Citations 4
Evaluating MAPT p.A152T as a risk factor for the 3R tauopathy Pick’s disease
Tamvaka, Nicole , Scotton, William J. , Lilley, Meredith T. , Shoai, Maryam , Gavrielatos, Marios , HECKMAN, M, Roemer, Shanu F, Baker, Matthew C, Rademakers, Rosa, Hardy, John , Cook, Casey , Lashley, Tammaryn , Jaunmuktane, Zane, Mok, Kin, Revesz, Tamas, Christopher, Elizabeth, DeTure, Michael, Koga, Shunsuke, Graff-Radford, Neill R, Boeve, Bradley F, Josephs, Keith A. , Petersen, Ronald C, Whitwell, Jennifer , Duara, Ranjan, Lyons, Kelly E, Miller, Bruce, Schlereth, Athena, Spina, Salvatore, Irwin, David J, Wolk, David A, Suh, EunRan, Deerlin, Vivianna M Van, Lee, Edward B, Frosch, Matthew P. , Molina-Porcel, Laura, Aldecoa, Iban, Balasa, Mircea, Borrego-Ecija, Sergi, Sanchez-Valle, Raquel, Gascón‐Bayarri, Jordi , Sanz-Cartagena, Pilar , Huélamo, Rosa Maria de Eugenio, Gefen, Tamar, Castellani, Rudolph J, Rogalskı, Emily , Weıntraub, Sandra , Bieniek, Kevin F, Zhu, Xiongwei, Redding-Ochoa, Javier, Troncoso, Juan C. , Ghetti, Bernardino, Newell, Kathy L. , Jacobsen, Max, Roncaroli, Federico, Jones, Matthew, Richardson, Anna, Snowden, Julie, Allinson, Kieren, Beach, Thomas G, Teich, Andrew F, Flowers, Xena, Heaps, Allison C, Leskinen, Sandra , Keith, Julia , Masellis, Mario, King, Andrew, Sarraj, Safa-Al, Hodges, John R. , Gearing, Marla , Roeber, Sigrun, Attems, Johannes, Boluda, Susana , Seilhean, Danielle, Ber, Isabelle Le, Turbant-Leclere, Sabrina, Mackenzie, Ian R. , Sieben, Anne, Cras, Patrick , Vil, Bart B De, Deyn, P P De, Keene, C Dirk, Latimer, Caitlin S. , Schantz, Aimee, Bird, Thomas D, Haroutunian, Vahram, Purohit, Dushyant, Rissman, Robert, Cykowski, Matthew D. , Wang, Shih-Hsiu J, Ervin, John F. , Nennesmo, Inger , Nagra, Rashed M. , Riehl, James, Kovacs, Gabor G, Neumann, Manuela, Ang, Lee-Cyn, Cunha, Cristina, Blauwendraat, Cornelis , Nalls, Mike A., Singleton, Andrew B, Perrin, Richard J. , Chaffee, Anne M, Scotton, William , Murray, Melissa E , Dickson, Dennis W , Ross, Owen A , Hardy, John , Shoai, Maryam , Lashley, Tammaryn , Heckman, Michael G. , Soto‐Beasley, Alexandra I. , Roemer, Shanu F. , Rademakers, Rosa , Murray, Melissa E. , Dickson, Dennis W. , Rohrer, Jonathan D. , Ross, Owen A. , Valentino, Rebecca R. , Macpherson, Hannah L. , Warner, Thomas T. , Jaunmuktane, Zane , Martínez-Carrasco, Alejandro , Revesz, Tamas, DeTure, Michael , Koga, Shunsuke , Graff‐Radford, Neill R. , Boeve, Bradley F. , Petersen, Ronald C. , Duara, Ranjan, Pahwa, Rajesh , Grinberg, Lea T. , Seeley, William W. , Miller, Bruce L , Spina, Salvatore , Suh, EunRan , Deerlin, Vivianna M. Van , Connors, Theresa R. , Oakley, Derek H. , Molina‐Porcel, Laura , Aldecoa, Ibán , Balasa, Mircea , Borrego‐Écija, Sergi , Sánchez‐Valle, Raquel , Piñol‐Ripoll, Gerard , Gelpí, Ellen , Gefen, Tamar , Castellani, Rudolph J. , Flanagan, Margaret E. , Schneider, Julie A. , Bieniek, Kevin F. , Redding‐Ochoa, Javier , Chang, Koping , Prokop, Stefan , Ghetti, Bernardino, Robinson, Andrew , Roncaroli, Federico , Kobylecki, Christopher , Richardson, Anna, Rowe, James B. , Quaegebeur, Annelies , Allinson, Kieren Simon James, Beach, Thomas G. , Serrano, Geidy E. , Teich, Andrew F. , Black, Sandra E. , Masellis, Mario, Troakes, Claire , Halliday, Glenda M. , Kril, Jillian J. , Kwok, John B. , Piguet, Olivier , Morris, Christopher M. , Thomas, Alan , White, Charles L. , Evers, Bret M. , Mechawar, Naguib , Seilhean, Danielle , Ber, Isabelle Le , Leclère-Turbant, Sabrina, Vil, Bart De , Deyn, Peter Paul De , Keene, C Dirk, Haroutunian, Vahram , Purohit, Dushyant P. , Walker, Jamie M. , Rissman, Robert A. , McLean, Catriona , Graff, Caroline , Riehl, James R. , Giaccone, Giorgio , Neumann, Manuela , Finger, Elizabeth C. , Carvalho, Agostinho , Morris, Huw R. , Singleton, Andrew B, Vitale, Dan , Chaffee, Ann, Wszołek, Zbigniew K.
