thompson, Jennifer C., Van Broeckhoven, Christine, Van Deerlin, Vivianna M., Van der Lee, Sven J., Van Swieten, John, Tagliavini, Fabrizio, van der Zee, Julie, Veronesi, Arianna, Vitale, Emilia, Waldo, Maria Landqvist, Yokoyama, Jennifer S., Nalls, Mike A., Momeni, Parastoo, Singleton, Andrew B., Hardy, John, and Escott-Price, Valentina

Published
2024
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30. Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups.

Author

Kaivola, Karri, Shah, Zalak, Chia, Ruth, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian G, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J, Troakes, Claire, Albert, Marilyn S, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dalgard, Clifton L, Dawson, Ted M, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David S, Graff-Radford, Neill R, Kaufmann, Horacio, Kukull, Walter A, Leverenz, James B, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L, Palma, Jose Alberto, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Rosenthal, Liana S, Ross, Owen A, Scherzer, Clemens R, Serrano, Geidy E, Shakkottai, Vikram G, Sidransky, Ellen, Tanaka, Toshiko, Topol, Eric, Torkamani, Ali, Troncoso, Juan C, Woltjer, Randy, Wszolek, Zbigniew K, and Scholz, Sonja W

Subjects
Genetics, Lewy Body Dementia, Neurodegenerative, Aging, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Alzheimer's Disease, Acquired Cognitive Impairment, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Alzheimer Disease, Apolipoprotein E4, Genome-Wide Association Study, Humans, Lewy Body Disease, alpha-Synuclein, International LBD Genomics Consortium, APOE, Alzheimer’s disease, co-pathology, dementia with Lewy bodies, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 6.58 × 10-9, OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 × 10-32, OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

Published
2022

32. A rapidly progressive multiple system atrophy-cerebellar variant model presenting marked glial reactions with inflammation and spreading of α-synuclein oligomers and phosphorylated α-synuclein aggregates

Author

Yamaguchi, Hiroo, Nishimura, Yuji, Matsuse, Dai, Sekiya, Hiroaki, Masaki, Katsuhisa, Tanaka, Tatsunori, Saiga, Toru, Harada, Masaya, Kira, Yuu-ichi, Dickson, Dennis W, Fujishima, Kei, Matsuo, Eriko, Tanaka, Kenji F., Yamasaki, Ryo, Isobe, Noriko, and Kira, Jun-ichi

Published
2024
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33. Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43

Author

Jiang, Yi Xiao, Cao, Qin, Sawaya, Michael R, Abskharon, Romany, Ge, Peng, DeTure, Michael, Dickson, Dennis W, Fu, Janine Y, Ogorzalek Loo, Rachel R, Loo, Joseph A, and Eisenberg, David S

Subjects
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Frontotemporal Dementia (FTD), Brain Disorders, Alzheimer's Disease, Acquired Cognitive Impairment, Prevention, Rare Diseases, Neurodegenerative, Dementia, Aging, Aetiology, 2.1 Biological and endogenous factors, Neurological, Amyloid, Cryoelectron Microscopy, DNA-Binding Proteins, Frontotemporal Lobar Degeneration, Humans, Membrane Proteins, Nerve Tissue Proteins, General Science & Technology
Abstract

Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition after Alzheimer's and Parkinson's diseases1. FTLD typically presents in 45 to 64 year olds with behavioural changes or progressive decline of language skills2. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions with TAR DNA-binding protein (TDP-43) immunoreactivity3. Here we extracted amyloid fibrils from brains of four patients representing four of the five FTLD-TDP subclasses, and determined their structures by cryo-electron microscopy. Unexpectedly, all amyloid fibrils examined were composed of a 135-residue carboxy-terminal fragment of transmembrane protein 106B (TMEM106B), a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP4. In addition to TMEM106B fibrils, we detected abundant non-fibrillar aggregated TDP-43 by immunogold labelling. Our observations confirm that FTLD-TDP is associated with amyloid fibrils, and that the fibrils are formed by TMEM106B rather than TDP-43.

