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

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