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

Daniel Alvarez Sirvent and colleagues fine-mapped seven independent HLA-II haplotypes in 6,053 people: 443 cognitively healthy centenarians, 3,219 population controls, and 2,391 people with Alzheimer disease. Three haplotypes overlapped prior Alzheimer disease or lifespan signals. Hap-B, defined by DRB1*04 subtypes, was enriched in centenarians and controls relative to Alzheimer disease and its association with tau pathology was replicated in an independent Netherlands Brain Bank cohort. Hap-R, DRB1*01:01, was associated with higher Alzheimer disease risk and lower healthy-longevity status, alongside lower microglial HLA-II activation. Hap-Y, DRB1*15:01, was linked to higher microglial HLA-II activation independent of quantitative Alzheimer neuropathology. The result supports a relationship between HLA architecture, brain immune state, and healthy longevity. It is a preprint and an observational genetic study. It identifies mechanisms and risk associations, not a supplement target or a proven intervention.

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.