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

EADB, GR at ACE study group, DEGESCO consortium, Demgene, EADI, GERAD, Asian Parkinson’s Disease, Genetics consortium

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish
Article numbere2302720120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number36
DOIs
StatePublished - 2023

Keywords

  • Alzheimer’s dementia
  • autoimmunity
  • HLA
  • neurodegeneration
  • Parkinson’s disease

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