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22 results on '"Arosio, B"'

1. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Author

de Rojas, I., Moreno-Grau, S., Tesi, N., Grenier-Boley, B., Andrade, V., Jansen, I. E., Pedersen, N. L., Stringa, N., Zettergren, A., Hernandez, I., Montrreal, L., Antunez, C., Antonell, A., Tankard, R. M., Bis, J. C., Sims, R., Bellenguez, C., Quintela, I., Gonzalez-Perez, A., Calero, M., Franco-Macias, E., Macias, J., Blesa, R., Cervera-Carles, L., Menendez-Gonzalez, M., Frank-Garcia, A., Royo, J. L., Moreno, F., Huerto Vilas, R., Baquero, M., Diez-Fairen, M., Lage, C., Garcia-Madrona, S., Garcia-Gonzalez, P., Alarcon-Martin, E., Valero, S., Sotolongo-Grau, O., Ullgren, A., Naj, A. C., Lemstra, A. W., Benaque, A., Perez-Cordon, A., Benussi, A., Rabano, A., Padovani, A., Squassina, A., de Mendonca, A., Arias Pastor, A., Kok, A. A. L., Meggy, A., Pastor, A. B., Espinosa, A., Corma-Gomez, A., Martin Montes, A., Sanabria, A., DeStefano, A. L., Schneider, A., Haapasalo, A., Kinhult Stahlbom, A., Tybjaerg-Hansen, A., Hartmann, A. M., Spottke, A., Corbaton-Anchuelo, A., Rongve, A., Borroni, B., Arosio, B., Nacmias, B., Nordestgaard, B. G., Kunkle, B. W., Charbonnier, C., Abdelnour, C., Masullo, C., Martinez Rodriguez, C., Munoz-Fernandez, C., Dufouil, C., Graff, C., Ferreira, C. B., Chillotti, C., Reynolds, C. A., Fenoglio, C., Van Broeckhoven, C., Clark, C., Pisanu, C., Satizabal, C. L., Holmes, C., Buiza-Rueda, D., Aarsland, D., Rujescu, D., Alcolea, D., Galimberti, D., Wallon, D., Seripa, D., Grunblatt, E., Dardiotis, E., Duzel, E., Scarpini, E., Conti, E., Rubino, E., Gelpi, E., Rodriguez-Rodriguez, E., Duron, E., Boerwinkle, E., Ferri, E., Tagliavini, F., Kucukali, F., Pasquier, F., Sanchez-Garcia, F., Mangialasche, F., Jessen, F., Nicolas, G., Selbaek, G., Ortega, G., Chene, G., Hadjigeorgiou, G., Rossi, G., Spalletta, G., Giaccone, G., Grande, G., Binetti, G., Papenberg, G., Hampel, H., Bailly, H., Zetterberg, H., Soininen, H., Karlsson, I. K., Alvarez, I., Appollonio, I., Giegling, I., Skoog, I., Saltvedt, I., Rainero, I., Rosas Allende, I., Hort, J., Diehl-Schmid, J., Van Dongen, J., Vidal, J. -S., Lehtisalo, J., Wiltfang, J., Thomassen, J. Q., Kornhuber, J., Haines, J. L., Vogelgsang, J., Pineda, J. A., Fortea, J., Popp, J., Deckert, J., Buerger, K., Morgan, K., Fliessbach, K., Sleegers, K., Molina-Porcel, L., Kilander, L., Weinhold, L., Farrer, L. A., Wang, L. -S., Kleineidam, L., Farotti, L., Parnetti, L., Tremolizzo, L., Hausner, L., Benussi, L., Froelich, L., Ikram, M. A., Deniz-Naranjo, M. C., Tsolaki, M., Rosende-Roca, M., Lowenmark, M., Hulsman, M., Spallazzi, M., Pericak-Vance, M. A., Esiri, M., Bernal Sanchez-Arjona, M., Dalmasso, M. C., Martinez-Larrad, M. T., Arcaro, M., Nothen, M. M., Fernandez-Fuertes, M., Dichgans, M., Ingelsson, M., Herrmann, M. J., Scherer, M., Vyhnalek, M., Kosmidis, M. H., Yannakoulia, M., Schmid, M., Ewers, M., Heneka, M. T., Wagner, M., Scamosci, M., Kivipelto, M., Hiltunen, M., Zulaica, M., Alegret, M., Fornage, M., Roberto, N., van Schoor, N. M., Seidu, N. M., Banaj, N., Armstrong, N. J., Scarmeas, N., Scherbaum, N., Goldhardt, O., Hanon, O., Peters, O., Skrobot, O. A., Quenez, O., Lerch, O., Bossu, P., Caffarra, P., Dionigi Rossi, P., Sakka, P., Hoffmann, P., Holmans, P. A., Fischer, P., Riederer, P., Yang, Q., Marshall, R., Kalaria, R. N., Mayeux, R., Vandenberghe, R., Cecchetti, R., Ghidoni, R., Frikke-Schmidt, R., Sorbi, S., Hagg, S., Engelborghs, S., Helisalmi, S., Botne Sando, S., Kern, S., Archetti, S., Boschi, S., Fostinelli, S., Gil, S., Mendoza, S., Mead, S., Ciccone, S., Djurovic, S., Heilmann-Heimbach, S., Riedel-Heller, S., Kuulasmaa, T., del Ser, T., Lebouvier, T., Polak, T., Ngandu, T., Grimmer, T., Bessi, V., Escott-Price, V., Giedraitis, V., Deramecourt, V., Maier, W., Jian, X., Pijnenburg, Y. A. L., Smith, A. D., Saenz, A., Bizzarro, A., Lauria, A., Vacca, A., Solomon, A., Anastasiou, A., Richardson, A., Boland, A., Koivisto, A., Daniele, A., Greco, A., Marianthi, A., McGuinness, B., Fin, B., Ferrari, C., Custodero, C., Ferrarese, C., Ingino, C., Mangone, C., Reyes Toso, C., Martinez, C., Cuesta, C., Muchnik, C., Joachim, C., Ortiz, C., Besse, C., Johansson, C., Zoia, C. P., Laske, C., Anastasiou, C., Palacio, D. L., Politis, D. G., Janowitz, D., Craig, D., Mann, D. M., Neary, D., Jurgen, D., Daian, D., Belezhanska, D., Kohler, E., Castano, E. M., Koutsouraki, E., Chipi, E., De Roeck, E., Costantini, E., Vardy, E. R. L. C., Piras, F., Roveta, F., Prestia, F. A., Assogna, F., Salani, F., Sala, G., Lacidogna, G., Novack, G., Wilcock, G., Thonberg, H., Kolsch, H., Weber, H., Boecker, H., Etchepareborda, I., Piaceri, I., Tuomilehto, J., Lindstrom, J., Laczo, J., Johnston, J., Deleuze, J. -F., Harris, J., Schott, J. M., Priller, J., Bacha, J. I., Snowden, J., Lisso, J., Mihova, K. Y., Traykov, L., Morelli, L., Brusco, L. I., Rainer, M., Takalo, M., Bjerke, M., Del Zompo, M., Serpente, M., Sanchez Abalos, M., Rios, M., Peltonen, M., Herrman, M. J., Kohler, M., Rojo, M., Jones, M., Orsini, M., Medel, N., Olivar, N., Fox, N. C., Salvadori, N., Hooper, N. M., Galeano, P., Solis, P., Bastiani, P., Mecocci, P., Passmore, P., Heun, R., Antikainen, R., Olaso, R., Perneczky, R., Germani, S., Lopez-Garcia, S., Love, S., Mehrabian, S., Bagnoli, S., Kochen, S., Andreoni, S., Teipel, S., Todd, S., Pickering-Brown, S., Natunen, T., Tegos, T., Laatikainen, T., Strandberg, T., Polvikoski, T. M., Matoska, V., Ciullo, V., Cores, V., Solfrizzi, V., Lisetti, V., Sevillano, Z., Aguilera, N., Alarcon, E., Boada, M., Buendia, M., Canabate, P., Carracedo, A., Diego, S., Gailhajenet, A., Guitart, M., Ibarria, M., Lafuente, A., Maronas, O., Martin, E., Martinez, M. T., Marquie, M., Mauleon, A., Moreno, M., Orellana, A., Pancho, A., Peleja, E., Preckler, S., Real, L. M., Ruiz, A., Saez, M. E., Serrano-Rios, M., Tarraga, L., Vargas, L., Adarmes-Gomez, A. D., Alonso, M. D., Alvarez, V., Amer-Ferrer, G., Antequera, M., Bernal, M., Bullido, M. J., Burguera, J. A., Carrillo, F., Carrion-Claro, M., Casajeros, M. J., Clarimon, J., Cruz-Gamero, J. M., de Pancorbo, M. M., Escuela, R., Garrote-Espina, L., Garcia-Alberca, J. M., Garcia Madrona, S., Garcia-Ribas, G., Gomez-Garre, P., Hevilla, S., Jesus, S., Labrador Espinosa, M. A., Legaz, A., Lleo, A., Lopez de Munain, A., Macias-Garcia, D., Manzanares, S., Marin, M., Marin-Munoz, J., Marin, T., Martinez, B., Martinez, V., Martinez-Lage Alvarez, P., Medina, M., Mendioroz Iriarte, M., Mir, P., Molinuevo, J. L., Pastor, P., Perez Tur, J., Perinan-Tocino, T., Pineda-Sanchez, R., Pinol-Ripoll, G., Real de Asua, D., Rodrigo, S., Sanchez del Valle Diaz, R., Sanchez-Juan, P., Sastre, I., Vicente, M. P., Vigo-Ortega, R., Vivancos, L., Macleod, C., McCracken, C., Brayne, C., Bresner, C., Grozeva, D., Bellou, E., Sommerville, E. W., Matthews, F., Leonenko, G., Menzies, G., Windle, G., Harwood, J., Phillips, J., Bennett, K., Luckuck, L., Clare, L., Woods, R., Saad, S., Burholt, V., Kehoe, P. G., Perez-Tur, J., Scheltens, P., Holstege, H., Amouyel, P., Schellenberg, G. D., Williams, J., Seshadri, S., van Duijn, C. M., Mather, K. A., Sanchez-Valle, R., Blennow, K., Huisman, M., Andreassen, O. A., Posthuma, D., van der Flier, W. M., Ramirez, A., Lambert, J. -C., and van der Lee, S. J.

