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2. APOLLOE4 Phase 3 study of oral ALZ‐801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics

Author

Susan Abushakra, Anton P. Porsteinsson, Marwan Sabbagh, David Watson, Aidan Power, Earvin Liang, Emer MacSweeney, Merce Boada, Susan Flint, Rosalind McLaine, J. Patrick Kesslak, John A. Hey, and Martin Tolar

Subjects
ALZ‐801, Alzheimer's disease, amyloid beta, amyloid beta oligomers, anti‐aggregation agents, anti‐oligomer agents, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract INTRODUCTION The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid‐related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ‐801/valiltramiprosate, an oral brain‐penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. METHODS This Phase 3 randomized, double‐blind, placebo‐controlled, 78‐week study of ALZ‐801 administered as 265 mg twice per day tablets, enrolled 50‐ to 80‐year‐old homozygotes with Mini‐Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating–Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug–placebo difference on the Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating–Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. RESULTS The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. DISCUSSION APOLLOE4 is the first disease‐modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ‐801 has the potential to be the first effective and safe anti‐amyloid treatment for the high‐risk APOE ε4/ε4 population. Highlights The APOLLOE4 Phase 3, placebo‐controlled, 78‐week study is designed to evaluate the efficacy and safety of ALZ‐801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype. The enrolled early AD population (N = 325) has 51% females, a mean age = 69 years, and a mean Mini‐Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD). The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating–Sum of Boxes, Amsterdam‐Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes. The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA). At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%). Study results will become available in the second half of 2024 and, if positive, ALZ‐801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.

Published
2024
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3. Altered microRNAs related to synaptic function as potential plasma biomarkers for Alzheimer’s disease

Author

Dolores Siedlecki-Wullich, Judit Català-Solsona, Cristina Fábregas, Isabel Hernández, Jordi Clarimon, Alberto Lleó, Merce Boada, Carlos A. Saura, José Rodríguez-Álvarez, and Alfredo J. Miñano-Molina

Subjects
Alzheimer’s disease, Mild cognitive impairment, Synapses, miRNAs, Plasma, Human, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Several evidences suggest that failure of synaptic function occurs at preclinical stages of Alzheimer’s disease (AD) preceding neuronal loss and the classical AD pathological hallmarks. Nowadays, there is an urgent need to identify reliable biomarkers that could be obtained with non-invasive methods to improve AD diagnosis at early stages. Here, we have examined plasma levels of a group of miRNAs related to synaptic proteins in a cohort composed of cognitive healthy controls (HC), mild cognitive impairment (MCI) and AD subjects. Methods Plasma and brain levels of miRNAs were analysed in two different cohorts including 38 HC, 26 MCI, 56 AD dementia patients and 27 frontotemporal dementia (FTD) patients. D’Agostino and Pearson and Shapiro-Wilk tests were used to evaluate data normality. miRNA levels between groups were compared using a two-sided nonparametric Mann-Whitney test and sensitivity and specificity was determined by receiver operating characteristic curve analysis. Results Significant upregulation of miR-92a-3p, miR-181c-5p and miR-210-3p was found in the plasma of both MCI and AD subjects. MCI patients that progress to AD showed higher plasma levels of these miRNAs. By contrast, no changes in miR-92a-3p, miR-181c-5p or miR-210-3p levels were observed in plasma obtained from a cohort of FTD. Conclusion Our study shows that plasma miR-92a-3p, miR-181c-5p and miR-210-3p constitute a specific molecular signature potentially useful as a potential biomarker for AD.

Published
2019
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4. Intepirdine as adjunctive therapy to donepezil for mild‐to‐moderate Alzheimer's disease: A randomized, placebo‐controlled, phase 3 clinical trial (MINDSET)

Author

Frederick M. Lang, Yi Mo, Marwan Sabbagh, Paul Solomon, Merce Boada, Roy W. Jones, Giovanni B. Frisoni, Timo Grimmer, Bruno Dubois, Mark Harnett, Sarah R. Friedhoff, Shari Coslett, and Jeffrey L. Cummings

