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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
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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.
Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2 : A genome‐wide association study in over 12,000 non‐demented participants
Grenier‐Boley, Benjamin , Simino, Jeannette , Adams, Hieab H.H. , White, Charles C. , Terzikhan, Natalie, Cruchaga, Carlos , Knol, Maria J. , Li, Shuo , Schraen, Susanna, Grove, Megan L. , Satizábal, Claudia L. , Amin, Najaf , Younkin, Steven G., Initiative, Alzheimer's Disease Neuroimaging, Gottesman, Rebecca F., Buée, Luc , Uitterlinden, André G. , DeCarli, Charles , Bressler, Jan , DeStefano, Anita L. , Dartigues, Jean‐François, Boerwinkle, Eric , Tzourio, Christophe , Fornage, Myriam , Jager, Phil De, Reitz, Christiane, Mosley, Thomas H. , Lambert, Jean‐Charles , Duijn, Cornelia M. van , DeCarli, Charles , Younkin, Steven, Cruchaga, Carlos , Adams, Hieab H H , Satizabal, Claudia L , Tzourio, Christophe , van Duijn, Cornelia M , Damotte, Vincent , Lee, Sven J. van der , Chouraki, Vincent Antoine , Tosto, Giuseppe , Berr, Claudine , Initiative, Alzheimer's Disease Neuroimaging, Beiser, Alexa , Knopman, David S. , Yang, Qiong , Ikram, M. Arfan , Amouyel, Philippe , Jager, Philip L. De , Seshadri, Sudha
Alzheimer's & Dementia | May 18, 2021 | Volume: 17 | Issue: 10 | Pages: 1663-1674
Abstract Introduction There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods We included 12,369 non‐demented participants from eight population‐based studies. Imputed genetic data and measured plasma Aβ1‐40, Aβ1‐42 levels and Aβ1‐42/Aβ1‐40 ratio were used to perform genome‐wide association studies, and gene‐based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results Single‐variant analysis identified associations with apolipoprotein E ( APOE ) for Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio, and BACE1 for Aβ1‐40. Gene‐based analysis of Aβ1‐40 additionally identified associations for APP , PSEN2 , CCK , and ZNF397 . There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion Identification of variants near/in known major Aβ‐processing genes strengthens the relevance of plasma‐Aβ levels as an endophenotype of AD.