Subjects
Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Protein Precursor, Apolipoproteins E, Case-Control Studies, Cohort Studies, Datasets as Topic, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Multifactorial Inheritance
Published
2021

2. Pin1 Contribution to Alzheimer’s Disease: Transcriptional and Epigenetic Mechanisms in Patients with Late-Onset Alzheimer’s Disease

Author

Beatrice Arosio, Mauro Maccarrone, Daniela Mari, Patrizia Romualdi, Claudio D'Addario, A. Bulbarelli, Bernardo Dell'Osso, Daniela Galimberti, Cristina Gussago, S. Bastias Candia, Elio Scarpini, L. Mastronardi, Carlo Altamura, Sanzio Candeletti, Luigi Bergamaschini, E. Lonati, Arosio, B, Bulbarelli, A, Bastias Candia, S, Lonati, E, Mastronardi, L, Romualdi, P, Candeletti, S, Gussago, C, Galimberti, D, Scarpini, E, Dell'Osso, B, Altamura, C, Maccarrone, M, Bergamaschini, L, D'Addario, C, Mari, D, Arosio B, Bulbarelli A, Bastias Candia S, Lonati E, Mastronardi L, Romualdi P, Candeletti S, Gussago C, Galimberti D, Scarpini E, Dell'Osso B, Altamura C, MacCarrone M, Bergamaschini L, D'Addario C, and Mari D.

Subjects
Male, BIOMARKER, Pathology, medicine.medical_specialty, Apolipoprotein E4, BACE1-AS, LATE-ONSET, Methylation, Peripheral blood mononuclear cell, Epigenesis, Genetic, Pathogenesis, PIN1, Alzheimer Disease, Serine, Amyloid precursor protein, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, Senile plaques, Phosphorylation, Promoter Regions, Genetic, ALZHEIMER, Aged, Aged, 80 and over, EPIGENETIC, Analysis of Variance, biology, Peptidylprolyl Isomerase, BIO/10 - BIOCHIMICA, NIMA-Interacting Peptidylprolyl Isomerase, Italy, Neurology, Case-Control Studies, Leukocytes, Mononuclear, Pin1, Alzheimer, biology.protein, Cancer research, Female, Neurology (clinical)
Abstract

Background: Neurofibrillary tangles and senile plaques are hallmarks of Alzheimer’s disease (AD) although the molecular basis of their coexistence remains elusive. The peptidyl-prolyl cis/trans isomerase Pin1 acts on both tau and amyloid precursor protein to regulate their functions by influencing tau phosphorylation and amyloid precursor protein processing. Objective: In order to identify potential biomarkers for AD in easily accessible cells and to gain insight into the relationship between the brain and peripheral compartments in AD pathology, we investigated Pin1 expression and activity in the peripheral blood mononuclear cells of subjects with late-onset AD (LOAD) and age-matched controls (CT). Methods: Gene and protein expression, promoter methylation, Ser16 phosphorylation and activity of Pin1 were evaluated in 32 samples from subjects with LOAD and in 28 samples from CT. Results: In LOAD subjects, there was a statistically significant reduction in Ser16 phosphorylation (–30%; p = 0.041) and promoter methylation (–8%; p = 0.001), whereas Pin1 expression was significantly increased (+74%; p = 0.018). Conclusion: The modifications of Pin1 found in LOAD subjects support its involvement in the pathogenesis of the disease with an important role being played by epigenetic mechanisms.

Published
2012

3. Common Variants at Abca7, Ms4A6A/Ms4A4E, Epha1, Cd33 and Cd2Ap Are Associated with Alzheimer'S Disease

Author

Neill R. Graff-Radford, Caroline S. Widdowson, John Hardy, Simon Lovestone, Stefan Schreiber, Ana Frank-García, Amy Gerrish, Kevin Mayo, Alexandra Stretton, Michael John Owen, Minerva M. Carrasquillo, Seth Love, Jade Chapman, Vincent Chouraki, Monique M.B. Breteler, Francesco Panza, Emma R L C Vardy, Ronald C. Petersen, Harald Hampel, S. Nicolhaus, Lenore J. Launer, Michelle K. Lupton, Eckart Rüther, A. David Smith, David C. Rubinsztein, Rebecca Sims, Gill Livingston, Diana Zelenika, Simon Mead, Martin N. Rossor, Hilkka Soininen, Christine Van Broeckhoven, Kristel Sleegers, Thorlakur Jonsson, M. Arfan Ikram, Helen Beaumont, Michael Conlon O'Donovan, Federico Licastro, Sudha Seshadri, Alexander Richards, Nick C. Fox, Markus M. Nöthen, Claudine Berr, T. Feulner, Benedetta Nacmias, Carlos Cruchaga, Peter Passmore, Oscar L. Lopez, Julie Williams, Matthias Riemenschneider, Florence Pasquier, John Gallacher, Didier Hannequin, Sigrid Botne Sando, Jens Wiltfang, Charlene Thomas, Gabriele Siciliano, Maria Barcikowska, Mikko Hiltunen, Carol Brayne, Dobril Ivanov, Anita L. DeStefano, Bernadette McGuinness, Norman Klopp, Gordon K. Wilcock, Aoibhinn Lynch, Wolfgang Maier, Peter Holmans, H.-Erich Wichmann, Giorgio Annoni, Beatrice Arosio, Alison Goate, Sigurbjorn Bjornsson, Karl-Heinz Jöckel, Dan Rujescu, Hugh Gurling, Nigel M. Hooper, Clive Holmes, Andrew McQuillin, Patricia Friedrich, John Powell, Rhian Gwilliam, R. Heun, Jacques Epelbaum, Isabella Heuser, Magda Tsolaki, Dennis W. Dickson, Alberto Pilotto, Stephen Todd, Dominique Campion, Michael Krawczak, Jan O. Aasly, Olivier Hanon, Patrick G. Kehoe, Johannes Kornhuber, Marc Delepine, Peter Paul De Deyn, Britta Schürmann, Brian A. Lawlor, Christophe Tzourio, Richard Abraham, Petra Nowotny, Jean-François Dartigues, Heike Kölsch, Michelangelo Mancuso, Marian L. Hamshere, Zbigniew K. Wszolek, Paola Piccardi, Paolo Bosco, Jean-Charles Lambert, Denise Harold, Frank Jessen, Palmi V. Jonsson, Paola Bossù, Paul Hollingworth, Jon Snaedal, Michael Gill, Onofre Combarros, David M. A. Mann, John C. Morris, Annette L. Fitzpatrick, Christopher Shaw, Alexis Brice, Philippe Amouyel, Elio Scarpini, Lesley Jones, Sebastiaan Engelborghs, Daniela Galimberti, Vincenzo Solfrizzi, V. Shane Pankratz, John Collinge, María J. Bullido, Kristelle Brown, Nicholas Bass, Andrew B. Singleton, Jaspreet Singh Pahwa, Kari Stefansson, Lutz Frölich, Steven G. Younkin, Ignacio Mateo, Annick Alpérovitch, Benjamin Genier-Boley, Ina Giegling, Caterina Riehle, Kimberley Dowzell, Mark Lathrop, Hreinn Stefansson, Sandro Sorbi, Rita Guerreiro, Thomas W. Mühleisen, Karolien Bettens, Michael Hüll, Martin Dichgans, Petroula Proitsi, Panagiotis Deloukas, Valentina Moskvina, Cornelia M. van Duijn, Donald Warden, Victoria Alvarez, Eliecer Coto, Kevin Morgan, Susanne Moebus, Ammar Al-Chalabi, Elisa Porcellini, Stefan Wagenpfeil, Hendrik van den Bussche, John S. K. Kauwe, Stacy Steinberg, David Craig, Nicola Jones, Manuel Mayhaus, Davide Seripa, Neurology, NCA - Neurodegeneration, HOLLINGWORTH P, HAROLD D, SIMS R, GERRISH A, LAMBERT JC, CARRASQUILLO MM, ABRAHAM R, HAMSHERE ML, PAHWA JS, MOSKVINA V, DOWZELL K, JONES N, STRETTON A, THOMAS C, RICHARDS A, IVANOV D, WIDDOWSON C, CHAPMAN J, LOVESTONE S, POWELL J, PROITSI P, LUPTON MK, BRAYNE C, RUBINSZTEIN DC, GILL M, LAWLOR B, LYNCH A, BROWN KS, PASSMORE PA, CRAIG D, MCGUINNESS B, TODD S, HOLMES C, MANN D, SMITH AD, BEAUMONT H, WARDEN D, WILCOCK G, LOVE S, KEHOE PG, HOOPER NM, VARDY ER, HARDY J, MEAD S, FOX NC, ROSSOR M, COLLINGE J, MAIER W, JESSEN F, RÜTHER E, SCHÜRMANN B, HEUN R, KÖLSCH H, VAN DEN BUSSCHE H, HEUSER I, KORNHUBER J, WILTFANG J, DICHGANS M, FRÖLICH L, HAMPEL H, GALLACHER J, HÜLL M, RUJESCU D, GIEGLING I, GOATE AM, KAUWE JS, CRUCHAGA C, NOWOTNY P, MORRIS JC, MAYO K, SLEEGERS K, BETTENS K, ENGELBORGHS S, DE DEYN PP, VAN BROECKHOVEN C, LIVINGSTON G, BASS NJ, GURLING H, MCQUILLIN A, GWILLIAM R, DELOUKAS P, AL-CHALABI A, SHAW CE, TSOLAKI M, SINGLETON AB, GUERREIRO R, MÜHLEISEN TW, NÖTHEN MM, MOEBUS S, JÖCKEL KH, KLOPP N, WICHMANN HE, PANKRATZ VS, SANDO SB, AASLY JO, BARCIKOWSKA M, WSZOLEK ZK, DICKSON DW, GRAFF-RADFORD NR, PETERSEN RC, ALZHEIMER'S DISEASE NEUROIMAGING INITIATIVE, VAN DUIJN CM, BRETELER MM, IKRAM MA, DESTEFANO AL, FITZPATRICK AL, LOPEZ O, LAUNER LJ, SESHADRI S, CHARGE CONSORTIUM, BERR C, CAMPION D, EPELBAUM J, DARTIGUES JF, TZOURIO C, ALPÉROVITCH A, LATHROP M, EADI1 CONSORTIUM, FEULNER TM, FRIEDRICH P, RIEHLE C, KRAWCZAK M, SCHREIBER S, MAYHAUS M, NICOLHAUS S, WAGENPFEIL S, STEINBERG S, STEFANSSON H, STEFANSSON K, SNAEDAL J, BJÖRNSSON S, JONSSON PV, CHOURAKI V, GENIER-BOLEY B, HILTUNEN M, SOININEN H, COMBARROS O, ZELENIKA D, DELEPINE M, BULLIDO MJ, PASQUIER F, MATEO I, FRANK-GARCIA A, PORCELLINI E, HANON O, COTO E, ALVAREZ V, BOSCO P, SICILIANO G, MANCUSO M, PANZA F, SOLFRIZZI V, NACMIAS B, SORBI S, BOSSÙ P, PICCARDI P, AROSIO B, ANNONI G, SERIPA D, PILOTTO A, SCARPINI E, GALIMBERTI D, BRICE A, HANNEQUIN D, LICASTRO F, JONES L, HOLMANS PA, JONSSON T, RIEMENSCHNEIDER M, MORGAN K, YOUNKIN SG, OWEN MJ, O'DONOVAN M, AMOUYEL P, WILLIAMS J, Epidemiology, Radiology & Nuclear Medicine, Clinical sciences, Pathologic Biochemistry and Physiology, Hollingworth, P, Harold, D, Sims, R, Gerrish, A, Lambert, J, Carrasquillo, M, Abraham, R, Hamshere, M, Pahwa, J, Moskvina, V, Dowzell, K, Jones, N, Stretton, A, Thomas, C, Richards, A, Ivanov, D, Widdowson, C, Chapman, J, Lovestone, S, Powell, J, Proitsi, P, Lupton, M, Brayne, C, Rubinsztein, D, Gill, M, Lawlor, B, Lynch, A, Brown, K, Passmore, P, Craig, D, Mcguinness, B, Todd, S, Holmes, C, Mann, D, Smith, A, Beaumont, H, Warden, D, Wilcock, G, Love, S, Kehoe, P, Hooper, N, Vardy, E, Hardy, J, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Rüther, E, Schürmann, B, Heun, R, Kölsch, H, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Gallacher, J, Hüll, M, Rujescu, D, Giegling, I, Goate, A, Kauwe, J, Cruchaga, C, Nowotny, P, Morris, J, Mayo, K, Sleegers, K, Bettens, K, Engelborghs, S, De Deyn, P, Van Broeckhoven, C, Livingston, G, Bass, N, Gurling, H, Mcquillin, A, Gwilliam, R, Deloukas, P, Al Chalabi, A, Shaw, C, Tsolaki, M, Singleton, A, Guerreiro, R, Mühleisen, T, Nöthen, M, Moebus, S, Jöckel, K, Klopp, N, Wichmann, H, Pankratz, V, Sando, S, Aasly, J, Barcikowska, M, Wszolek, Z, Dickson, D, Graff Radford, N, Petersen, R, van Duijn, C, Breteler, M, Ikram, M, Destefano, A, Fitzpatrick, A, Lopez, O, Launer, L, Seshadri, S, Berr, C, Campion, D, Epelbaum, J, Dartigues, J, Tzourio, C, Alpérovitch, A, Lathrop, M, Feulner, T, Friedrich, P, Riehle, C, Krawczak, M, Schreiber, S, Mayhaus, M, Nicolhaus, S, Wagenpfeil, S, Steinberg, S, Stefansson, H, Stefansson, K, Snædal, J, Björnsson, S, Jonsson, P, Chouraki, V, Genier Boley, B, Hiltunen, M, Soininen, H, Combarros, O, Zelenika, D, Delepine, M, Bullido, M, Pasquier, F, Mateo, I, Frank Garcia, A, Porcellini, E, Hanon, O, Coto, E, Alvarez, V, Bosco, P, Siciliano, G, Mancuso, M, Panza, F, Solfrizzi, V, Nacmias, B, Sorbi, S, Bossù, P, Piccardi, P, Arosio, B, Annoni, G, Seripa, D, Pilotto, A, Scarpini, E, Galimberti, D, Brice, A, Hannequin, D, Licastro, F, Jones, L, Holmans, P, Jonsson, T, Riemenschneider, M, Morgan, K, Younkin, S, Owen, M, O'Donovan, M, Amouyel, P, and Williams, J