Subjects
5‐HT6, Alzheimer's disease, clinical trial, intepirdine, phase 3, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Introduction A previous phase 2b study supported the use of the 5‐HT6 receptor antagonist intepirdine as adjunctive therapy to donepezil for Alzheimer's disease (AD) dementia. A phase 3 study, MINDSET, was performed to test this hypothesis. Methods MINDSET was a global, double‐blind, randomized, placebo‐controlled trial in 1315 mild‐to‐moderate AD dementia patients on stable donepezil. Patients received 35 mg/day intepirdine or placebo for 24 weeks. The co‐primary endpoints were change from baseline to week 24 on the Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) and Alzheimer's Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL). Results There were no statistically significant differences between intepirdine and placebo groups (adjusted mean [95% confidence interval]) on the co‐primary endpoints ADAS‐Cog (−0.36 [−0.95, 0.22], P = 0.2249) and ADCS‐ADL (−0.09 [−0.90, 0.72], P = 0.8260). Intepirdine demonstrated a favorable safety profile similar to placebo. Discussion Intepirdine as adjunctive therapy to donepezil did not produce statistical improvement over placebo on cognition or activities of daily living in mild‐to‐moderate AD dementia patients.

Published
2021
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5. Identification of a sex-specific genetic signature in dementia with Lewy bodies: a meta-analysis of genome-wide association studies

Author

Elizabeth Gibbons, Arvid Rongve, Itziar de Rojas, Alexey Shadrin, Kaitlyn Westra, Allison Baumgartner, Levi Rosendall, Zachary Madaj, Dena G. Hernandez, Owen A. Ross, Valentina Escott-Price, Claire Shepherd, Laura Parkkinen, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Lorraine Clark, Lawrence S Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St. George-Hyslop, Elisabet Londos, Henrik Zetterberg, Kevin Morgan, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Vivianna Van Deerlin, Geidy E Serrano, Thomas G Beach, Suzanne Lesage, Douglas Galasko, Eliezer Masliah, Isabel Santana, Pau Pastor, Monica Diez-Fairen, Miquel Aguilar, Marta Marquie, Pablo Garcia-Gonzalez, Claudia Olive, Raquel Puerta, Amanda Cano, Oscar Sotolongo-Grau, Sergi Valero, Vanesa Veronica Pytel, Maitee Rosende-Roca, Montserrat Alegret, Lluis Tarraga, Merce Boada, Angel Carracedo, Emilio Franco-Macias, Jordi Perez-Tur, Jose Luis Royo, Jose Maria Garcia-Alberca, Luis Miguel Real, Maria Eugenia Saez, Maria Jesus Bullido, Miguel Calero, Miguel Medina, Pablo Mir, Pascual Sanchez-Juan, Victoria Alvarez, Kayenat Parveen, Kumar Parijat Tripathi, Stefanie Heilmann-Heimbach, Alfredo Ramirez, Pentti J. Tienari, Olivier Bousiges, Frederic Blanc, Chiara Fenoglio, Alessandro Padovani, Barbara Borroni, Andrea Pilotto, Flavio Nobili, Ingvild Saltvedt, Tormod Fladby, Geir Selbaek, Ingunn Bosnes, Geir Brathen, Annette Hartmann, Afina W. Lemstra, Dan Rujescu, Brit Mollenhauer, Byron Creese, Marie-Christine Chartier-Harlin, Lavinia Athanasiu, Srdjan Djurovic, Leonidas Chouliaras, John T. OBrien, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F Boeve, Ronald C. Petersen, Tanis J Ferman, Neill Graff-Radford, Nigel J. Cairns, John C. Morris, Glenda M. Halliday, John Hardy, Dennis W. Dickson, Andrew Singleton, David J. Stone, Ole A. Andreassen, Agustin Ruiz, Dag Aarsland, Rita Guerreiro, and Jose Bras

