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

TL;DR

This review explores how the HLA system, a key part of the immune system, might be linked to Alzheimer's disease and highlights five key research questions to better understand this connection.

Contribution

The paper systematically outlines five unresolved research questions to clarify the role of HLA in Alzheimer's disease mechanisms.

Findings

HLA genetic variants are strongly associated with late-onset Alzheimer's disease.

HLA proteins may influence Alzheimer's through unconventional roles in the brain and antigen presentation.

T cells specific to Alzheimer's-related antigens could be a potential therapeutic target.

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.

Capitani et al. review the relationship between the Human Leukocyte Antigen system and Alzheimer’s disease, presenting five perspectives; genetic association, HLA class I in the brain, infection hypothesis, antigen presentation and T-cell responses. Understanding the link between Human Leukocyte Antigen and Alzheimer’s disease may open the door to new immunotherapeutics.

Graphical Abstract

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