Language
English
Publication Date
9-5-2023
Journal
Proceedings of the National Academy of Sciences of the United States of America
DOI
10.1073/pnas.2302720120
PMID
37643212
PMCID
PMC10483635
PubMedCentral® Posted Date
8-29-2023
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Humans, Alzheimer Disease, Histocompatibility Antigens, HLA Antigens, HLA-DRB1 Chains, Parkinson Disease, HLA, Alzheimer’s dementia, Parkinson’s disease, neurodegeneration, autoimmunity
Published Open-Access
yes
Recommended Citation
Le Guen, Yann; Luo, Guo; Ambati, Aditya; et al., "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" (2023). Faculty and Staff Publications. 3149.
https://digitalcommons.library.tmc.edu/baylor_docs/3149
Included in
Cognition and Perception Commons, Cognitive Science Commons, Diseases Commons, Geriatrics Commons, Medical Sciences Commons, Neurology Commons