Abstract

BackgroundGenome-wide Association Studies (GWAS) have reshaped our understanding of the genetic bases of complex diseases in general and neurodegenerative diseases in particular. Despite being a common disorder, dementia with Lewy bodies (DLB), which, together with Parkinson’s disease dementia (PDD), comprise the umbrella term Lewy body dementias (LBD), is far from being well-characterized genetically. This is primarily due to a lack of familial cases and difficulty recruiting large, deeply characterized cohorts, given the high rate of misdiagnosis. By performing the largest GWAS in DLB, we aimed to identify novel risk loci to gain a better understanding of this disease’s pathobiology.MethodsHere, we conducted the largest meta-analysis of genome-wide association studies performed in LBD, using a total of 5,119 cases and 20,988 controls, from five independent datasets, aggregating all previously published DLB genome-wide association results to date, as well as two previously undescribed cohorts. Additionally, we performed a sex stratified GWAS using the discovery datasets. We updated the heritability estimates for DLB and, to fine map these estimates, we used local heritability analysis. We calculated genetic correlation estimates between DLB and a range of other diseases and traits to identify potential pleiotropy. We also performed gene-set analysis to identify genes with excess burden of rare variability and pathway analysis. Lastly, we used the UK Biobank data to perform a PheWas using individuals at the extremes of genetic risk for DLB.FindingsBetween November 2018 and September 2022 we analyzed 8.6 million single nucleotide polymorphisms in 3293 DLB cases, 1826 LBD cases and 20,988 controls, as well as phenotypes from the UK Biobank dataset. Despite more than doubling the sample size from the previous GWAS in DLB, we did not identify significant loci in addition to those previously reported atGBA, SNCA, STX1B, andAPOE. However, the sex-stratified analysis revealed that theGBAandSNCAsignals are mainly driven by males, suggesting a sex-specific genetic architecture of disease. Using only clinical and neuropathologically diagnosed cases, we highlight four loci surpassing the significance threshold. Using the largest cohort of DLB we update our heritability estimates to 13% and fine map these results highlighting regions of the genome with high heritability but no genome-wide significant result so far.InterpretationThese data provide the most comprehensive analysis of genetic variability in DLB to date. The fact that no novel risk loci have been identified after doubling the cohort size indicates the potentially significant role of rare variants in the genetic architecture of DLB and stresses the urgent need for larger, well-characterized cohorts of this disease for genetic studies. The sex-stratified analysis shows that males and females have different signatures of genetic risk for DLB. These results have widespread implications for clinical practice and clinical trials’ design in DLB.

Published
2022
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6. Protective association of HLA-DRB1*04 subtypes in neurodegenerative diseases implicates acetylated tau PHF6 sequences

Author

Emmanuel Mignot, Yann Le Guen, Guo Luo, Aditya Ambati, Vincent Damotte, Iris Jansen, Eric Yu, Aude Nicolas, Itziar de Rojas, Thiago Leal, Akinori Miyashita, Céline Bellenguez, Michelle Lian, Kayenat Parveen, Takashi Morizono, Hyeonseul Park, Benjamin Grenier-Boley, Tatsuhiko Naito, Fahri Küçükali, Seth Talyansky, Selina Yogeshwar, Vicente Sempere, Wataru Sempere, Victoria Álvarez, Beatrice Arosio, Michael Belloy, Luisa Benussi, Anne Boland, Barbara Borroni, Maria Jesus Bullido, Paolo Caffarra, Jordi Clarimon, Antonio DANIELE, Daniel Darling, Stéphanie Debette, Jean-François Deleuze, Martin Dichgans, Carole Dufouil, Emmanuel During, Emrah Düzel, Daniela Galimberti, Guillermo Garcia-Ribas, Jose María García-Alberca, Pablo García-González, Vilmantas Giedraitis, Oliver Goldhardt, Caroline Graff, Edna Grünblatt, Oliver Hanon, Lucrezia Hausner, Stefanie Heilmann-Heimbach, Henne Holstege, Jakub Hort, Yoo Jin Jung, Jürgen Deckert, Silke Kern, Teemu Kuulasmaa, Ling Ling, Carlo Masullo, Patrizia Mecocci, Shima Mehrabian, Alexandre de Mendonça, Merce Boada, Pablo Mir, Susanne Moebus, Fermin Moreno, Benedetta Nacmias, Gaël Nicolas, Shumpei Niida, Børge Nordestgaard, Goran Papenberg, Janne Papma, Lucilla Parnetti, Florence Pasquier, Pau Pastor, Oliver Peters, Yolande Pijnenburg, Gerard Piñol-Ripoll, Julius Popp, Laura Molina-Porcel, Raquel Puerta Fuentes, Jordi Pérez-Tur, Innocenzo Rainero, Inez Ramakers, Luis Real, Steffi Riedel-Heller, Eloy Rodriguez-Rodriguez, Jose Luis Royo, Dan Rujescu, Nikolaos Scarmeas, Philip Scheltens, Norbert Scherbaum, Anja Schneider, Davide Seripa, Ingmar Skoog, Vincenzo Solfrizzi, Gianfranco Spalletta, Alessio Squassina, John van Swieten, Raquel Sánchez-Valle, Eng-King Tan, Thomas Tegos, Charlotte Teunissen, Jesper Qvist Thomassen, Lucio Tremolizzo, Martin Vyhnalek, Frans Verhey, Margda Waern, Jens Wiltfang, Jing Zhang, Henrik Zetterberg, Kaj Blennow, Julie Williams, Philippe Amouyel, Frank Jessen, Patrick Kehoe, Ole Andreassen, Cornelia van Duijn, magda tsolaki, Pascual Sanchez-Juan, Ruth Frikke-Schmidt, Kristel Sleegers, Tatsushi Toda, Anna Zettergren, Martin Ingelsson, Yukinori Okada, Giacomina Rossi, Mikko Hiltunen, Jungsoo Gim, Kouichi Ozaki, Rebecca Sims, Jia Nee Foo, Wiesje van der Flier, Takeshi Ikeuchi, Alfredo Ramirez, Ignacio Mata, Agustín Ruiz, Ziv Gan-Or, Kun Ho Lee, Jean-Charles Lambert, and Michael Greicius