Subjects
Male, ABCA7 protein, human, ATP-Binding Cassette Transporters/genetics, Sialic Acid Binding Ig-like Lectin 3, CD33, SORL1, Medizin, genetics [Alzheimer Disease], Adaptor Proteins, Signal Transducing/genetics, Disease, PICALM, ABCA7, Disease susceptibility, 0302 clinical medicine, genetics [Adaptor Proteins, Signal Transducing], Databases, Genetic, GWAS, GENE-EXPRESSION, Medicine(all), Aged, 80 and over, Genetics, 0303 health sciences, Alzheimer's disease, genetic predisposition, Receptor, EphA1, ALZHEIMER’S DISEASE, Antigens, CD/genetics, genetics [Receptor, EphA1], genetics [Membrane Proteins], Multigene Family, Female, genetics [Antigens, Differentiation, Myelomonocytic], APOE, Antigens, Differentiation, Myelomonocytic, Single-nucleotide polymorphism, Case-control studies, Cytoskeletal Proteins/genetics, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, CD33 protein, human, Alzheimer Disease, Antigens, CD, ddc:570, Humans, Genetic Predisposition to Disease, Membrane Proteins/genetics, CLUSTERIN, Aged, genetics [Cytoskeletal Proteins], Adaptor Proteins, Signal Transducing, 030304 developmental biology, Alzheimer Disease/genetics, Antigens, Differentiation, Myelomonocytic/genetics, Genetic Variation, Membrane Proteins, CD2-associated protein, genetics [Antigens, CD], Cytoskeletal Proteins, MS4A4E protein, human, Case-Control Studies, Susceptibility locus, biology.protein, ATP-Binding Cassette Transporters, Human medicine, genetics [ATP-Binding Cassette Transporters], aged, 80 and over, Receptor, EphA1/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ĝ‰Currency sign 1 × 10 -5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10 -17; including ADGC data, meta P = 5.0 × 10 -21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10 -14; including ADGC data, meta P = 1.2 × 10 -16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10 -4; including ADGC data, meta P = 8.6 × 10 -9), CD33 (GERAD+, P = 2.2 × 10 -4; including ADGC data, meta P = 1.6 × 10 -9) and EPHA1 (GERAD+, P = 3.4 × 10 -4; including ADGC data, meta P = 6.0 × 10 -10). © 2011 Nature America, Inc. All rights reserved.

Published
2011

4. APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Author

Genin, Emmanuelle, Hannequin, Didier, Wallon, David, Sleegers, Kristel, Hiltunen, Mikko, Combarros Pascual, Onofre, Bullido, María Jesús, Brouwers, Nathalie, Bettens, Karolien, Berr, Claudine, Pasquier, Florence, Dubois, Bruno, DeKosky, Steven T., Tognoni, Gloria, Fiévet, Nathalie, Engelborghs, Sebastiaan, Arosio, Beatrice, Coto García, Elicer, Deyn, Peter De, Zompo, Maria Del, Mateo Fernández, José Ignacio, Epelbaum, Jacques, Frank García, Ana, Helisalmi, Seppo, Porcellini, Elisa, Pilotto, Alberto, Forti, Paola, Ferri, Raffaele, Scarpini, Elio, Siciliano, Gabriele, Solfrizzi, Vincenzo, Sorbi, Sandro, Spalletta, Gianfranco, Ravaglia, Giovanni, Valdivieso Amato, Fernando, Vepsäläinen, Saila, Álvarez, Victoria, Bosco, Paolo, Mancuso, Michelangelo, Panza, Francesco, Nacmias, Benedetta, Bossù, Paola, Hanon, Olivier, Piccardi, Paola, Annoni, Giorgio, Seripa, Davide, Galimberti, Daniela, Licastro, Federico, Soininen, Hilkka, Dartigues, Jean-François, Tzourio, Christophe, Van Broeckhoven, Christine, Kamboh, M. Ilyas, Alpérovitch, Annick, Lambert, Jean Charles, Amouyel, Philippe, Campion, Dominique, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Vrije Universiteit Brussel, Universidad de Cantabria, Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, Pasquier F, Dubois B, Tognoni G, Fiévet N, Brouwers N, Bettens K, Arosio B, Coto E, Del Zompo M, Mateo I, Epelbaum J, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Valdivieso F, Vepsäläinen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Hanon O, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Soininen H, Dartigues JF, Kamboh MI, Van Broeckhoven C, Lambert JC, Amouyel P, Campion D., Genin, E, Hannequin, D, Wallon, D, Sleegers, K, Hiltunen, M, Combarros, O, Bullido, M, Engelborghs, S, De Deyn, P, Berr, C, Pasquier, F, Dubois, B, Tognoni, G, Fiévet, N, Brouwers, N, Bettens, K, Arosio, B, Coto, E, Del Zompo, M, Mateo, I, Epelbaum, J, Frank Garcia, A, Helisalmi, S, Porcellini, E, Pilotto, A, Forti, P, Ferri, R, Scarpini, E, Siciliano, G, Solfrizzi, V, Sorbi, S, Spalletta, G, Valdivieso, F, Vepsäläinen, S, Alvarez, V, Bosco, P, Mancuso, M, Panza, F, Nacmias, B, Bossù, P, Hanon, O, Piccardi, P, Annoni, G, Seripa, D, Galimberti, D, Licastro, F, Soininen, H, Dartigues, J, Kamboh, M, Van Broeckhoven, C, Lambert, J, Amouyel, P, and Campion, D

Subjects
Apolipoprotein E, APOE, Alzheimer, genetics, lifetime risks, epidemiology, Male, Heredity, Genotype, Epidemiology, Apolipoprotein E4, Apolipoprotein E3, Physiology, Genome-wide association study, Biology, Article, Cellular and Molecular Neuroscience, Alzheimer Disease, Odds Ratio, Humans, GWAS, Genetic Predisposition to Disease, genetics, Allele, Risk factor, Molecular Biology, ALZHEIMER, Alleles, Aged, Genetics, Medicine(all), Incidence, ALZHEIMER’S DISEASE, Case-control study, Age Factors, Odds ratio, Middle Aged, Major gene, United States, Psychiatry and Mental health, lifetime risks, Case-Control Studies, Female, Human medicine, France, APOE
Abstract

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.Molecular Psychiatry advance online publication, 10 May 2011; doi:10.1038/mp.2011.52.