Brain Communications | July 9, 2026 | Volume: 8 | Issue: 4 | Pages: No page available
Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.
Slow-wave sleep across the Alzheimer's disease continuum: cognitive trajectories and sex differences
Fernández‐Arcos, Ana, Mayà, Gerard, Hernández, Laura, Knezevic, Iva, Soldevila-Domenech, Natalia, Zetterberg, Henrik, Blennow, Kaj, Grinberg, Lea T, Muñoz-Lopetegi, Amaia, Martín‐Sobrino, Isabel, Arqueros, Aurora, GAIG, CARLES, Lladó, Albert, Val-Guardiola, Andrea, Iranzo, Álex, Study, Alfa, Tort‐Colet, Núria , Mayà, Gerard , Stankeviciute, Laura S , Minguillón, Carolina , Soldevila‐Domenech, Natalia , Sánchez‐Benavides, Gonzalo , Kassinopoulos, Michalis , Suárez‐Calvet, Marc , Holst, Sebastian C. , Zetterberg, Henrik , Blennow, Kaj , Grinberg, Lea T. , Muñoz‐Lopetegi, Amaia , Martín-Sobrino, Isabel , Montini, Angelica , Gaig, Carles , Lladó, Albert , Sánchez‐Valle, Raquel , Piñol‐Ripoll, Gerard , Val‐Guardiola, Andrea, Iranzo, Álex , Gispert, Juan Domingo , Molinuevo, José Luís , Falgàs, Neus , Grau‐Rivera, Oriol
No container title available | June 18, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Background Sleep disturbances are common in Alzheimer's disease and have been reported in its preclinical stage. A detailed characterization of sleep disruption across the Alzheimer’s disease continuum is required to clarify its role as a potential therapeutic target and to evaluate the utility of sleep-related biomarkers. Methods Sleep architecture was characterized through detailed spectral and temporal analysis of the slow-wave activity using polysomnography across the Alzheimer’s disease continuum . Participants included: cognitively unimpaired individuals without abnormal Alzheimer’s disease biomarkers (n = 30), cognitively unimpaired individuals with abnormal Alzheimer’s disease biomarkers (n = 45), and individuals with mild cognitive impairment or mild dementia due to Alzheimer’s disease (n = 41). Associations between slow-wave features and longitudinal cognitive performance were tested in cognitively unimpaired participants. Sex differences were also explored. Results A stepwise increased wake after sleep onset and latency to rapid eye movement sleep was observed, alongside reduced spectral power of slow-wave activity and a progressive flattening of slow-waves across the Alzheimer’s disease continuum in both sexes. In cognitively unimpaired individuals, higher slow-wave slope and greater peak-to-peak amplitude were associated with better cognitive trajectories over time. Conclusions Sleep macro- and microarchitecture are altered early and progressively deteriorate across the Alzheimer’s disease continuum . Slow-wave features relate to cognitive trajectories in preclinical Alzheimer’s disease, with exploratory analyses suggesting stronger associations in men. These findings support slow-wave morphology as a candidate non-invasive marker for future sleep-based intervention studies.