Published
2022

34. Human iPSC 4R tauopathy model uncovers modifiers of tau propagation

Author

Parra Bravo, Celeste, Giani, Alice Maria, Madero-Perez, Jesus, Zhao, Zeping, Wan, Yuansong, Samelson, Avi J., Wong, Man Ying, Evangelisti, Alessandro, Cordes, Ethan, Fan, Li, Ye, Pearly, Zhu, Daphne, Pozner, Tatyana, Mercedes, Maria, Patel, Tark, Yarahmady, Allan, Carling, Gillian K., Sterky, Fredrik H., Lee, Virginia M.Y., Lee, Edward B., DeTure, Michael, Dickson, Dennis W., Sharma, Manu, Mok, Sue-Ann, Luo, Wenjie, Zhao, Mingrui, Kampmann, Martin, Gong, Shiaoching, and Gan, Li

Published
2024
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35. Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons

Author

Al-Dalahmah, Osama, Lam, Matti, McInvale, Julie J., Qu, Wenhui, Nguyen, Trang, Mun, Jeong-Yeon, Kwon, Sam, Ifediora, Nkechime, Mahajan, Aayushi, Humala, Nelson, Winters, Tristan, Angeles, Ellen, Jakubiak, Kelly A., Kühn, Rebekka, Kim, Yoon A., De Rosa, Maria Caterina, Doege, Claudia A., Paryani, Fahad, Flowers, Xena, Dovas, Athanassios, Mela, Angeliki, Lu, Hong, DeTure, Michael A., Vonsattel, Jean Paul, Wszolek, Zbigniew K., Dickson, Dennis W., Kuhlmann, Tanja, Zaehres, Holm, Schöler, Hans R., Sproul, Andrew A., Siegelin, Markus D., De Jager, Philip L., Goldman, James E., Menon, Vilas, Canoll, Peter, and Hargus, Gunnar

Published
2024
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36. 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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37. Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD

Author

Pineda, S. Sebastian, Lee, Hyeseung, Ulloa-Navas, Maria J., Linville, Raleigh M., Garcia, Francisco J., Galani, Kyriakitsa, Engelberg-Cook, Erica, Castanedes, Monica C., Fitzwalter, Brent E., Pregent, Luc J., Gardashli, Mahammad E., DeTure, Michael, Vera-Garcia, Diana V., Hucke, Andre T.S., Oskarsson, Bjorn E., Murray, Melissa E., Dickson, Dennis W., Heiman, Myriam, Belzil, Veronique V., and Kellis, Manolis

Published
2024
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38. Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy

Author

Min, Yuhao, Wang, Xue, İş, Özkan, Patel, Tulsi A., Gao, Junli, Reddy, Joseph S., Quicksall, Zachary S., Nguyen, Thuy, Lin, Shu, Tutor-New, Frederick Q., Chalk, Jessica L., Mitchell, Adriana O., Crook, Julia E., Nelson, Peter T., Van Eldik, Linda J., Golde, Todd E., Carrasquillo, Minerva M., Dickson, Dennis W., Zhang, Ke, Allen, Mariet, and Ertekin-Taner, Nilüfer

Published
2023
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39. TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains

Author

Estades Ayuso, Virginia, Pickles, Sarah, Todd, Tiffany, Yue, Mei, Jansen-West, Karen, Song, Yuping, González Bejarano, Jesús, Rawlinson, Bailey, DeTure, Michael, Graff-Radford, Neill R., Boeve, Bradley F., Knopman, David S., Petersen, Ronald C., Dickson, Dennis W., Josephs, Keith A., Petrucelli, Leonard, and Prudencio, Mercedes

Published
2023
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42. Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s disease related proteins

