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Cited by 4Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

HLA’s hidden hand in Alzheimer’s disease—five research questions en route to an answer

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Capitani, Lorenzo, Carpanini, Sarah M·2025·Brain Communications
DOI 10.1093/braincomms/fcaf438PMC PMC12631126
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Abstract

The association of genetic variants in the Human Leukocyte Antigen (HLA) locus with late-onset Alzheimer’s disease has been stringently replicated across several, powerful genome-wide association studies. However, no clear picture has yet emerged of the mechanistic relationship between Alzheimer’s disease and this top genetic hit, despite the fact that the HLA locus is one of the most influential gene loci of the immune system, known to influence antigen presentation, T cell responses and brain plasticity. In this review, we explore this association by outlining five research questions, namely: (i) the association of HLA Class I and Class II genes with Alzheimer’s disease at the allelic and haplotypic levels, (ii) the unconventional role of HLA Class I in the brain, (iii) the infection hypothesis of Alzheimer’s disease in the context of the known role HLA proteins play in immunity, (iv) the possible antigen presentation of Alzheimer’s disease relevant self-antigens and in turn (v) the possibility of T cells existing that are specific for these antigens. Identifying the functional mechanisms underlying this important genetic association with Alzheimer’s disease may hold the key to unravelling new avenues of Alzheimer’s disease immunotherapeutics.

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  • Several AD GWAS loci implicate B cell relevant genes including SCIMP, BLNK, PLCG2, HLA class II region and IGHG1.

    “Indeed, several AD GWAS loci implicate B cell relevant genes as well, albeit with varying strength of evidence and confidence in causal gene assignment. These include SCIMP , BLNK , PLCG2 , HLA class II region and IGHG1 [26 -32].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [31]

    In “HLA allele associations—which of the many?” (page unavailable), the paper reports AD GWAS associations at the HLA class II locus and cautions that linkage makes causal-gene assignment difficult. It does not identify SCIMP, BLNK, PLCG2, or IGHG1 as AD GWAS loci, or characterize the listed loci collectively as B-cell relevant. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • HLA class II locus encompassing HLA-DRB1/HLA-DQA1 is a well established AD risk locus, although extensive linkage disequilibrium makes it difficult to pin down the specific causal gene.

    “The HLA class II locus encom­ passing HLA-DRB1/HLA-DQA1 is also a well established AD risk locus, although extensive linkage disequilibrium across this region makes it difficult to pin down the specific causal gene.”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [31]

  • SCIMP is expressed across myeloid and B cell lineages and has been identified as an AD-associated locus.

    “SCIMP is expressed accross myeloid and B cell lineages and has been identified as an AD-associated locus.”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [31]

    The Introduction discusses AD-associated HLA variants and expression of MHC-II in microglia, but neither passage addresses SCIMP. Searches of our copy for “SCIMP” and for myeloid and B-cell lineages found no passage establishing SCIMP expression or its identification as an AD-associated locus. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • IGHG1 is less well established as a causal AD gene and is more accurately described as residing within an AD associated locus rather than as a validated risk gene.

    “IGHG1 , in contrast, is less well established as a causal AD gene and is more accurately described as residing within an AD associated locus rather than as a validated risk gene.”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [31]

    The Introduction’s “HLA allele associations—which of the many?” section discusses AD-associated variants in the HLA locus and cautions that linkage can make causative genes difficult to identify (page unavailable). Searches for IGHG1 and its expanded gene name found no passage addressing whether IGHG1 lies in an AD-associated locus or is a validated risk gene. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • BLNK is a central adaptor downstream of BCR, and PLCG2 is a major BCR proximal signaling node implicated in germinal center and memory B cell formation.

    “Two further loci provide more direct mechanistic links to B cell receptor (BCR) signaling: BLNK is a central adaptor downstream of the BCR, and PLCG2 is a major BCR proximal signaling node implicated in germinal center and memory B cell formation.”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [31]

    The Introduction discusses HLA-mediated antigen presentation and T-cell responses in Alzheimer’s disease, but the passages in our copy do not address BLNK, PLCG2, BCR signaling, or germinal-center and memory B-cell formation. Searches for both gene names and those B-cell processes found no passage supporting the attributed mechanisms. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Authors
Capitani, L., & Carpanini, S. M.
Affiliations
UK Dementia Research Institute (GB)
Corresponding author
Carpanini, Sarah M
ORCID
Venue
Brain Communications
Publisher
Oxford University Press (OUP)
Published
2025
Volume
7
Issue
6
Pages
fcaf438-fcaf438
ISSN
2632-1297 (ISSN-L)
DOI
10.1093/braincomms/fcaf438
PMC
PMC12631126
OpenAlex
W4416099426
Cited by
4
References
7
Citations by year
2026: 4
FWCI
0.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
Funders
  • UK Dementia Research Institute
  • Medical Research Council
  • Alzheimer’s Research UK
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, HLA, HLA class I, HLA class II, HLA haplotypes, late-onset Alzheimer's disease, genetic association, antigen presentation, T cell response, infection hypothesis, autoantigens, brain immunity, immunotherapy

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Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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