Published
2011

5. Association of Rare APOE Missense Variants V236E and R251G with Risk of Alzheimer Disease

Author

Le Guen, Yann, Belloy, Michael E, Eger, Sarah J, Mir, Pablo, Moreno, Fermin, Pastor, Pau, Piñol-Ripoll, Gerard, Molina-Porcel, Laura, Pérez-Tur, Jordi, Rodríguez-Rodríguez, Eloy, Royo, Jose Luís, Sánchez-Valle, Raquel, Dichgans, Martin, Rasmussen, Katrine Laura, Rujescu, Dan, Thomassen, Jesper Qvist, Deleuze, Jean-François, He, Zihuai, Napolioni, Valerio, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick Gavin, van Duijn, Cornelia, Grenier-Boley, Benjamin, Tsolaki, Magda, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Rossi, Giacomina, Hiltunen, Mikko, Sims, Rebecca, van der Flier, Wiesje M, Ramirez, Alfredo, Andreassen, Ole A, de Rojas, Itziar, Frikke-Schmidt, Ruth, Williams, Julie, Ruiz, Agustín, Lambert, Jean-Charles, Greicius, Michael D, Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, Groups, EADI, Arosio, Beatrice, Benussi, Luisa, Boland, Anne, Castillo-Morales, Atahualpa, Borroni, Barbara, Caffarra, Paolo, Daian, Delphine, Daniele, Antonio, Debette, Stéphanie, Dufouil, Carole, Düzel, Emrah, Galimberti, Daniela, Giedraitis, Vilmantas, Grimmer, Timo, Jansen, Iris, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Jürgen, Deckert, Kuulasmaa, Teemu, van der Lugt, Aad, Nicolas, Aude, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Moebus, Susanne, Nacmias, Benedetta, Nicolas, Gael, Olaso, Robert, Papenberg, Goran, Parnetti, Lucilla, Bellenguez, Céline, Pasquier, Florence, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Julius, Rainero, Innocenzo, Ramakers, Inez, Riedel-Heller, Steffi, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Dalmasso, Carolina, Schneider, Anja, Seripa, Davide, Soininen, Hilkka, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Tegos, Thomas J, Tremolizzo, Lucio, Verhey, Frans, Küçükali, Fahri, Vyhnalek, Martin, Wiltfang, Jens, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Real, Luis M, Álvarez, Victoria, Bullido, María J, Clarimon, Jordi, García-Alberca, José María, Neurology, Amsterdam Neuroscience - Neurodegeneration, VU University medical center, APH - Personalized Medicine, APH - Methodology, National Institutes of Health (US), National Institute on Aging (US), European Research Council, Pérez-Tur, Jordi [0000-0002-9111-1712], RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychology 2, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), Le Guen, Y, Belloy, M, Grenier-Boley, B, de Rojas, I, Castillo-Morales, A, Jansen, I, Nicolas, A, Bellenguez, C, Dalmasso, C, Küçükali, F, Eger, S, Rasmussen, K, Thomassen, J, Deleuze, J, He, Z, Napolioni, V, Amouyel, P, Jessen, F, Kehoe, P, van Duijn, C, Tsolaki, M, Sánchez-Juan, P, Sleegers, K, Ingelsson, M, Rossi, G, Hiltunen, M, Sims, R, van der Flier, W, Ramirez, A, Andreassen, O, Frikke-Schmidt, R, Williams, J, Ruiz, A, Lambert, J, Greicius, M, Arosio, B, Benussi, L, Boland, A, Borroni, B, Caffarra, P, Daian, D, Daniele, A, Debette, S, Dufouil, C, Düzel, E, Galimberti, D, Giedraitis, V, Grimmer, T, Graff, C, Grünblatt, E, Hanon, O, Hausner, L, Heilmann-Heimbach, S, Holstege, H, Hort, J, Jürgen, D, Kuulasmaa, T, van der Lugt, A, Masullo, C, Mecocci, P, Mehrabian, S, de Mendonça, A, Moebus, S, Nacmias, B, Nicolas, G, Olaso, R, Papenberg, G, Parnetti, L, Pasquier, F, Peters, O, Pijnenburg, Y, Popp, J, Rainero, I, Ramakers, I, Riedel-Heller, S, Scarmeas, N, Scheltens, P, Scherbaum, N, Schneider, A, Seripa, D, Soininen, H, Solfrizzi, V, Spalletta, G, Squassina, A, van Swieten, J, Tegos, T, Tremolizzo, L, Verhey, F, Vyhnalek, M, Wiltfang, J, Boada, M, García-González, P, Puerta, R, Real, L, Álvarez, V, Bullido, M, Clarimon, J, García-Alberca, J, Mir, P, Moreno, F, Pastor, P, Piñol-Ripoll, G, Molina-Porcel, L, Pérez-Tur, J, Rodríguez-Rodríguez, E, Royo, J, Sánchez-Valle, R, Dichgans, M, Rujescu, D, Epidemiology, Radiology & Nuclear Medicine, Graduate School, Medical Psychology, APH - Quality of Care, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), EADB Group, GR@ACE Groupp, DEGESCO Group, DemGene Group, GERAD Group, EADI Group, Repositório da Universidade de Lisboa, and Pérez-Tur, Jordi

Subjects
Male, Genotype, Apolipoprotein E2, epidemiology [Alzheimer Disease], Apolipoprotein E4, Medizin, genetics [Alzheimer Disease], APOLIPOPROTEIN-E, Apolipoproteins E, Settore BIO/13 - Biologia Applicata, Alzheimer Disease, genetics [Apolipoprotein E2], Humans, BEHAVIORAL DEFICITS, ddc:610, Age of Onset, PROGRESS, Alleles, genetics [Apolipoprotein E4], Alzheimer's disease, genetics, APOE, risk factor, A-BETA, Original Investigation, Settore MED/26 - NEUROLOGIA, ALLELE, genetics [Apolipoproteins E], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, INFERENCE, Neurology (clinical), Human medicine
Abstract

34 páginas, 2 tablas, 2 figuras. 2 ficheros con material suplementario. Data used in preparation of this manuscript can be obtained upon application at: - dbGaP (https://www.ncbi.nlm.nih.gov/gap/advanced_search/) - NIAGADS and NIAGADS DSS (https://www.niagads.org/) - LONI (https://ida.loni.usc.edu/) - Synapse (https://adknowledgeportal.synapse.org/) - RADC Rush (https://www.radc.rush.edu/) - NACC (https://naccdata.org/) - UK Biobank (https://biobank.ndph.ox.ac.uk/showcase/), The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly., This work was supported by the National Institute of Health and National Institute of Aging grants AG060747 (MDG), AG066206 (ZH), AG066515 (ZH, MDG), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650, YLG), the Alzheimer’s Association (AARF-20-683984, MEB), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme – Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine, and the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to Alzheimer’s disease). EADB thank the study participants, researchers, and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille, and the staff at CEA-CNRGH for their help with sample preparation and genotyping, and technical assistance. Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in the Supplemental Online Content.

Published
2022

6. The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study

Author

Rudolph E. Tanzi, Dominique Campion, Brit Maren Michaud Schjeide, Diana Zelenika, Lars Lannfelt, Nathalie Fievet, Paola Forti, M. Ilyas Kamboh, Antonio González-Pérez, Hilkka Soininen, Elicer Coto, Steven T. DeKosky, Victoria Alvarez, Carmen Antúnez, Karolien Bettens, Margaret A. Pericak-Vance, Michelangelo Mancuso, Jacques Epelbaum, Kristel Sleegers, Federico Licastro, Giorgio Annoni, Florence Pasquier, Gianfranco Spalletta, Claudine Berr, Florence Richard, Christine Van Broeckhoven, Ana Frank-García, Lars Bertram, Mikko Hiltunen, Daniela Galimberti, Jean-Charles Lambert, Philippe Marambaud, Elisa Porcellini, Maria Del Zompo, Seppo Helisalmi, Nathalie Brouwers, Ignacio Mateo, Corinne Lendon, Gabriele Siciliano, David M. A. Mann, Fernando Valdivieso, Annick Alpérovitch, Jean-François Dartigues, Paola Piccardi, Jesús López-Arrieta, Alberto Pilotto, Mercè Boada, Olivier Hanon, Elio Scarpini, Vilmentas Giedraitis, Didier Hannequin, Benedetta Nacmias, Onofre Combarros, Giovanni Ravaglia, Mark Lathrop, Christophe Tzourio, Paola Bossù, María J. Bullido, Martin Ingelsson, Sandro Sorbi, Paolo Bosco, Philippe Amouyel, Vincenzo Solfrizzi, Sebastiaan Engelborghs, Beatrice Arosio, Francesco Panza, Marc Delepine, Saila Vepsäläinen, Jonathan L. Haines, Peter Paul De Deyn, Gary W. Beecham, Agustín Ruiz, Davide Seripa, Gloria Tognoni, Raffaele Ferri, Lambert JC, Sleegers K, González-Pérez A, Ingelsson M, Beecham GW, Hiltunen M, Combarros O, Bullido MJ, Brouwers N, Bettens K, Berr C, Pasquier F, Richard F, Dekosky ST, Hannequin D, Haines JL, Tognoni G, Fiévet N, Dartigues JF, Tzourio C, Engelborghs S, Arosio B, Coto E, De Deyn P, Del Zompo M, Mateo I, Boada M, Antunez C, Lopez-Arrieta J, Epelbaum J, Schjeide BM, Frank-Garcia A, Giedraitis V, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Delepine M, Zelenika D, Lathrop M, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Ravaglia G, Valdivieso F, Vepsäläinen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Hanon O, Piccardi P, Annoni G, Mann D, Marambaud P, Seripa D, Galimberti D, Tanzi RE, Bertram L, Lendon C, Lannfelt L, Licastro F, Campion D, Pericak-Vance MA, Soininen H, Van Broeckhoven C, Alpérovitch A, Ruiz A, Kamboh MI, Amouyel P., Lambert, J, Sleegers, K, González Pérez, A, Ingelsson, M, Beecham, G, Hiltunen, M, Combarros, O, Bullido, M, Brouwers, N, Bettens, K, Berr, C, Pasquier, F, Richard, F, Dekosky, S, Hannequin, D, Haines, J, Tognoni, G, Fiévet, N, Dartigues, J, Tzourio, C, Engelborghs, S, Arosio, B, Coto, E, De Deyn, P, Del Zompo, M, Mateo, I, Boada, M, Antunez, C, Lopez Arrieta, J, Epelbaum, J, Schjeide, B, Frank Garcia, A, Giedraitis, V, Helisalmi, S, Porcellini, E, Pilotto, A, Forti, P, Ferri, R, Delepine, M, Zelenika, D, Lathrop, M, Scarpini, E, Siciliano, G, Solfrizzi, V, Sorbi, S, Spalletta, G, Ravaglia, G, Valdivieso, F, Vepsäläinen, S, Alvarez, V, Bosco, P, Mancuso, M, Panza, F, Nacmias, B, Bossù, P, Hanon, O, Piccardi, P, Annoni, G, Mann, D, Marambaud, P, Seripa, D, Galimberti, D, Tanzi, R, Bertram, L, Lendon, C, Lannfelt, L, Licastro, F, Campion, D, Pericak Vance, M, Soininen, H, Van Broeckhoven, C, Alpérovitch, A, Ruiz, A, Kamboh, M, Amouyel, P, Clinical sciences, and Neurology

Subjects
Apolipoprotein E, Male, CALHM1, Calcium Channels/genetics, Apolipoprotein E4, Single-nucleotide polymorphism, Biology, Article, polymorphism, Alzheimer Disease/epidemiology, Alzheimer Disease, Genetic variation, Genotype, Humans, Apolipoprotein E4/genetics, Allele, Age of Onset, Polymorphism, Genetic/genetics, Alleles, apolipoprotein E, Aged, Medicine(all), Genetics, Aged, 80 and over, Membrane Glycoproteins, Polymorphism, Genetic, General Neuroscience, Haplotype, Age at onset, General Medicine, Membrane Glycoproteins/genetics, Alzheimer's disease, Middle Aged, Psychiatry and Mental health, Clinical Psychology, Case-Control Studies, Female, Human medicine, Calcium Channels, Geriatrics and Gerontology, Age of onset
Abstract

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the epsilon 4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the epsilon 4 allele of the APOE gene.