Author

Oatman, Stephanie R., Reddy, Joseph S., Quicksall, Zachary, Carrasquillo, Minerva M., Wang, Xue, Liu, Chia-Chen, Yamazaki, Yu, Nguyen, Thuy T., Malphrus, Kimberly, Heckman, Michael, Biswas, Kristi, Nho, Kwangsik, Baker, Matthew, Martens, Yuka A., Zhao, Na, Kim, Jun Pyo, Risacher, Shannon L., Rademakers, Rosa, Saykin, Andrew J., DeTure, Michael, Murray, Melissa E., Kanekiyo, Takahisa, Dickson, Dennis W., Bu, Guojun, Allen, Mariet, and Ertekin-Taner, Nilüfer

Published
2023
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43. TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A

Author

Ma, X Rosa, Prudencio, Mercedes, Koike, Yuka, Vatsavayai, Sarat C, Kim, Garam, Harbinski, Fred, Briner, Adam, Rodriguez, Caitlin M, Guo, Caiwei, Akiyama, Tetsuya, Schmidt, H Broder, Cummings, Beryl B, Wyatt, David W, Kurylo, Katherine, Miller, Georgiana, Mekhoubad, Shila, Sallee, Nathan, Mekonnen, Gemechu, Ganser, Laura, Rubien, Jack D, Jansen-West, Karen, Cook, Casey N, Pickles, Sarah, Oskarsson, Björn, Graff-Radford, Neill R, Boeve, Bradley F, Knopman, David S, Petersen, Ronald C, Dickson, Dennis W, Shorter, James, Myong, Sua, Green, Eric M, Seeley, William W, Petrucelli, Leonard, and Gitler, Aaron D

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Stem Cell Research - Nonembryonic - Human, Dementia, Neurosciences, Brain Disorders, Acquired Cognitive Impairment, Human Genome, Stem Cell Research, Neurodegenerative, ALS, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Exons, Frontotemporal Dementia, Genome-Wide Association Study, Humans, Motor Neurons, Nerve Tissue Proteins, General Science & Technology
Abstract

A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2-4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.

Published
2022

44. Structure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro

Author

Seidler, Paul M, Murray, Kevin A, Boyer, David R, Ge, Peng, Sawaya, Michael R, Hu, Carolyn J, Cheng, Xinyi, Abskharon, Romany, Pan, Hope, DeTure, Michael A, Williams, Christopher K, Dickson, Dennis W, Vinters, Harry V, and Eisenberg, David S

Subjects
Biochemistry and Cell Biology, Medicinal and Biomolecular Chemistry, Chemical Sciences, Biological Sciences, Acquired Cognitive Impairment, Alzheimer's Disease, Complementary and Integrative Health, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Neurodegenerative, Brain Disorders, Dementia, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Neurological, Alzheimer Disease, Amyloid, Amyloidosis, Catechin, Cryoelectron Microscopy, Drug Evaluation, Preclinical, Humans, Tea, tau Proteins
Abstract

Alzheimer's disease (AD) is the consequence of neuronal death and brain atrophy associated with the aggregation of protein tau into fibrils. Thus disaggregation of tau fibrils could be a therapeutic approach to AD. The small molecule EGCG, abundant in green tea, has long been known to disaggregate tau and other amyloid fibrils, but EGCG has poor drug-like properties, failing to fully penetrate the brain. Here we have cryogenically trapped an intermediate of brain-extracted tau fibrils on the kinetic pathway to EGCG-induced disaggregation and have determined its cryoEM structure. The structure reveals that EGCG molecules stack in polar clefts between the paired helical protofilaments that pathologically define AD. Treating the EGCG binding position as a pharmacophore, we computationally screened thousands of drug-like compounds for compatibility for the pharmacophore, discovering several that experimentally disaggregate brain-derived tau fibrils in vitro. This work suggests the potential of structure-based, small-molecule drug discovery for amyloid diseases.

