Fine-mapping HLA-II haplotypes in Alzheimer's disease and healthy longevity reveals distinct associations with microglial HLA-II load and neuropathology
- 1Amsterdam UMC
Abstract
Human leukocyte antigen (HLA) class II variation is implicated in Alzheimers disease (AD) and longevity, but its mechanisms within the major histocompatibility complex remain unclear. We fine-mapped six independent HLA-II haplotypes in 6,053 individuals (443 cognitively healthy centenarians [CHCs], 3,219 population controls, 2,391 AD patients). Three haplotypes overlapped previous AD and lifespan signals. Hap-B (DRB1*04 subtypes) was protective, enriched in CHCs and controls versus AD, with its neuroprotective association with tau pathology replicated in an independent Netherlands Brain Bank cohort. Hap-R (DRB1*01:01) increased AD risk and reduced healthy longevity, with nominally reduced microglial HLA-II activation. Hap-Y (DRB1*15:01) showed increased microglial HLA-II activation in post-mortem brain tissue, independent of quantitative AD neuropathology. These findings indicate distinct HLA-II haplotypes shape AD susceptibility and healthy longevity through separate mechanisms, linking HLA architecture to brain immune states beyond classical neuropathology.
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BibTeX
@misc{sirvent2026finemapping,
title = {{Fine-mapping HLA-II haplotypes in Alzheimer's disease and healthy longevity reveals distinct associations with microglial HLA-II load and neuropathology}},
author = {D. Alvarez Sirvent and M. C. Luimes and N. Tesi and S. K. Rohde and A. N. Salazar and L. J. Bijker and N. M. van Schoor and B. M. Tijms and E. G. B. Vijverberg and E. M. M. Strijbis and E. J. Hoekstra and The Netherlands Brain Bank and I. R. Holtman and S. J. van der Lee and M. Hulsman and H. Holstege},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.24.26361177},
url = {https://www.medrxiv.org/content/10.64898/2026.08.24.26361177v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Fine-mapping HLA-II haplotypes in Alzheimer's disease and healthy longevity reveals distinct associations with microglial HLA-II load and neuropathology
AU - D. Alvarez Sirvent
AU - M. C. Luimes
AU - N. Tesi
AU - S. K. Rohde
AU - A. N. Salazar
AU - L. J. Bijker
AU - N. M. van Schoor
AU - B. M. Tijms
AU - E. G. B. Vijverberg
AU - E. M. M. Strijbis
AU - E. J. Hoekstra
AU - The Netherlands Brain Bank
AU - I. R. Holtman
AU - S. J. van der Lee
AU - M. Hulsman
AU - H. Holstege
PY - 2026
DA - 2026/08/24
PB - medRxiv
DO - 10.64898/2026.08.24.26361177
UR - https://www.medrxiv.org/content/10.64898/2026.08.24.26361177v2
AB - Human leukocyte antigen (HLA) class II variation is implicated in Alzheimers disease (AD) and longevity, but its mechanisms within the major histocompatibility complex remain unclear. We fine-mapped six independent HLA-II haplotypes in 6,053 individuals (443 cognitively healthy centenarians [CHCs], 3,219 population controls, 2,391 AD patients). Three haplotypes overlapped previous AD and lifespan signals. Hap-B (DRB1*04 subtypes) was protective, enriched in CHCs and controls versus AD, with its neuroprotective association with tau pathology replicated in an independent Netherlands Brain Bank cohort. Hap-R (DRB1*01:01) increased AD risk and reduced healthy longevity, with nominally reduced microglial HLA-II activation. Hap-Y (DRB1*15:01) showed increased microglial HLA-II activation in post-mortem brain tissue, independent of quantitative AD neuropathology. These findings indicate distinct HLA-II haplotypes shape AD susceptibility and healthy longevity through separate mechanisms, linking HLA architecture to brain immune states beyond classical neuropathology.
ER -