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

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*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 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.