Published
2010

7. Tumor necrosis-factor-alpha -308 A/G polymorphism is associated with age at onset of Alzheimer's disease

Author

Carlo Vergani, Antonino Crivello, Federico Licastro, Domenico Lio, Beatrice Arosio, Calogero Caruso, Giuseppina Candore, Giorgio Annoni, Lorenza Galimberti, Giuseppina Colonna-Romano, Giusi Irma Forte, Letizia Scola, Lio D., Annoni G., Licastro F., Forte IG., Scola L., Colonna-RomanoG., Candore G., Galimberti L., Vergani C., Caruso C., Lio, D, Annoni, G, Licastro, F, Crivello, A, Forte, G, Scola, L, Colonna Romano, G, Candore, G, Arosio, B, Galimberti, L, Vergani, C, Caruso, C, LIO D, ANNONI G, LICASTRO F, CRIVELLO A, FORTE GI, SCOLA L, COLONNA-ROMANO G, CANDORE G, AROSIO B, GALIMBERTI L, VERGANI C, and CARUSO C

Subjects
Male, Apolipoprotein E, Aging, Genotype, medicine.medical_treatment, SNP, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, Alzheimer Disease, Risk Factors, cytokine, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, Allele, Aged, Aged, 80 and over, Tumor Necrosis Factor-alpha, alzheimer TNF polymorphisms age of onset, Middle Aged, Alzheimer's disease, medicine.disease, Cytokine, Italy, inflammation, Immunology, Female, Tumor necrosis factor alpha, MED/09 - MEDICINA INTERNA, Age of onset, TNF-alpha, Developmental Biology
Abstract

Pro-inflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their production have been shown to be associated with AD. Tumor necrosis factor (TNF)-α is an inflammatory cytokine involved in the local immune response occurring in the central nervous system of AD patients. Genetic variation could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 222 patients (152 women, 70 men; age range 60–87) and 240 non-demented age-matched healthy controls for TNF-α −308 G/A single nucleotide polymorphism (SNP). No significant differences were observed in genotyped frequencies between patients and controls, whereas carriers of −308A showed a significantly lower mean age at onset than non-carriers of this allele. This difference was more evident taking into account ApolipoproteinE (ApoE) status since the lowest age at onset was observed in patients carrying the −308ATNF+/APOE4+ genotypes. In conclusion, our data support previous suggestions that, at least in Caucasians, the TNF gene is a disease modifier gene in patients in which AD is rising, bringing to light the importance of genetic variation at the pro-inflammatory components in the progression of AD.

Published
2006

8. No association between frailty index and epigenetic clocks in Italian semi-supercentenarians

Author

Daniela Monti, Maria Giulia Bacalini, Matteo Cesari, Daniela Mari, Paolo Garagnani, Claudio Franceschi, Giuseppe Passarino, Beatrice Arosio, Giulia Ogliari, Chiara Pirazzini, Davide Gentilini, Bacalini M.G., Gentilini D., Monti D., Garagnani P., Mari D., Cesari M., Ogliari G., Passarino G., Franceschi C., Pirazzini C., and Arosio B.

Subjects
0301 basic medicine, Gerontology, Epigenomics, Male, Aging, Epigenetic clock, Epigenomic, Biological age, Longevity, Frailty Index, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Centenarians, Medicine, Humans, Epigenetics, Centenarian, Association (psychology), Aged, 80 and over, Frailty index, Frailty, business.industry, Ageing, Epigenetic clocks, 030104 developmental biology, Italy, Cohort, Biomarker (medicine), Female, business, 030217 neurology & neurosurgery, Developmental Biology, Cohort study, Human
Abstract

Centenarians experience successful ageing, although they still present high heterogeneity in their health status. The frailty index is a biomarker of biological age, able to capture such heterogeneity, even at extreme old age. At the same time, other biomarkers (e.g., epigenetic clocks) may be informative the biological age of the individual and potentially describe the ageing status in centenarians. In this article, we explore the relationship between epigenetic clocks and frailty index in a cohort of Italian centenarians. No association was reported, suggesting that these two approaches may describe different aspects of the same ageing process.

Published
2021

9. Whole-genome sequencing analysis of semi-supercentenarians

Author

Evelyn Ferri, Luciano Xumerle, Julien Marquis, Oliviero Olivieri, Gastone Castellani, Cristina Giuliani, Patrizia D'Aquila, Sandro Sorbi, Daniela Mari, Claudia Sala, Maria Giulia Bacalini, Paolo Garagnani, Patrick Descombes, Nicola Martinelli, Beatrice Arosio, Sebastiano Collino, Jérôme Carayol, Frederic Raymond, Benedetta Nacmias, Luca Bertamini, Davide Pettener, Domenico Girelli, Giuseppe Passarino, Vincenzo Iannuzzi, Katarzyna Malgorzata Kwiatkowska, Martina Casati, Donata Luiselli, Claudio Franceschi, Daniela Monti, Massimo Delledonne, Francesco De Rango, Elena Marasco, Armand Valsesia, Chiara Pirazzini, Alberto Ferrarini, Garagnani P., Marquis J., Delledonne M., Pirazzini C., Marasco E., Kwiatkowska K.M., Iannuzzi V., Bacalini M.G., Valsesia A., Carayol J., Raymond F., Ferrarini A., Xumerle L., Collino S., Mari D., Arosio B., Casati M., Ferri E., Monti D., Nacmias B., Sorbi S., Luiselli D., Pettener D., Castellani G., Sala C., Passarino G., De Rango F., D'aquila P., Bertamini L., Martinelli N., Girelli D., Olivieri O., Giuliani C., Descombes P., and Franceschi C.

Subjects
0301 basic medicine, Male, DNA Repair, semi-supercentenarians, medicine.disease_cause, Genome, Germline, genomic, Cohort Studies, 0302 clinical medicine, 80 and over, genetics, Biology (General), media_common, Genetics, Aged, 80 and over, Mutation, geroscience, General Neuroscience, Longevity, General Medicine, sequencing, Middle Aged, 3. Good health, Italy, ageing, clonal hematopoiesis, genomics, human, longevity, Cohort, Medicine, Female, Genetic Background, Research Article, QH301-705.5, DNA repair, Science, media_common.quotation_subject, semi-supercentenarian, Genomics, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Humans, Aged, Whole genome sequencing, General Immunology and Microbiology, Whole Genome Sequencing, Genetics and Genomics, 030104 developmental biology, Clonal Hematopoiesi, genetic, Cohort Studie, 030217 neurology & neurosurgery
Abstract

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.

Published
2021

10. Telomeres Increasingly Develop Aberrant Structures in Aging Humans

Author

Carlo Riccardi, Virginia Boccardi, Giuseppe Paolisso, Roberta Cecchetti, Carmelinda Ruggiero, Luigi Cari, Beatrice Arosio, Utz Herbig, Giuseppe Nocentini, Patrizia Mecocci, Boccardi, V., Cari, L., Nocentini, G., Riccardi, C., Cecchetti, R., Ruggiero, C., Arosio, B., Paolisso, G., Herbig, U., and Mecocci, P.

Subjects
0301 basic medicine, Adult, Male, Aging, THE JOURNAL OF GERONTOLOGY: Biological Sciences, Polymerase Chain Reaction, Donor age, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Medicine, Humans, Telomeres, Human aging, Health, Metaphase, Human aging, In Situ Hybridization, Fluorescence, Telomere Shortening, Aged, Aged, 80 and over, business.industry, Healthy subjects, Middle Aged, Telomere, Healthy Volunteers, Cell biology, Telomeres, 030104 developmental biology, chemistry, Health, Leukocytes, Mononuclear, Chromatid, Female, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, DNA
Abstract

Telomeres progressively shorten with age, and it has been proposed that critically short and dysfunctional telomeres contribute to aging and aging-associated diseases in humans. For many years it was thought that telomere erosion was strictly a consequence of the “end replication problem,” or the inability of replicative polymerases to completely duplicate linear DNA ends. It is becoming increasingly evident, however, that telomere shortening of cultured human cells is also caused because of other replication defects in telomeric repeats, those that cause fragile telomeres and other aberrant telomeric structures that can be detected on metaphase chromosomes. Whether these replication defects contribute to telomere erosion also in human tissues is currently unknown. By analyzing peripheral blood mononuclear cells from a total of 35 healthy subjects ranging in age from 23 to 101 years, we demonstrated that telomeres increasingly display aberrant structures with advancing donor age. Although the percentages of fragile telomeres increased only until adulthood, the percentages of chromosomes displaying sister telomere loss and sister telomere chromatid fusions increased consistently throughout the entire human life span. Our data, therefore, suggest that telomeric replication defects other than the end replication problem contribute to aging-associated telomere erosion in humans.

Published
2018

11. 25 hydroxyvitamin D deficiency and its relationship to autoimmune thyroid disease in the elderly

Author

Paolo Garagnani, Giovanna Muscogiuri, Letizia Maria Fatti, Daniela Mari, Carolina Di Somma, Giovanni Vitale, Maria Celeste Cantone, Silvia Prolo, Beatrice Arosio, Muscogiuri, G., Mari, D., Prolo, S., Fatti, L. M., Cantone, M. C., Garagnani, P., Arosio, B., Di Somma, C., and Vitale, G.

