Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB104 subtypes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 36; p. e2302720120
• Main Authors: Le Guen, Yann, Luo, Guo, Ambati, Aditya, Damotte, Vincent, Jansen, Iris, Yu, Eric, Nicolas, Aude, de Rojas, Itziar, Peixoto Leal, Thiago, Miyashita, Akinori, Bellenguez, Céline, Lian, Michelle Mulan, Parveen, Kayenat, Morizono, Takashi, Park, Hyeonseul, Grenier-Boley, Benjamin, Naito, Tatsuhiko, Küçükali, Fahri, Talyansky, Seth D, Yogeshwar, Selina Maria, Sempere, Vicente, Satake, Wataru, Alvarez, Victoria, Arosio, Beatrice, Belloy, Michael E, Benussi, Luisa, Boland, Anne, Borroni, Barbara, Bullido, María J, Caffarra, Paolo, Clarimon, Jordi, Daniele, Antonio, Darling, Daniel, Debette, Stéphanie, Deleuze, Jean-François, Dichgans, Martin, Dufouil, Carole, During, Emmanuel, Düzel, Emrah, Galimberti, Daniela, Garcia-Ribas, Guillermo, García-Alberca, José María, García-González, Pablo, Giedraitis, Vilmantas, Goldhardt, Oliver, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Jung, Yoo Jin, Jürgen, Deckert, Kern, Silke, Kuulasmaa, Teemu, Lee, Kun Ho, Lin, Ling, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Boada, Mercè, Mir, Pablo, Moebus, Susanne, Moreno, Fermin, Nacmias, Benedetta, Nicolas, Gael, Niida, Shumpei, Nordestgaard, Børge G, Papenberg, Goran, Papma, Janne, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peters, Oliver, Pijnenburg, Yolande A L, Piñol-Ripoll, Gerard, Popp, Julius, Porcel, Laura Molina, Puerta, Raquel, Pérez-Tur, Jordi, Rainero, Innocenzo, Ramakers, Inez, Real, Luis M, Riedel-Heller, Steffi, Rodriguez-Rodriguez, Eloy, Ross, Owen A, Royo, Luis Jose, Rujescu, Dan, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Skoog, Ingmar, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 2023; The National Academy of Sciences
• Subjects: Adaptive immunity; Alzheimer Disease; Alzheimer Disease - genetics; Alzheimer's dementia; Alzheimer's disease; Antigens; autoimmunity; Biological Sciences; Cerebrospinal fluid; Disease control; Drb1 protein; genetics; Histocompatibility antigen HLA; Histocompatibility Antigens; HLA; HLA Antigens; HLA-DRB1 Chains; HLA-DRB1 Chains - genetics; Humans; Immune response; Immune system; Life Sciences; Lysine; Medicin och hälsovetenskap; Movement disorders; neurodegeneration; Neurodegenerative diseases; Neurofibrillary tangles; Neurosciences; Neurovetenskaper; Parkinson Disease; Parkinson Disease - genetics; Parkinson's disease; Tau protein; neurodegeneration; autoimmunity; HLA; Parkinson’s disease; Alzheimer’s dementia
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2302720120

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 *04 subtypes best accounted for the association, strongest with *04:04 and *04:07, and intermediary with *04:01 and *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 *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 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.