Published
2022

45. 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

47. 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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48. AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation

Author

Sayed, Faten A, Kodama, Lay, Fan, Li, Carling, Gillian K, Udeochu, Joe C, Le, David, Li, Qingyun, Zhou, Lu, Wong, Man Ying, Horowitz, Rose, Ye, Pearly, Mathys, Hansruedi, Wang, Minghui, Niu, Xiang, Mazutis, Linas, Jiang, Xueqiao, Wang, Xueting, Gao, Fuying, Brendel, Matthew, Telpoukhovskaia, Maria, Tracy, Tara E, Frost, Georgia, Zhou, Yungui, Li, Yaqiao, Qiu, Yue, Cheng, Zuolin, Yu, Guoqiang, Hardy, John, Coppola, Giovanni, Wang, Fei, DeTure, Michael A, Zhang, Bin, Xie, Lei, Trajnowski, John Q, Lee, Virginia MY, Gong, Shiaoching, Sinha, Subhash C, Dickson, Dennis W, Luo, Wenjie, and Gan, Li

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Genetics, Aging, Brain Disorders, Neurodegenerative, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Neurosciences, Acquired Cognitive Impairment, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Animals, Brain, Female, Humans, Membrane Glycoproteins, Mice, Microglia, Mutation, Proto-Oncogene Proteins c-akt, Receptors, Immunologic, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)–TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD.

Published
2021

49. Demographic and psychosocial factors associated with the decision to learn mutation status in familial frontotemporal dementia and the impact of disclosure on mood

Author

Bajorek, Lynn P, Kiekhofer, Rachel, Hall, Matthew, Taylor, Joanne, Lucente, Diane E, Brushaber, Danielle, Appleby, Brian, Coppolla, Giovanni, Bordelon, Yvette M, Botha, Hugo, Dickerson, Brad C, Dickson, Dennis W, Domoto‐Reilly, Kimiko, Fagan, Anne M, Fields, Julie A, Fong, Jamie C, Foroud, Tatiana M, Forsberg, Leah K, Galasko, Doug R, Gavrilova, Ralitza H, Geschwind, Daniel H, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Neill R, Graff‐Radford, Jonathan, Grant, Ian, Grossman, Murray, Heuer, Hilary W, Hsiung, Ging‐Yuek Robin, Huang, Eric J, Huey, Edward D, Irwin, David J, Jones, David T, Kantarci, Kejal, Kornak, John, Kremers, Walter K, Lapid, Maria I, Leger, Gabriel C, Litvan, Irene, Ljubenkov, Peter A, Mackenzie, Ian R, Masdeu, Joseph C, McMillan, Corey, Mendez, Mario, Miller, Bruce L, Miyagawa, Toji, Onyike, Chiadi U, Pascual, Belen, Pedraza, Otto, Petrucelli, Leonard, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine P, Rascovsky, Katya, Rexach, Jessica E, Ritter, Aaron, Roberson, Erik D, Savica, Rodolfo, Rojas, Julio C, Seeley, William W, Tartaglia, Maria Carmela, Toga, Arthur W, Weintraub, Sandra, Wong, Bonnie, Wszolek, Zbigniew, Vandevrede, Lawren, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Staffaroni, Adam M, and Consortium, ALLFTD

Subjects
Clinical Trials and Supportive Activities, Aging, Dementia, Genetics, Neurodegenerative, Clinical Research, Prevention, Acquired Cognitive Impairment, Mental Health, Depression, Brain Disorders, Clinical Sciences, Neurosciences, Geriatrics
Abstract