Abstract

Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s (PD) or Alzheimer’s (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10-13; AD: OR=0.91[0.89; 0.93]; p=1.8x10-22), and with a protective HLA association recently reported in amyotrophic lateral sclerosis (ALS). Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. An HLA-DRB1*04-mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.

Published
2022
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7. Person-centered Assessment in Early Alzheimer’s Disease (P1-1.Virtual)

Author

Galende, Alberto Villarejo, primary, Garcia-Arcelay, Elena, additional, Pinol-Ripoll, Gerard, additional, del Olmo-Rodriguez, Antonio, additional, Vinuela, Felix, additional, Rovira, Merce Boada, additional, Franco-Macias, Emilio, additional, Ibañez, Almudena, additional, Riverol, Mario, additional, Pijoan, Albert Puig, additional, Abizanda, Pedro, additional, Gonzalez, Rafael Arroyo, additional, Baquero, Miquel, additional, Feria, Inmaculada, additional, Balasa, Mircea, additional, Berbel, Angel, additional, Rodriguez-Rodriguez, Eloy, additional, Vieira, Alba, additional, Garcia-Ribas, Guillermo, additional, Rodrigo-Herrero, Silvia, additional, Lleo, Alberto, additional, Morales, Eduardo Aguera, additional, Catalán-Flores, Carmen, additional, and Maurino, Jorge, additional

Published
2022
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8. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author

Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS

Subjects
Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Published
2021
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9. Matrix metalloproteinase 10 is linked to the risk of progression to dementia of the Alzheimer's type

Author

Pamela V Martino Adami, Adelina Orellana, Pablo García, Luca Kleineidam, Emilio Alarcón-Martín, Laura Montrreal, Nuria Aguilera, Ana Espinosa, Carla Abdelnour, Maitee Rosende-Roca, Juan Pablo Tartari, Liliana Vargas, Ana Mauleón, Ester Esteban-De Antonio, Rogelio López-Cuevas, Maria Carolina Dalmasso, Rafael Campos Martin, Kayenat Parveen, Victor M Andrade Fuentes, Najaf Amin, Shahzad Ahmad, M Arfan Ikram, Piotr Lewczuk, Johannes Kornhuber, Oliver Peters, Lutz Frölich, Eckart Rüther, Jens Wiltfang, Lluis Tarraga, Merce Boada, Wolfgang Maier, Itziar de Rojas, Amanda Cano, Angela Sanabria, Montserrat Alegret, Isabel Hernández, Marta Marquié, Sergi Valero, Cornelia M van Duijn, Michael Wagner, Frank Jessen, Anja Schneider, María Eugenia Sáez Goñi, Antonio González Pérez, Agustín Ruiz, Alfredo Ramírez, Epidemiology, and Radiology & Nuclear Medicine

