{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Amsterdam UMC"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "D. Alvarez Sirvent"
    },
    {
      "name": "M. C. Luimes"
    },
    {
      "name": "N. Tesi"
    },
    {
      "name": "S. K. Rohde"
    },
    {
      "name": "A. N. Salazar"
    },
    {
      "name": "L. J. Bijker"
    },
    {
      "name": "N. M. van Schoor"
    },
    {
      "name": "B. M. Tijms"
    },
    {
      "name": "E. G. B. Vijverberg"
    },
    {
      "name": "E. M. M. Strijbis"
    },
    {
      "name": "E. J. Hoekstra"
    },
    {
      "name": "The Netherlands Brain Bank"
    },
    {
      "name": "I. R. Holtman"
    },
    {
      "name": "S. J. van der Lee"
    },
    {
      "name": "M. Hulsman"
    },
    {
      "affs": [
        0
      ],
      "name": "H. Holstege"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7m20dffm41tkh.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.24.26361177",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.08.24.26361177v2.full",
  "id": "7m20dffm41tkh",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.08.24.26361177v2",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "genetic and genomic medicine"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7204445624",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.08.24.26361177v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-24",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7m20dffm41tkh.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:32Z",
      "native_id": "10.64898/2026.08.24.26361177",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.08.24.26361177v2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:genetic and genomic medicine",
      "subfield": "human-genetics"
    }
  ],
  "title": "Fine-mapping HLA-II haplotypes in Alzheimer's disease and healthy longevity reveals distinct associations with microglial HLA-II load and neuropathology",
  "title_text": "Fine-mapping HLA-II haplotypes in Alzheimer's disease and healthy longevity reveals distinct associations with microglial HLA-II load and neuropathology",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:32Z",
  "url": "https://research.draconitic.com/paper/7m20dffm41tkh",
  "venue": "medRxiv",
  "versions": []
}