Subjects
Male, Health, Toxicology and Mutagenesis, lcsh:Medicine, Thyrotropin, 030204 cardiovascular system & hematology, Autoantigens, 0302 clinical medicine, Elderly, Iron-Binding Proteins, Vitamin D, Aged, 80 and over, biology, Autoantibodie, Triiodothyronine, Female, Antibody, Human, medicine.medical_specialty, vitamin D, autoimmune thyroid disease, elderly, lifestyle, environment, 030209 endocrinology & metabolism, Autoimmune thyroid disease, Environment, Iodide Peroxidase, Thyroglobulin, Article, vitamin D deficiency, Autoimmune thyroiditis, 03 medical and health sciences, Thyroid-stimulating hormone, Autoantigen, Internal medicine, medicine, Vitamin D and neurology, Humans, Iron-Binding Protein, Autoantibodies, Aged, business.industry, lcsh:R, Public Health, Environmental and Occupational Health, Thyroiditis, Autoimmune, medicine.disease, Lifestyle, Vitamin D Deficiency, Thyroxine, Endocrinology, Free triiodothyronine, biology.protein, business, Hormone
Abstract

Background: Low 25(OH) vitamin D levels have been associated with several autoimmune diseases and recently with autoimmune thyroiditis (AT). The aim of the study was to investigate the association of AT with low 25(OH) vitamin D levels in the elderly. Methods: One hundred sixty-eight elderly subjects (mean age: 81.6 ± 9.4 years) were enrolled. Serum levels of 25(OH) vitamin D, anti-thyroid peroxidase (TPO-Ab), anti-thyroglobulin (TG-Ab) antibodies, free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) were measured. Results: The prevalence of AT was significantly higher in subjects with vitamin D deficiency (25(OH) vitamin D < 20 ng/mL) when compared with subjects with normal 25(OH) vitamin D (25(OH) vitamin D ≥ 20 ng/mL) levels (28% vs. 8%, respectively, p = 0.002). Patients with AT and vitamin D deficiency had a comparable hormonal profile compared to patients with AT and vitamin D sufficiency in terms of TSH (p = 0.39), FT3 (p = 0.30), FT4 (p = 0.31), TG-Ab (0.44) and TPO-Ab (0.35). Interestingly, a significant correlation between 25(OH) vitamin D and TPO-Ab (r = −0.27, p = 0.03) and FT3 (r = 0.35, p = 0.006) has been found in subjects with AT while no correlation was found between 25(OH) vitamin D levels and TG-Ab (r = −0.15, p = 0.25), TSH (r = −0.014, p = 0.09) and FT4 (r = 0.13, p = 0.32). Conclusions: These findings suggest that vitamin D deficiency was significantly associated with AT in the elderly. Therefore, the screening for AT should be suggested in subjects with vitamin D deficiency.

Published
2016

12. Neurocognitive Impairment in HIV-Infected Naïve Patients with Advanced Disease: The Role of Virus and Intrathecal Immune Activation

Author

Andrea Gori, Benedetta Tagliabue, Alessandra Bandera, Alessandro Soria, Giorgio Annoni, Daria Trabattoni, Monica Airoldi, Veronica Rainone, Giuseppe Lapadula, Beatrice Arosio, Mario Clerici, Airoldi, M, Bandera, A, Trabattoni, D, Tagliabue, B, Arosio, B, Soria, A, Rainone, V, Lapadula, G, Annoni, G, Clerici, M, and Gori, A

Subjects
lcsh:Immunologic diseases. Allergy, Adult, Male, Chemokine, AIDS Dementia Complex, Article Subject, Anti-HIV Agents, Immunology, HIV Infections, Viremia, Virus Replication, Virus, Proinflammatory cytokine, Cerebrospinal fluid, Antiretroviral Therapy, Highly Active, Humans, Immunology and Allergy, Medicine, Longitudinal Studies, biology, business.industry, General Medicine, Middle Aged, Viral Load, medicine.disease, CD4 Lymphocyte Count, Cross-Sectional Studies, Viral replication, Clinical Study, HIV-1, biology.protein, Cytokines, RNA, Viral, Female, lcsh:RC581-607, Cognition Disorders, business, Viral load, Neurocognitive, HIV, Neurodegenaration, Inflammatory response
Abstract

Objective.To investigate intrathecal immune activation parameters and HIV-RNA in HIV-associated neurocognitive disorders (HAND) of advanced naïve HIV-infected patients and to evaluate their dynamics before and after initiation of antiretroviral therapy (ART).Methods.Cross-sectional and longitudinal analysis of HIV RNA, proinflammatory cytokines (IL-6, IL-10, INF-γ, TNF-α, TGF-β1, and TGF-β2) and chemokines (MIP-1α, MIP-1β, and MCP-1) in plasma and cerebrospinal fluid (CSF) of HIV-infected patients with CD4 μL.Results.HAND was diagnosed at baseline in 6/12 patients. Baseline CSF HIV-RNA was comparable in patients with or without HAND, whereas CSF concentration of IL-6 and MIP-1β, proinflammatory cytokines, was increased in HAND patients. CSF evaluation at 12 weeks was available in 10/12 cases. ART greatly reduced HIV-RNA in all patients. Nevertheless, IL-6 and MIP-1βremained elevated after 12 weeks of therapy in HAND patients, in whom CSF HIV RNA decay was slower than the plasmatic one as well.Conclusion.Immune activation, as indicated by inflammatory cytokines, but not higher levels of HIV-RNA is observed in advanced naïve HIV-infected patients with HAND. In HAND patients, ART introduction resulted in a less rapid clearance of CSF viremia compared to plasma and no modifications of intratechal immune activation.

Published
2012

13. Leukocyte Telomere Length in Alzheimer's Disease Patients with a Different Rate of Progression

Author

Dorothy Bray, Beatrice Arosio, Evelyn Ferri, Joël Belmin, Daniela Mari, François Piette, Paolo Mazzola, Anne Bornand, Jean Mariani, Martina Casati, Delphine Asselineau, Khadija Benlhassan, Enzo Tedone, Mohamed Doulazmi, Federico Colombo, Cristina Gussago, Giorgio Annoni, Laura Porretti, Paolo Dionigi Rossi, Sylvie Pariel, Développement, Réparation et Vieillissement Cérébral (DRVC), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Tedone, E, Arosio, B, Colombo, F, Ferri, E, Asselineau, D, Piette, F, Gussago, C, Belmin, J, Pariel, S, Benlhassan, K, Casati, M, Bornand, A, Rossi, P, Mazzola, P, Annoni, G, Doulazmi, M, Mariani, J, Porretti, L, Bray, D, Mari, D, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Lipopolysaccharides, Male, [SDV]Life Sciences [q-bio], Alzheimer’s disease, disease progression, interleukin-10, peripheral blood mononuclear cells, telomere, Inflammation, Enzyme-Linked Immunosorbent Assay, Biology, Peripheral blood mononuclear cell, Flow cytometry, disease progression, Apolipoproteins E, Alzheimer Disease, medicine, Humans, RNA, Messenger, Cells, Cultured, Aged, Aged, 80 and over, Analysis of Variance, Mini–Mental State Examination, Amyloid beta-Peptides, medicine.diagnostic_test, General Neuroscience, Case-control study, General Medicine, Alzheimer's disease, Telomere, medicine.disease, peripheral blood mononuclear cells, Flow Cytometry, 3. Good health, Interleukin-10, Psychiatry and Mental health, Clinical Psychology, Interleukin 10, Case-Control Studies, Immunology, Leukocytes, Mononuclear, Female, Analysis of variance, Geriatrics and Gerontology, medicine.symptom, Mental Status Schedule
Abstract

International audience; Background: Age and short leukocyte telomeres have been associated with a higher risk of Alzheimer's disease (AD). Inflammation is involved in AD and it is suggested that anti-inflammatory interleukin-10 (IL-10) may partly antagonize these processes. Objective: The aim is to correlate telomere length (TL) in peripheral blood mononuclear cells (PBMC) from patients with AD to disease progression rate. Moreover, we evaluated whether TL was associated with IL-10 production by unstimulated or amyloid-beta (A beta)-stimulated PBMC. Methods: We enrolled 31 late-onset AD and 20 age-matched healthy elderly (HE). After a two-year follow-up period, patients were retrospectively evaluated as slow-progressing (ADS) (Mini Mental State Examination (MMSE) decline over the two years of follow-up = 5 points). TL was measured by flow cytometry and in vitro IL-10 production by enzyme-linked immunosorbent assay. Results: TL (mean +/- SD) for HE, ADS, and ADFwas 2.3 +/- 0.1, 2.0 +/- 0.1, and 2.5 +/- 0.1 Kb, respectively. ADS showed a shorter TL compared to HE (p = 0.034) and to ADF (p = 0.005). MMSE decline correlated with TL in AD (R-2 = 0.284; p = 0.008). We found a significant difference in IL-10 production between unstimulated and A beta-stimulated PBMC from ADS (40.7 +/- 13.7 versus 59.0 +/- 27.0; p = 0.004) but not from ADF (39.7 +/- 14.4 versus 42.2 +/- 22.4). HE showed a trend toward significance (47.1 +/- 25.4 versus 55.3 +/- 27.9; p = 0.10). Conclusion: PBMC from ADF may be characterized by an impaired response induced by A beta and by a reduced proliferative response responsible for the longer telomeres. TL might be a contributing factor in predicting the rate of AD progression.

Published
2015

14. Interleukin-10 Production in Response to Amyloid-beta Differs between Slow and Fast Decliners in Patients with Alzheimer's Disease

Author

Evelyn Ferri, Joël Belmin, Cristina Gussago, Khadija Benlhassan, Jean Mariani, Jean-Louis Beaudeux, Beatrice Arosio, Dorothy Bray, Giorgio Annoni, François Piette, Daniela Mari, Enzo Tedone, Paolo Mazzola, Martina Casati, Anne Bornand, Delphine Asselineau, Sylvie Pariel, Mohamed Doulazmi, Développement, Réparation et Vieillissement Cérébral (DRVC), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Asselineau, D, Benlhassan, K, Arosio, B, Mari, D, Ferri, E, Casati, M, Gussago, C, Tedone, E, Annoni, G, Mazzola, P, Piette, F, Belmin, J, Pariel, S, Bornand, A, Beaudeux, J, Doulazmi, M, Mariani, J, and Bray, D

Subjects
Male, Amyloid, Genotype, [SDV]Life Sciences [q-bio], interleukin-10, Alpha interferon, Enzyme-Linked Immunosorbent Assay, Alzheimer’s disease, disease progression, IFN-γ, interleukin-6, interleukin-10, peripheral blood mononuclear cells, single nucleotide polymorphisms, Peripheral blood mononuclear cell, Statistics, Nonparametric, IFN-gamma, 03 medical and health sciences, single nucleotide polymorphisms, 0302 clinical medicine, disease progression, Interferon, Alzheimer Disease, medicine, Humans, Interleukin 6, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, Amyloid beta-Peptides, biology, General Neuroscience, interleukin-6, Interferon-alpha, General Medicine, Middle Aged, Alzheimer's disease, medicine.disease, peripheral blood mononuclear cells, 3. Good health, Psychiatry and Mental health, Clinical Psychology, Interleukin 10, Case-Control Studies, Immunology, biology.protein, Leukocytes, Mononuclear, Tumor necrosis factor alpha, Female, Geriatrics and Gerontology, Mental Status Schedule, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; We investigated IL-10 and IL-6 production in amyloid-beta (A beta) stimulated peripheral blood mononuclear cells (PBMCs) in twenty Alzheimer's disease (AD) patients with slow progression, eleven with fast progression, and twenty age-matched controls. Promoter polymorphisms in IL-10 (position -592, -819, -1082), IL-6 (-174), transforming growth factor-beta 1 (TGF-beta 1) (-10, -25), interferon-beta (IFN-gamma) (-874), and tumor necrosis factor-alpha (TNF-alpha) (-308) genes were analyzed. IL-10 production after A beta stimulation was high in PBMCs from slow decliners and almost completely abrogated in fast decliners. Association between AA IFN-gamma low-producing genotype and fast progression was demonstrated. Investigations in a larger sample will clarify these findings.

