2025-07-082025-07-082023-08-29Le Guen, Y., Luo, G., Ambati, A., Damotte, V., Jansen, I.E., Yu, E.,...,Swieten, J.V. (2023). 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. Proceedings of The National Academy of Sciences of The United States of America, 120 (36), e2302720120. https://doi.org/10.1073/pnas.2302720120.1091-64900027-8424https://hdl.handle.net/11441/175132We report that specific HLA-DRB1*04 alleles are protective against Alzheimer’s dementia (AD), Parkinson’s disease (PD), and other neurodegenerative disorders. Further, we found that these HLA (Human Leukocyte Antigen) subtypes selectively bind a piece of Tau crucial to aggregation but only when it is acetylated (a-PHF6). This a-PHF6 piece is significant as it is a common posttranslational modification of Tau found in Alzheimer’s brains. Only when someone is HLA-DRB1*04:04 or HLA-DRB1*04:01 can PHF6 be presented as a T cell epitope to T cell receptors and mount a memory immune response against this pro-aggregation fragment. This immune response would protect against AD, PD, and neurodegeneration, explaining the HLA association. Vaccination with a-PHF6 in HLA-DRB1*04 individuals could have preventive effects.application/pdf11 p.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/HLAAlzheimer’s dementiaParkinson’s diseaseNeurodegenerationAutoimmunityinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccess10.1073/pnas.2302720120