Subjects
Amyloid beta-Peptides, biomarkers, tau Proteins, cerebrospinal fluid [Matrix Metalloproteinase 10], Peptide Fragments, pathology [Alzheimer Disease], disease progression, mild cognitive impairment, diagnosis [Cognitive Dysfunction], Matrix Metalloproteinase 10, ageing, Alzheimer Disease, Disease Progression, Humans, Cognitive Dysfunction, Neurology (clinical), ddc:610, Longitudinal Studies, Alzheimer’s disease, Biomarkers
Abstract

Alzheimer’s disease has a long asymptomatic phase that offers a substantial time window for intervention. Using this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer’s disease pathology at predementia stages, thus allowing identification of patients who will most probably progress to dementia of the Alzheimer’s type and benefit from specific disease-modifying therapies. Consequently, we searched for CSF proteins associated with disease progression along with the clinical disease staging. We measured the levels of 184 proteins in CSF samples from 556 subjective cognitive decline and mild cognitive impairment patients from three independent memory clinic longitudinal studies (Spanish ACE, n = 410; German DCN, n = 93; German Mannheim, n = 53). We evaluated the association between protein levels and clinical stage, and the effect of protein levels on the progression from mild cognitive impairment to dementia of the Alzheimer’s type. Mild cognitive impairment subjects with increased CSF level of matrix metalloproteinase 10 (MMP-10) showed a higher probability of progressing to dementia of the Alzheimer’s type and a faster cognitive decline. CSF MMP-10 increased the prediction accuracy of CSF amyloid-β 42 (Aβ42), phospho-tau 181 (P-tau181) and total tau (T-tau) for conversion to dementia of the Alzheimer’s type. Including MMP-10 to the [A/T/(N)] scheme improved considerably the prognostic value in mild cognitive impairment patients with abnormal Aβ42, but normal P-tau181 and T-tau, and in mild cognitive impairment patients with abnormal Aβ42, P-tau181 and T-tau. MMP-10 was correlated with age in subjects with normal Aβ42, P-tau181 and T-tau levels. Our findings support the use of CSF MMP-10 as a prognostic marker for dementia of the Alzheimer’s type and its inclusion in the [A/T/(N)] scheme to incorporate pathologic aspects beyond amyloid and tau. CSF level of MMP-10 may reflect ageing and neuroinflammation.

Published
2021
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11. Additional file 1: of Altered microRNAs related to synaptic function as potential plasma biomarkers for Alzheimer’s disease

Author

Siedlecki-Wullich, Dolores, Català-Solsona, Judit, Fábregas, Cristina, Hernández, Isabel, Clarimon, Jordi, Lleó, Alberto, Merce Boada, Saura, Carlos, Rodríguez-Álvarez, José, and Miñano-Molina, Alfredo

Abstract

Figure S1. miRNA levels in human entorhinal cortex (A), hippocampus (B) and cerebellum (C) at different stages of AD pathology compared with cognitively healthy controls. Figure S2. Correlation plots for plasma miRNAs expression levels vs age. Figure S3. Circulating miRNAs levels comparison between sexes. Figure S4. NPTX1 and NPTXR protein levels in AD human entorhinal cortex. Table S1. Tissue samples information. Table S2. Validated miRNA-target interactions for candidate miRNAs based on miRWalk2.0 database. Only selected synaptic-related targets are shown. Table S3. Follow-up of MCI patients. (PDF 1295 kb)

Published
2019
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12. The Spanish version of Face-Name Associative Memory Exam (S-FNAME) performance is related to amyloid burden in Subjective Cognitive Decline

Author

Angela, Sanabria, Montserrat, Alegret, Octavio, Rodriguez-Gomez, Sergi, Valero, Oscar, Sotolongo-Grau, Gemma, Monté-Rubio, Carla, Abdelnour, Ana, Espinosa, Gemma, Ortega, Alba, Perez-Cordon, Anna, Gailhajanet, Isabel, Hernandez, Maitee, Rosende-Roca, Liliana, Vargas, Ana, Mauleon, Domingo, Sanchez, Elvira, Martin, Dorene M, Rentz, Francisco, Lomeña, Agustin, Ruiz, Lluis, Tarraga, Merce, Boada, and A, Vivas