Published
2015

15. Protein signature in cerebrospinal fluid and serum of Alzheimer’s disease patients: The case of apolipoprotein A-1 proteoforms

Author

Beatrice Arosio, Cecilia Gelfi, Daniele Capitanio, Enrica Torretta, Chiara Fania, Daniela Mari, Evelyn Ferri, Cristina Gussago, Fania, C, Arosio, B, Capitanio, D, Torretta, E, Gussago, C, Ferri, E, Mari, D, and Gelfi, C

Subjects
Male, 0301 basic medicine, Serum Proteins, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Apolipoprotein B, Physiology, lcsh:Medicine, Nervous System, Biochemistry, 0302 clinical medicine, Cerebrospinal fluid, Medicine and Health Sciences, Electrophoresis, Gel, Two-Dimensional, Phosphorylation, lcsh:Science, Cerebrospinal Fluid, Aged, 80 and over, Principal Component Analysis, Multidisciplinary, biology, Neurodegenerative Diseases, Blood proteins, Body Fluids, Neurology, Area Under Curve, Proteome, Female, Anatomy, CSF, Apolipoprotein AI, MALDI-profiling, proteomics, Alzheimer's disease, iNPH, Alzheimer's disease, Hydrocephalus, Research Article, Gene isoform, Lipoproteins, Enzyme-Linked Immunosorbent Assay, tau Proteins, Statistics, Nonparametric, 03 medical and health sciences, Alzheimer Disease, Diagnostic Medicine, Mental Health and Psychiatry, medicine, Humans, Dementia, Aged, Amyloid beta-Peptides, Apolipoprotein A-I, lcsh:R, Case-control study, Biology and Life Sciences, Proteins, medicine.disease, Peptide Fragments, Apolipoproteins, 030104 developmental biology, ROC Curve, Case-Control Studies, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Immunology, biology.protein, lcsh:Q, Peptides, Biomarkers, 030217 neurology & neurosurgery
Abstract

In the diagnosis of Alzheimer’s disease (AD) total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and the 42 amino acid isoform of alpha β-amyloid (Aβ) are well established surrogate CSF markers. However, there is a constant need for new diagnostic markers to identify the disease at a very early stage. The identification of new molecules for AD diagnosis and monitoring in CSF is hampered by several “confounding” factors including intra- and inter-individual, pre-analytical and analytical variabilities. In an attempt to partially overcome patient’s variability and to determine new molecules significantly dysregulated in CSF, we assessed the proteome profile of low molecular weight protein species in CSF and serum of the same patients. CSFs and sera from 36 ADs, 32 iNPHs (idiopathic normal pressure hydrocephalus) and 12 controls were compared by MALDI profiling (non-parametric statistics, CV0.750). After protein identification by mass spectrometry, the proteoform composition was assessed by 2-D DIGE/MS. Results indicated that CSF of iNPH can be used as control. Serum and CSF of AD patients shows a specific protein profile compared to iNPH samples. A variation (p

Published
2017

16. Selective DNA Methylation of BDNF Promoter in Bipolar Disorder: Differences Among Patients with BDI and BDII

Author

Beatrice Arosio, Daniela Mari, L. Lietti, Sanzio Candeletti, Chiara Fenoglio, Bernardo Dell'Osso, Andrea Di Francesco, Luigi Bergamaschini, Beatrice Benatti, Manuela Di Benedetto, Claudio D'Addario, Maria Carlotta Palazzo, Elio Scarpini, A. Carlo Altamura, Francesca Cortini, Nereo Bresolin, Mauro Maccarrone, E. Cattaneo, Patrizia Romualdi, Daniela Galimberti, D'Addario C, Dell'Osso B, Palazzo MC, Benatti B, Lietti L, Cattaneo E, Galimberti D, Fenoglio C, Cortini F, Scarpini E, Arosio B, Di Francesco A, Di Benedetto M, Romualdi P, Candeletti S, Mari D, Bergamaschini L, Bresolin N, Maccarrone M, and Altamura AC.

Subjects
Adult, Male, Candidate gene, medicine.medical_specialty, Genotype, Down-Regulation, Internal medicine, Gene expression, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, Bipolar disorder, Promoter Regions, Genetic, Aged, EPIGENETIC, Pharmacology, Genetics, Brain-derived neurotrophic factor, Brain-Derived Neurotrophic Factor, METHYLATION, HUMAN, BIPOLAR DISORDER, Promoter, DNA Methylation, Middle Aged, medicine.disease, Psychiatry and Mental health, BDNF, Endocrinology, DNA methylation, Female, Original Article, Psychology, Antipsychotic Agents
Abstract

The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I=49, BD II=45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; P

Published
2012

17. NALP1/NLRP1 genetic variants are associated with Alzheimer disease

Author

Eulalia Catamo, Sergio Crovella, Daniela Mari, Alessandra Pontillo, Beatrice Arosio, Pontillo, Alessandra, Catamo, Eulalia, Arosio, B, Mari, D, and Crovella, Sergio

Subjects
Male, Genotype, Single-nucleotide polymorphism, NLR Proteins, NLRP1 Gene, Biology, association study, NALP1 inflammosome, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Pathogenesis, Polymorphism (computer science), Alzheimer Disease, medicine, Dementia, Humans, Genetic Predisposition to Disease, Allele, Alzheimer disease (AD), Adaptor Proteins, Signal Transducing, Aged, 80 and over, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Italy, Immunology, Female, Geriatrics and Gerontology, Alzheimer's disease, Apoptosis Regulatory Proteins, Gerontology
Abstract

Alzheimer disease (AD) is a complex neurodegenerative disease. Genetic and molecular studies have confirmed that in the human brain, amyloid-β fibrils can induce, through the activation of NALP1 inflammosome, inflammatory and apoptotic responses involved in the pathogenesis of AD. Considering that AD pathogenesis is multifactorial, we hypothesized that NALP1/NLRP1 could be a susceptibility gene involved in the devolvement of the disease. The possible association between 9 selected polymorphisms in the NALP1/NLRP1 gene and AD was evaluated by comparing their frequency distribution in an Italian cohort of AD patients (AD, n = 276) and in a group of Italian sex-matched and age-matched healthy controls without dementia (HC, n = 266). Our study, evidences the association of 4 nonsynonymous polymorphisms in the NLRP1 gene (rs2137722, rs34733791, rs11657747, rs11651595) with AD. The major alleles of all 4 single nucleotide polymorphisms and the corresponding homozygote genotypes were more frequent in AD patients than in healthy controls, suggesting an association of these variants in the predisposition versus the development of the disease. These findings seem to support the previously reported role of NALP1 in neuronal damage, and provide evidence of an association between single nucleotide variations in the NLRP1 gene and AD.

Published
2011

18. The -308 (G/A) single nucleotide polymorphism in the TNF-alpha gene and the risk of major depression in the elderly

Author

Chiara Viazzoli, Roberto Confalonieri, Giorgio Annoni, Carlo Vergani, Beatrice Arosio, Anna Paola Cerri, Cerri, A, Arosio, B, Viazzoli, C, Confalonieri, R, Vergani, C, and Annoni, G

Subjects
Oncology, Male, medicine.medical_specialty, Genotype, Single-nucleotide polymorphism, Disease, Polymorphism, Single Nucleotide, Genetic determinism, Pathogenesis, Gene Frequency, Internal medicine, Major depression, Medicine, SNP, Humans, Allele, Aged, Inflammation, Aged, 80 and over, Psychiatric Status Rating Scales, Depressive Disorder, Major, business.industry, Tumor Necrosis Factor-alpha, Gene polymorphism, Psychiatry and Mental health, Italy, TNF-α, Immunology, Geriatric Depression Scale, Female, Geriatrics and Gerontology, business
Abstract

Objective The immune system (IS) plays a key role in the mechanisms underlying major depression (MD) and pro-inflammatory cytokines seem to be particularly involved in the pathogenesis of the disease. There is growing evidence of a relationship between commonly studied single nucleotide polymorphisms (SNPs) in cytokine genes and an increased risk of MD. The aim of our study was to investigate the association between the −308(G/A) SNP in the tumour necrosis factor-α (TNF-α) gene and late-life MD in elderly people without dementia. Methods Blood samples were obtained from 50 subjects enrolled at the Geriatric Department of the San Gerardo Hospital in Monza, Italy, after screening with the geriatric depression scale (GDS ≥ 15) and mini-mental state evaluation (MMSE ≥ 24). The −308 (G/A) SNP was genotyped by SSP-PCR amplification. Two hundred and forty age-matched healthy volunteers were taken as the control group. Results Genotype and allele distributions in patients with MD were significantly different from those of the controls. In subjects affected by MD we found a higher percentage of the GG genotype (84 vs. 68,3%; p = 0.007) and thus of the G allele (92 vs. 81,9%; p = 0.05). The GG genotype was associated with a greater risk of developing the disease (OR 2.433, CI 1.09–5.43). Conclusions Our study suggests that the −308 (G/A) polymorphism in the TNF-α gene could play a role in determining susceptibility to MD. An activation of the TNF-α system could contribute to the development of MD in the elderly. Copyright © 2009 John Wiley & Sons, Ltd.