Relationship between locus coeruleus and slow‐wave sleep in aging and Alzheimer's disease
Falgàs, Neus , Tort‐Colet, Núria, Martín‐Sobrino, Isabel, Mayà, G., Peña‐González, Marta, Rudilosso, Salvatore , Gaig, Carles, Arqueros, Aurora, Piñol‐Ripoll, Gerard, Balasa, Mircea, Lladó, Albert, Ruiz, M. Morales, Muñoz‐Moreno, Emma, Grau‐Rivera, Oriol, Iranzo, Alex, Grinberg, Lea T., Sánchez‐Valle, Raquel, Tort‐Colet, Núria , Martín-Sobrino, Isabel , Mayà, Gerard , Gaig, Carles , Bosch, Beatríz , Pérez‐Millan, Agnès , Tort‐Merino, Adrià , Fernández‐Villullas, Guadalupe , Piñol‐Ripoll, Gerard , Balasa, Mircea , Lladó, Albert , Muñoz‐Moreno, Emma , Grau‐Rivera, Oriol , Iranzo, Álex , Sánchez‐Valle, Raquel
Alzheimer's & Dementia | February 3, 2026 | Volume: 22 | Issue: 2 | Pages: No page available
Abstract INTRODUCTION Sleep disruption, particularly loss of slow‐wave sleep (SWS), is common in Alzheimer's disease (AD), but its neurobiological underpinnings remain unclear. We investigated whether locus coeruleus (LC) integrity relates to SWS across the AD continuum and whether sex and perivascular spaces (PVSs) modify these associations. METHODS In a cohort (11 controls, 30 mild cognitive impairment, 17 AD dementia) we combined overnight polysomnography with LC‐sensitive magnetic resonance imaging of the LC, basal ganglia and centrum semiovale PVS ratings, and cerebrospinal fluid noradrenaline. Multivariable linear regression adjusted for demographics, disease stage, and medication use. RESULTS Higher LC integrity was associated with greater slow‐wave activity and slow oscillation power, with stronger effects in females. Basal ganglia PVS burden was related to lower SWS spectral power, whereas noradrenaline levels were not associated with sleep. DISCUSSION LC integrity, sex, and PVS burden show associations with SWS alterations in aging and AD, supporting restorative sleep as a potential therapeutic target.
Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
Guen, Yann Le , Luo, Guo , Damotte, Vincent , Jansen, Iris E. , Nicolas, Aude , Rojas, Itziar de, Bellenguez, Céline , Lian, Michelle Mulan , Parveen, Kayenat, Morizono, Takashi, Park, Hyeonseul, Grenier‐Boley, Benjamin , Naito, Tatsuhiko , Talyansky, Seth D., Yogeshwar, Selina , Sempere, Vicente Peris, Satake, Wataru , Álvarez, Victoria , Arosio, Beatrice , Boland, Anne , Daniele, Antonio , Darling, D.H., Dichgans, Martin , Dufouil, Carole , Düzel, Emrah , García‐Ribas, Guillermo, García‐Alberca, José María , García-González, Pablo, Giedraitis, Vilmantas , Graff, Caroline , Grünblatt, Edna , Hausner, Lucrezia , Jung, Yoo Jin , Deckert, Jürgen, Kern, Silke , Kuulasmaa, Teemu , Lee, Kun Ho , Lin, Ling , Masullo, Carlo , Mehrabian, Shima , Mendonça, Alexandre de , Boada, Merçé , Mir, Pablo , Moreno, Fermín , Nicolas, Gaël , Niida, Shumpei , Nordestgaard, Børge G. , Papenberg, Goran, Papma, Janne M., Pástor, Pau , Peters, Oliver , Popp, Julius , Molina‐Porcel, Laura , Puerta, Raquel , Pérez‐Tur, Jordi , Ramakers, Inez H.G.B. , Real, Luís Miguel , Riedel‐Heller, Steffi