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Fine-mapping HLA-II haplotypes in Alzheimer's disease and healthy longevity reveals distinct associations with microglial HLA-II load and neuropathology

Alvarez Sirvent, D.; Luimes, M. C.; Tesi, N.; Rohde, S. K.; Salazar, A. N.; Bijker, L. J.; van Schoor, N. M.; Tijms, B. M.; Vijverberg, E. G. B.; Strijbis, E. M. M.; Hoekstra, E. J.; Holtman, I. R.; van der Lee, S. J.; Hulsman, M.; Holstege, H.

2026-08-27 genetic and genomic medicine
10.64898/2026.08.24.26361177 medRxiv
Show abstract

Human leukocyte antigen (HLA) class II variation is implicated in Alzheimer's disease (AD) and longevity, but its mechanisms within the major histocompatibility complex remain unclear. We fine-mapped seven 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*04subtypes) 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 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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