Published
2009

19. PIN-1 promoter polymorphisms in mild cognitive impairment and susceptibility to Alzheimer's disease: a preliminary report

Author

Sergio Crovella, Daria Trabattoni, Mariella Zanetti, Carlo Vergani, Michele Milanese, Ludovica Segat, Carmen Calabresi, Beatrice Arosio, Giorgio Annoni, Lorenza Galimberti, Arosio, B, Segat, L, Milanese, M, Galimberti, L, Calabresi, C, Zanetti, M, Trabattoni, D, Annoni, G, Crovella, Sergio, Vergani, C., Crovella, S, and Vergani, C

Subjects
Male, Aging, medicine.medical_specialty, Pathology, Genotype, PIN-1, Single-nucleotide polymorphism, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Alzheimer Disease, Internal medicine, mental disorders, medicine, SNP, genetic polymorphism, Humans, Genetic Predisposition to Disease, Allele, Promoter Regions, Genetic, Gene, Allele frequency, Aged, Aged, 80 and over, business.industry, Neurodegeneration, Promoter, Alzheimer's disease, Peptidylprolyl Isomerase, medicine.disease, MCI, nervous system diseases, NIMA-Interacting Peptidylprolyl Isomerase, Endocrinology, Female, Geriatrics and Gerontology, MED/09 - MEDICINA INTERNA, business, Cognition Disorders, human activities
Abstract

Background and aims: Peptydil prolyl cis-trans isomerase (PIN-1), which specifically regulates the conformational changes following phosphorylation of several proteins, targets the inactive hyper-phosphorylated tau on the Thr231-Pro motif and directly restores its biological function. Interestingly, PIN-1 is oxiclatively inhibited not only in Alzheimer's disease brain but also in the hippocampi of mild cognitive impairment (MCI) subjects. The PIN-1 gene is characterized by two single nucleotide polymorphisms (SNPs) in the promoter region which are associated with the risk of Alzheimer's disease. The aim of this study was to analyse the genotype and allele distributions of these PIN-1 SNPs in MCI subjects diagnosed respectively as amnestic MCI (a-MCI) and multiple impaired cognitive domains (mcd-MCI) on the basis of cognitive features. Methods: -667 T/C and -842 C/G SNPs were genotyped by polymerase chain reaction (PCR) amplification and direct sequencing in 43 MCI subjects, with the intention of comparing -667 and -842 SNP frequencies with those previously described in I I I Alzheimer's disease patients (AD) and 73 healthy controls (HC). Results: The allele frequencies of the -842 C/G SNP in a-MCI subjects are similar to those of AD subjects, while those of mcd-MCI are comparable to HC (G allele 83% in both a-MCI and AD; 95% and 94% in mcd-MCI and HC, respectively). A similar trend is also observed in -842 C/G genotypes. Conclusions: Since a-MCI is thought to be the preclinical form of AD, the similar genotype distribution of -842 SNP in AD and a-MCI, but not in mcd-MCI, suggests that it is potentially involved in the conversion of a-MCI to AD. In conclusion, these findings support the theory that polymorphisms of the PIN-1 gene can affect neurodegeneration and its clinical progression

Published
2007

20. PIN1 promoter polymorphisms are associated with Alzheimer's disease

Author

Giorgio Annoni, Ludovica Segat, Daria Trabattoni, Sergio Crovella, Carlo Vergani, Mario Clerici, Alessandra Pontillo, Beatrice Arosio, Segat, Ludovica, Pontillo, Alessandra, Annoni, G, Trabattoni, D, Vergani, C, Clerici, M, Arosio, B, Crovella, Sergio, Segat, L, Pontillo, A, Clerici, A, and Crovella, S

Subjects
Male, Aging, Linkage disequilibrium, Heterozygote, Genotype, DNA Mutational Analysis, Single-nucleotide polymorphism, genotype-phenotype correlation, Biology, neurofibrillary degeneration, Polymorphism, Single Nucleotide, Risk Assessment, Promoter Regions, PIN1, Genetic, Polymorphism (computer science), Alzheimer Disease, Risk Factors, genetic polymorphism, Humans, Single Nucleotide, Promoter Region, Genetic Predisposition to Disease, Aged, Alzheimer Disease, Biological Markers, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, Genetic Testing, Genotype, Heterozygote, Humans, Incidence, Italy, Male, Peptidylprolyl Isomerase, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Risk Assessment, Risk Factors, Genetic Testing, Allele, Polymorphism, Promoter Regions, Genetic, Gene, Aged, Peptidylprolyl isomerase, Genetics, General Neuroscience, Incidence, Haplotype, Single Nucleotide, Alzheimer's disease, Peptidylprolyl Isomerase, NIMA-Interacting Peptidylprolyl Isomerase, Italy, Biological Markers, Female, Neurology (clinical), MED/09 - MEDICINA INTERNA, Geriatrics and Gerontology, Biomarkers, Developmental Biology
Abstract

In our study, we analyzed the coding and promoter regions of the PIN I gene in a group of I I I Alzheimer's disease (AD) patients looking for a possible genotype-phenotype correlation. The presence of SNPs - which could affect and modify the clinical phenotype of AD patients was also investigated. We identified two single nucleotide polymorphisms (SNPs) at positions -842 (G -> C) and -667 (C -> T) in the promoter region of the PIN1 gene. Our results evidenced a significantly higher percentage of -842C allele carriers in AD subjects with respect to healthy controls. We found that this allele significantly raised the risk of developing AD (OR 3.044, CI 1.42-6.52). The -842 and -667 SNPs were in linkage disequilibriurn and combined to form haplotypes. The CC haplotype conferred a higher risk of developing AD (OR 2.95, confidence interval 1.31-6.82). Finally, protein expression analyses revealed that subjects carrying the -842 CC genotype or the CC haplotype showed reduced levels of the PIN1 protein in peripheral mononuclear cells. (c) 2005 Elsevier Inc. All rights reserved.

Published
2005

21. Interleukin-10 and interleukin-6 gene polymorphisms as risk factors for Alzheimer's disease

Author

Paolo Bucciarelli, Francesca Fasano, Giorgio Annoni, Daria Trabattoni, Carlo Lorenzo Cazzullo, Beatrice Arosio, Mario Clerici, Lorenza Galimberti, Carlo Vergani, Carmen Calabresi, Arosio, B, Trabattoni, D, Galimberti, L, Bucciarelli, P, Fasano, F, Calabresi, C, Cazzullo, C, Vergani, C, Annoni, G, and Clerici, M

Subjects
Apolipoprotein E, Male, Aging, Genotype, medicine.medical_treatment, DNA Mutational Analysis, T lymphocytes, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Proinflammatory cytokine, Apolipoproteins E, Gene Frequency, single nucleotide polymorphism, Alzheimer Disease, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Interleukin 6, Promoter Regions, Genetic, apolipoprotein E, Aged, Aged, 80 and over, Amyloid beta-Peptides, Polymorphism, Genetic, Interleukin-6, General Neuroscience, Interleukin, Brain, Alzheimer's disease, Interleukin-10, Interleukin 10, Cytokine, Italy, inflammation, Immunology, biology.protein, Encephalitis, Female, Neurology (clinical), Geriatrics and Gerontology, MED/09 - MEDICINA INTERNA, Developmental Biology
Abstract

In the pathogenesis of Alzheimer disease (AD), it has been proposed that the anti-inflammatory interleukins such as IL-10 regulate beta-amyloid-induced microglial inflammatory responses inhibiting the proinflammatory cytokine IL-6. Since the promoters of the IL-10 and IL-6 genes show single nucleotide polymorphisms (SNPs) (IL-10: -1082 G --> A; IL-6: -174 G --> C), we investigated these SNPs and cytokine production by peripheral blood mononuclear cells in 65 AD patients and 65 controls (HC). In AD there was a significant increase of the -1082A IL-10 allele (P = 0.009) and a decrease of -1082GG genotype (P = 0.019). The frequency of the GG IL-6 genotype in AD was lower and the C allele significantly higher (P < 0.005). The co-occurrence of IL-10 A and IL-6 C alleles significantly raised the odds ratio (OR 11.2, confidence interval: CI 1.3-97.3; P < 0.05) independently of apolipoprotein E4 (adjusted OR 10.3, CI 1-108; P < 0.05). Only amyloid-stimulated IL-10 production differed between the groups (P = 0.023). These results raise questions regarding the inflammatory theory in AD, pointing to a pivotal role of IL-10 and IL-6 and a selective alteration in this network. (C) 2003 Elsevier Inc. All rights reserved.

Published
2003

22. Heterogeneity of Thyroid Function and Impact of Peripheral Thyroxine Deiodination in Centenarians and Semi-Supercentenarians: Association With Functional Status and Mortality

Author

Francesco De Rango, Patrizia D'Aquila, Daniela Mari, Giovanni Vitale, Renato Pasquali, Rita Ostan, Beatrice Arosio, Laura Bucci, Claudio Franceschi, Flaminia Fanelli, Daniela Monti, Davide Gentilini, Stefano Mariotti, Giuseppe Passarino, Evelyn Ferri, and Ostan R, Monti D, Mari D, Arosio B, Gentilini D, Ferri E, Passarino G, De Rango F, D'Aquila P, Mariotti S, Pasquali R, Fanelli F, Bucci L, Franceschi C, Vitale G.

Subjects
0301 basic medicine, Male, endocrine system, Aging, endocrine system diseases, Offspring, Health Status, Population, Longevity, Physiology, Thyrotropin, Thyroid function tests, Human aging, Longevity, Mortality, Health, Thyroid hormones, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Cognition, medicine, Humans, Insulin, Mortality, 10. No inequality, education, Aged, Aged, 80 and over, education.field_of_study, medicine.diagnostic_test, Hand Strength, business.industry, Depression, Thyroid, Cholesterol, HDL, Blood Proteins, Middle Aged, 3. Good health, Peripheral, Thyroxine, 030104 developmental biology, medicine.anatomical_structure, Triiodothyronine, Female, Geriatrics and Gerontology, Centenarian, Thyroid function, Insulin Resistance, business, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, Hormone
Abstract

Thyroid hormones (FT3, FT4) and thyroid-stimulating hormone (TSH) were evaluated in a population of 672 well-characterized Italian subjects (age range: 52-113 years), including an unprecedented number of centenarians, semi-supercentenarians, as well as centenarian's offspring and age-matched elderly (CENT, 105+, CENTOFF, and CTRL, respectively). The results show that FT3 level and FT3/FT4 ratio decrease while FT4 and TSH increase in an age-dependent manner. In CENT/105+, higher FT4 level, and lower FT3/FT4 ratio are associated with an impaired functional status and an increased mortality. A cluster analysis identified three clusters of CENT/105+ based on their FT3, FT4, and TSH levels. Cluster 3, characterized by lower FT3 and TSH and higher FT4, shows the worst health status and the shortest survival. Thus, the age-related changes of thyroid hormones extend to the most advanced age, and CENT/105+ are highly heterogeneous regarding thyroid function. This heterogeneity is related to different health, functional and cognitive status, as well as with survival/mortality in CENT/105+. Finally, we investigated a remarkable number of CENT/105+ showing a thyroid profile suggestive of non-thyroidal illness syndrome (NTIS) (excluded from the previous analysis). NTIS CENT/105+ are characterized by a worse functional and cognitive status and an increased mortality with respect to CENT/105+ without NTIS.

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