G. , Rodríguez‐Rodríguez, Eloy , Ross, Owen A. , Scarmeas, Nikolaos , Schneider, Anja , Solfrizzi, Vincenzo , Spalletta, Gianfranco , Tan, Eng‐King , Tegos, Thomas, Thomassen, Jesper Qvist , Tremolizzo, Lucio , Verhey, Frans, EADB, group, GR@ACE study, DemGene, EADI, GERAD, Blennow, Kaj , He, Zihuai , Jessen, Frank , Kehoe, Patrick G. , Duin, Cornelia van, Sánchez‐Juan, Pascual , Zettergren, Anna , Okada, Yukinori , Rossi, Giacomina, Gim, Jungsoo , Sims, Rebecca, Ramı́rez, Alfredo , Lambert, Jean‐Charles , Greicius, Michael D. , Mignot, Emmanuel , Moreno–Grau, Sonia , Rojas, Itziar de, Prokic, Ivana, Aarsland, Dag, García‐González, Pablo , Abdelnour, Carla , Armstrong, Nicola J. , Anthoula, Tsolaki, Archetti, Silvana, Pastor, Alfonso Arias, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa , Baquero, Miquel , Pastor, Ana Belén , Besse, Céline , Bizarro, Alessandra, Blesa, Rafael , Bossù, Paola , Brusco, Luis Ignacio , Buiza‐Rueda, Dolores, Bürger, Katharina , Burholt, Vanessa, Cecchetti, Roberta, Chillotti, Caterina , Ciccone, Simona, Claassen, Jurgen A.H.R., Clark, Christopher , Costantini, Emanuele Maria , Daian, Delphine , Dartigues, Jean‐François, Escott-Price, Valentina, Ewers, Michael , Fernández‐Fuertes, Marta , Ferreira, Catarina B. , Fin, Bertrand, Fließbach, Klaus , Franco-Macías, Emlio, García-González, Pablo, García‐Madrona, Sebastián, Giegling, Ina, Giorgio, Giaccone, González-Pérez, Antonio, Grande, Giulia , Green, Emma , Grimmer, Timo, Hardy, John, Hartmann, Annette M. , Harwood, Janet , Helisalmi, Seppo , Hernández, Isabel, Hoffmann, Per, Vilas, Raquel Huerto, Hulsman, Marc , Johansson, Charlotte , Kilander, Lena, Ståhlbom, Anne Kinhult, Koivisto, Anne M. , Lage, Carmen , Lerch, Ondřej , Munain, Adolfo Lopez de, Löwemark, Malin, Luckcuck, Lauren, Maier, Wolfgang, Marco, Spallazzi, Montes, Ángel Martín, Rodríguez, Carmen Martínez, Meggy, Alun, Mendoza, Silvia, Moebus, Susanne, Morelli, Laura , Möthen, Markus M., Muchnik, Carolina , Orsini, Michela, Péricard, Pierre , Piñol-Ripoll, Gerard, Polak, Thomas, Quenez, Olivier , Rábano, Alberto , Ramakers, Inez, Riederer, Peter, Rongve, Arvid, Allende, Irene Rosas, Rujescu, Dan, Sakka, Paraskevi , Sánchez‐Arjona, María Bernal, Sando, Sigrid Botne , Scamosci, Michela, Scherbaum, Norbert, Scherer, Martin, Schott, Jonathan M., Shadrin, Alexey A, Skrobot, Olivia Anna, Solfrizzi, Vincenzo, Spottke, Annika , Stordal, Eystein , Tartan, Juan Pablo, Traykov, Latchezar , Tybjærg‐Hansen, Anne, Ullgren, Abbe, Ulstein, Ingun, Dongen, Jasper Van , Wallon, David, Windle, Gill, Woods, Bob , Zulaica, Miren , Laczó, Jan , Maťoška, Václav , Piras, Federica, Ciullo, Valentina , Shofany, Jacob, Andreoni, Simona, Zompo, Maria Del, Bastiani, Patrizia, Natunen, Teemu , Antikaínen, Riitta , Abraham, Richard, Al-Chalabi, Ammar, Brayne, Carol, Brown, Kristelle S., Collinge, John, Craig, David W. , Deloukas, Pangiotis, Gerrish, Amy, Gwilliam, Rhian, Hardy, John , Hollingworth, Paul, Johnston, Jarret A., Jones, Lesley , Lawlor, Brian, Lynch, Aoibhinn, McQuillin, Andrew, Owen, Michael