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

Capitani, Lorenzo and Carpanini, Sarah M. 2025. HLA’s hidden hand in Alzheimer’s disease—five research questions en route to an answer. Brain Communications 7 (6) , fcaf438. 10.1093/braincomms/fcaf438

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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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Publisher:	Oxford University Press
Date of First Compliant Deposit:	21 November 2025
Date of Acceptance:	6 November 2025
Last Modified:	21 Nov 2025 10:30
URI:	https://orca.cardiff.ac.uk/id/eprint/182559

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