BACKGROUND: Up to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f-FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f-FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important. Furthermore, understanding the mood impacts of genetic disclosure may guide genetic counseling practice. METHOD: F-FTD participants (n=568) from families with a known pathogenic mutation (MAPT, C9orf72, GRN) were enrolled through the ARTFL/LEFFTDS Longitudinal FTD Study (ALLFTD) and provided the opportunity for disclosure. Independent-sample t-tests compared demographic and psychosocial factors between participants who did and did not receive their results. In participants who were asymptomatic at baseline and follow up (n=199,177 with follow-up), linear mixed effects modeling was used to investigate pre- to post-disclosure changes in the 15-item Geriatric Depression Scale (GDS). RESULT: Of participants from families with a known pathogenic genetic mutation, 47% received genetic disclosure. Of the asymptomatic subset (n=386), 36% know their mutation status. Of these asymptomatic learners, 46% received disclosure through the study, and the remainder learned their genetic status prior to study enrollment. None of the analyzed demographic or psychosocial factors (i.e., sex, age, education, having children) differed between learners and non-learners (p's > 0.05). In the longitudinal analysis of asymptomatic participants, learners showed a pre- to post-increase of 0.31 GDS points/year (95%CI: -0.08, 0.69, p = 0.12), whereas non-learners showed a slight decline (-0.15 points/year, 95%CI: -0.36, 0.06, p = 0.16). This difference between slopes was statistically significant (0.46, 95%CI: 0.02, 0.89, p=0.04) but represents a small clinical effect. In asymptomatic learners, slopes did not differ based on mutation status (0.28, 95%CI: -0.66, 1.20, p=0.55). Conclusions were based on the estimates and full range of confidence intervals. CONCLUSION: The majority of asymptomatic research participants do not know their genetic status, which will be a consideration for clinical trials that require disclosure. No considered demographic factors were strongly associated with the decision to receive disclosure. The findings suggest that disclosure in asymptomatic participants has minimal impact on depressive symptoms regardless of genetic results.

Published
2021

50. Gearing up for the future: Exploring facilitators and barriers to inform clinical trial design in frontotemporal lobar degeneration

Author

Banga, Yasmin B, Lai, Yujung, Kim, Priscilla, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Forsberg, Leah K, Heuer, Hilary W, Brushaber, Danielle, Appleby, Brian, Biernacka, Joanna M, Bordelon, Yvette M, Botha, Hugo, Bozoki, Andrea C, Brannelly, Patrick, Dickerson, Brad C, Dickinson, Susan, Dickson, Dennis W, Domoto‐Reilly, Kimiko, Faber, Kelley, Fagan, Anne M, Fields, Julie A, Fishman, Ann, Foroud, Tatiana M, Galasko, Doug R, Gavrilova, Ralitza H, Gendron, Tania F, Geschwind, Daniel H, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Jonathan, Graff‐Radford, Neill R, Grant, Ian, Grossman, Murray, Hsiung, Ging‐Yuek Robin, Huang, Eric J, Huey, Edward D, Irwin, David J, Jones, David T, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Knopman, David S, Kramer, Joel H, Kremers, Walter K, Kornak, John, Kukull, Walter A, Lagone, Emma, Leger, Gabriel C, Litvan, Irene, Ljubenkov, Peter A, Lucente, Diane E, Mackenzie, Ian R, Manoochehri, Masood, Masdeu, Joseph C, McGinnis, Scott, Mendez, Mario F, Miller, Bruce L, Miyagawa, Toji, Nelson, Kevin M, Onyike, Chiadi U, Pantelyat, Alex, Pascual, Belen, Pearlman, Rodney, Petrucelli, Leonard, Pottier, Cyril P, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine P, Rascovsky, Katya, Rexach, Jessica E, Ritter, Aaron, Roberson, Erik D, Rojas, Julio C, Sabbagh, Marwan N, Salmon, David P, Savica, Rodolfo, Seeley, William W, Staffaroni, Adam M, Syrjanen, Jeremy A, Tartaglia, Maria Carmela, Tatton, Nadine, Taylor, Jack C, Toga, Arthur W, Weintraub, Sandra, Wheaton, Diana, Wong, Benjamin, Wszolek, Zbigniew, and Consortium, ALLFTD

Subjects
Frontotemporal Dementia (FTD), Rare Diseases, Behavioral and Social Science, Neurodegenerative, Acquired Cognitive Impairment, Basic Behavioral and Social Science, Brain Disorders, Clinical Research, Dementia, Aging, Biomedical Imaging, Clinical Trials and Supportive Activities, Neurological, Clinical Sciences, Neurosciences, Geriatrics
Abstract

BACKGROUND: Frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates. OBJECTIVE: The objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD. METHODS: Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation. RESULTS: 29% of respondents self-reported as patients (63±10 years), 26% self-reported as caregivers answering on behalf of patients (65±10 years), and 45% self-reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%). CONCLUSIONS: Favorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation.

Published
2021

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