J., Passmore, Peter , Proitsi, Petra, Rossor, Martin, Gurling, Hugh, Todd, Stephen, Mummery, Catherine J. , Ryan, Nathalie, Lacidogna, Giordano , Adarmes-Gómez, Ad, Mauleón, Ana , Pancho, Ana, Gailhajenet, A., Lafuente, Asunción, Martín, Elvira, Pelejà, Esther, Carrillo, F, Merlín, Isabel Sastre, Garrote-Espina, L. , Carrión‐Claro, Mario, Marín, María Esmeralda Arreola , Labrador, Ma, Buendía, Mar, Guitart, Marina, Moreno, Mariona, Ibarria, Marta, Periñán, Mt, Aguilera, Núria , Gómez-Garre, P, Escuela, R, Pineda-Sanchez, R., Vigo-Ortega, R, Preckler, Sílvia , Rodrigo‐Herrero, Silvia , Diego, Susana, Salvadori, Nicola, Chipi, Elena , Laske, Christoph , Janowitz, Daniel , Anastasiou, Anna, Parveen, Kayenat, López‐García, Sara , Antonell, Anna , Belezhanska, Diyana , Solís, Patricia , Medel, Nancy , Lisso, Julieta, Sevillano, Zulma, Politis, Daniel Gustavo , Cores, Valeria, Cuesta, Carolina , Ortíz, Cecilia, Bacha, Juan Ignacio, Rios, Mario, Saenz, Aldo, Abalos, Mariana Sanchez, Köhler, Eduardo, Palacio, Dana Lis, Etchepareborda, Ignacio, Prestia, Federico Ariel, Galeano, Pablo , Castaño, Eduardo M., Germani, Sandra, Toso, Carlos Reyes, Rojo, Matias, Ingino, Carlos A. , Mangone, Carlos A., Engelborghs, Sebastiaan , Nielsen, Sune Fallgaard, Farotti, Lucia , Biessels, Geert Jan , Fiévet, Nathalie, Forsell, Charlotte , Thonberg, Håkan, Bjerke, Maria , Roeck, Ellen De , Olivar, Natividad , Sachdev, Perminder S. , Magda, Tsolaki, Rossi, Giacomina, Andreassen, Ole A., Sims, Rebecca , Aguilera, N., Alarcón, Estefanía Burgos, Buendia, Marie‐Annick , Rojas, Itziar de , Diego, S. , Guitart, M., González-Péerez, A, Lafuente, A., Martin, Elisabeth , Martinez, M.T.M., Marquié, M, Olivé, C. , Pelejà, E., Puerta, R, Sáez, ME, Táarraga, L, Valero, S, Alonso, MD, Amer-Ferrer, G., Antequera, M., Antúnez, Carmen , Bernal, M. , 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Manuel, Riemenschneider, Matthias, Pinchler, Sabrina, Feulner, Thomas, Bussche, Hendrik den, Scherer, Martin, Hüll, Michael, Frölich, Lutz, Wichmann, H‐Erich, Jöckel, Karl‐Heinz , Moebus, Susanne, Kauwe, John, Mayo, Kevin H. , Escott-Price, Valentina, Peng, Rong , Tan, Louis, Tandiono, Moses , Ng, Ebonne, Prakash, Kumar‐M., Au, Wing‐Lok , Meah, Wee-Yang, Mok, Shi Qi, Chan, Anne , Chen, Ling , Jeon, Beom S., Lin, Juei‐Jueng , Pei, Zhong , Shi, Changhe , Song, Kyuyoung, Wu, Yih‐Ru , Xu, Yuming , Yan, Yaping , Yang, Jing , Zhang, Bao Rong, Le Guen, Yann , Damotte, Vincent , During, Emmanuel , Hort, Jakub , Lin, Ling , Niida, Shumpei , Pasquier, Florence , Real, Luis M , Rujescu, Dan , Spalletta, Gianfranco , Zetterberg, Henrik , Andreassen, Ole A , Tsolaki, Magda , Foo, Jia Nee , Mignot, Emmanuel , Dichgans, Martin , Ramirez, Alfredo , Ross, Owen A , Sachdev, Perminder S , Hardy, John , Nicolas, Gaël , Alvarez, Victoria , Mir, Pablo , Pastor, Pau , Boada, Merce , García-González, Pablo , Molina-Porcel, Laura , de Mendonça, Alexandre , Graff, Caroline , Ambati, Aditya , Yu, Eric , Rojas, Itziar de, Leal, Thiago Peixoto , Miyashita, Akinori , Küçükali, Fahri , Belloy, Michaël E. , Benussi, Luisa , Borroni, Barbara , Bullido, María J. , Caffarra, Paolo , Clarimón, Jordi , Darling, Daniel, Debette, Stéphanie , Deleuze, Jean‐François , Galimberti, Daniela , García-González, Pablo, Goldhardt, Oliver , Hanon, Olivier , Heilmann‐Heimbach, Stefanie , Holstege, Henne H. , Hort, Jakub , Mecocci, Patrizia , Moebus, Susanne , Nacmias, Benedetta , Parnetti, Lucilla , Pasquier, Florence , Pijnenburg, Yolande A.L. , Piñol‐Ripoll, Gerard , Rainero, Innocenzo , Royo, José Luís , Scheltens, Philip , Scherbaum, Norbert , Seripa, Davide , Skoog, Ingmar , Squassina, Alessio , Swieten, John C. van , Sánchez‐Valle, Raquel , Teunissen, Charlotte E. , Vyhnálek, Martin , Wærn, Margda , Wiltfang, Jens , Zhang, Jing , EADB, group, GR@ACE study, DemGene, EADI, GERAD, Zetterberg, Henrik , Williams, Julie , Amouyel, Philippe , Tsolaki, Magda , Frikke-Schmidt, Ruth , Sleegers, Kristel , Toda, Tatsushi , Ingelsson, Martin , Rossi, Giacomina, Hiltunen, Mikko O. , Ozaki, Kouichi , Sims, Rebecca, Foo, Jia Nee , Flier, Wiesje M. van der , Ikeuchi, Takeshi , Mata, Ignácio F. , Ruiz, Agustı́n , Gan‐Or, Ziv , Andrade, Víctor , Amin, Najaf , Campos-Martín, Rafael , Holmans, Peter , Kleineidam, Luca , Lee, Sven J. van der , Rojas, Itziar de, Yaqub, Amber , Prokic, Ivana, Costa, Marcos R. , Chapuis, Julien , Ahmad, Shahzad , Aarsland, Dag, Alarcón‐Martín, Emilio , Alcolea, Daniel , Alegret, Montserrat , Álvarez, Ignacio , Appollonio, Ildebrando Marco , Arcaro, Marina , Athanasiu, Lavinia, Berr, Claudine , Bessi, Valentina , Binetti, Giuliano , Boschi, Silvia , Bråthen, Geir , Bresner, Catherine , Brodaty, Henry , Brookes, Keeley J. , Burholt, Vanessa, Calero, Miguel , Chêne, Geneviève , Carracedo, Ãngel , Cervera‐Carles, Laura , Charbonnier, Camille , Claassen, Jurgen A.H.R. , Conti, Elisa , Corma‐Gómez, Anaïs , Custodero, Carlo , Dalmasso, Carolina , Dardiotis, Efthimios , Deyn, Peter Paul De , Ser, Teodoro del , Denning, Nicola , Diehl‐Schmid, Janine , Díez-Fairén, Mónica , Rossi, Paolo Dionigi , Djurovic, Srdjan , Duron, Emmanuelle , Escott-Price, Valentina, Espinosa, Ana , Ferri, Evelyn , Fischer, Peter A. , Fladby, Tormod , Fortea, Juan , Fostinelli, Silvia , Fox, Nick C. , Frank, Ana , Froelich, Lutz , García-González, Pablo, Ghidoni, Roberta , Giegling, Ina, Grimmer, Timo , Guetta‐Baranes, Tamar , Haapasalo, Annakaisa , Hadjigeorgiou, Georgios M. , Hampel, Harald , Hardy, John, Heneka, Michael T. , Hernández, Isabel, Herrmann, Martin J. , Hoffmann, Per, Holmes, Clive , Kivipelto, Miia , Kornhuber, Johannes , Kosmidis, Mary H. , Laukka, Erika J. , Lauria, Alessandra , Lehtisalo, Jenni , Lleó, Alberto , Munain, Adolfo Lopez de, Macías, Juan, MacLeod, Catherine Anne , Mangialasche, Francesca , Marquié, Marta , Marshall, Iain James , Mead, Simon , Medina, Miguel , 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Proceedings of the National Academy of Sciences | August 29, 2023 | Volume: 120 | Issue: 36 | Pages: No page available
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.