Association between Alzheimer's disease and MHC-I antigen processing and presentation pathway: a narrative review

Alzheimer's disease (AD) is the most common cause of dementia worldwide and remains a major public health burden. Although amyloid-beta deposition and tau pathology are the defining pathological features of AD, increasing evidence indicates that immune dysregulation and chronic neuroinflammation also contribute to disease onset and progression. However, the specific immune pathways involved in AD and their mechanistic relevance remain incompletely understood. The major histocompatibility complex class I (MHC-I) antigen processing and presentation pathway has attracted growing attention because of its classical role in adaptive immunity and its potential functions within the central nervous system. In this narrative review, we summarize current evidence linking AD to the MHC-I, or human leukocyte antigen class I (HLA-I), pathway from genetic, molecular, cellular, and immunological perspectives. Available studies implicate the broader HLA region in AD susceptibility and suggest that alterations in HLA-I-related loci, antigen-processing machinery, MHC-I-associated molecules, and downstream immune responses may contribute to disease heterogeneity. At the molecular and cellular levels, changes in MHC-I molecules, antigen-processing machinery, and associated signaling pathways have been reported in microglia, neurons, astrocytes, and oligodendroglial lineage cells. In parallel, changes involving β₂-microglobulin and the presence of expanded or cytotoxic like CD8⁺ T cells suggest that adaptive immune mechanisms may participate in AD pathology. Nevertheless, direct evidence demonstrating immune responses specific to particular antigens and restricted by HLA-I in human AD remains limited. Overall, current findings indicate that the MHC-I/HLA-I pathway may represent an important component of AD pathophysiology and contribute to disease progression by influencing immune homeostasis and cellular interactions within the central nervous system. Further studies integrating human tissue analysis, immunopeptidomics, spatial profiling, and paired T cell receptor approaches are needed to clarify its mechanistic, biomarker, and therapeutic significance.