Subjects
Cingulate cortex, Male, medicine.medical_specialty, Amyloid beta, lcsh:Medicine, Disease, Audiology, Neuropsychological Tests, 050105 experimental psychology, Article, 03 medical and health sciences, 0302 clinical medicine, Memory, Activities of Daily Living, Medicine, Humans, 0501 psychology and cognitive sciences, Cognitive Dysfunction, Cognitive decline, lcsh:Science, Episodic memory, Aged, Language, Aged, 80 and over, Multidisciplinary, Amyloid beta-Peptides, biology, business.industry, 05 social sciences, lcsh:R, Neuropsychology, Cognition, Content-addressable memory, Middle Aged, Positron-Emission Tomography, biology.protein, lcsh:Q, Female, business, 030217 neurology & neurosurgery
Abstract

The Face-Name Associative Memory Exam (FNAME) is a paired associative memory test created to detect memory deficits in individuals with preclinical Alzheimer’s disease (AD). Worse performance on FNAME in cognitively healthy individuals were found related to higher amyloid beta (Aβ) burden measured with Positron-Emission-Tomography using 11C-PiB (PiB-PET). We previously reported normative data of a Spanish version of FNAME (S-FNAME) in cognitively healthy Spanish-speaking subjects. The aim of the present study was to determine whether performance on S-FNAME was associated with Aβ burden in subjective cognitive decline (SCD) individuals. 200 SCD subjects received neurological and neuropsychological assessments, including the S-FNAME and the Word List task from the Wechsler-Memory-Scale-III (WMS-III). Moreover, they received an MRI and (18)F-Florbetaben Positron-Emission-Tomography (FBB-PET) to measure Aβ burden. Three cognitive factor composites were derived for the episodic memory measures (face-name [SFN-N], face-occupation [SFN-O] and WMS-III) to determine whether episodic memory performance was related to Aβ deposition. Higher global Aβ deposition was significantly related to worse performance on SFN-N but not with SFN-O or WMS-III Composite. Moreover, worse SFN-N performance was significantly related to higher Aβ deposition in bilateral Posterior Cingulate Cortex. The S-FNAME may be a promising neuropsychological tool for detecting SCD individuals with preclinical AD.

Published
2017

13. Contributors

Author

Abdelnour, Carla, Abela, Angela, Arnaldi, Dario, Au, Rhoda, Balma, Michele, Barbarino, Paola, Barbera, Mariagnese, Bauckneht, Matteo, Bilbo, Staci D., Biskup, Ewelina, Campbell, Stephen, Chadha, Antonella Santuccione, Chincarini, Andrea, Delage, Charlotte, Dimech, Annemarie Schumacher, Diviani, Nicola, Downie, Sue, Esteban, Ester, Ferraro, Pilar M., Ferretti, Maria Teresa, Foldi, Nancy S., Galea, Liisa A.M., Gammada, Emnet Z., Grazzini, Matteo, Håkansson, Krister, Hill-Strathy, MaryJane, Ilinca, Stefania, Ippati, Stefania, Matthias Ittner, Lars, Jordan, Valeria, Diana Ke, Yazi, Kivipelto, Miia, Lapucci, Caterina, Lee, Bonnie H., Lehtisalo, Jenni, Lorenz-Dant, Klara, Lynch, Chris, Malacon, Karen E., Martinkova, Julie N., Massa, Federico, Meli, Riccardo, Mellino, Simona, Mielke, Michelle M., Mittelman, Mary, Morbelli, Silvia, Nasta, Beatrice, Nobili, Flavio, Pardini, Matteo, Peira, Enrico, Phillips, Susan, Puri, Tanvi A., Raffa, Stefano, Rauen, Katrin, Rendina, Danielle N., Roccatagliata, Luca, Rosenberg, Anna, Rosende-Roca, Maitee, Rovira, Mercè Boada, Rubinelli, Sara, Scerri, Anthony, Scerri, Charles, Sindi, Shireen, Stephen, Ruth, Suzuki, Elina, Szoeke, Cassandra, Toopchiani, Sima, Tremblay, Marie-Ève, Udeh-Momoh, Chinedu, and Weidner, Wendy

Published
2021
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