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Gene expression analysis of inflammatory markers focusing on APOE in Alzheimer`s disease and multiple sclerosis
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Abstract: Neuroinflammation is a key driver in the pathogenesis of neurological disorders, including autoimmune diseases like multiple sclerosis (MS) and neurodegenerative conditions such as Alzheimer’s disease (AD). While acute inflammation is essential for central nervous system (CNS) repair and homeostasis, chronic or dysregulated inflammation contributes to neuronal dysfunction and degeneration. In both AD and MS, sustained activation of microglia and astrocytes fuels neuroinflammation. These immune cells release pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interleukins (e.g. IL1B and IL6), amplifying the immune response. This prolonged inflammatory state disrupts synaptic function, compromises the blood-brain barrier (BBB) and accelerates neuronal loss. In MS, immune-mediated attacks on the myelin sheath cause severe nerve damage and impair signal transmission. Similarly, in AD, chronic neuroinflammation increases amyloid plaque and tau tangle accumulation, contributing to neuronal damage and cognitive decline. Genetic factors such as the APOE genotype also influence disease progression. The APOE4 allele is strongly associated with increased AD risk, potentially due to its role in lipid metabolism, amyloid clearance and neuroinflammatory. Beyond its important role in AD, the APOE genotype may also influence the clinical course and progression of MS. Some evidence suggests that APOE4 may lead to a more aggressive disease course, with faster progression and increased neurodegeneration in MS patients. While inflammation within the CNS is a key feature of these disorders, peripheral inflammation can directly influence neuroinflammation through mechanisms such as blood-brain barrier (BBB) disruption, immune cell migration, and systemic cytokine signalling. For example, studies have shown that elevated levels of pro-inflammatory markers, as well as elevated levels of soluble triggering receptor expressed on myeloid cells 2 (TREM2) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in the blood are associated with microglial activation and neurodegeneration in AD and MS. Therefore, we analysed whole-blood expression levels across healthy controls (HC), mild cognitive impairment (MCI), AD and MS and found disease-specific peripheral signatures: RIPK3 and MMP9 were elevated in MCI/AD, whereas APOE and IL10 were reduced in MS, with TREM2 increased in AD and MS. Across these cohorts, APOE expression correlated positively with IL10 and negatively with RELA which showed disease-context coupling positive with NLRP3 in MCI/AD/MS but negative with RIPK1 and RIPK3 in controls. This is consistent with an APOE anti-inflammatory axis that is rewired throughout pathology. Cell subset analyses in MS (sorted CD8⁺, CD14⁺ and CD19⁺) revealed no statistically significant differences across subsets, suggesting broadly shared or subtle shifts in circulating compartments. Finally, peripheral APOE expressions did not differ by genotype within cohorts, indicating that blood APOE levels are more context-/disease-dependent than genotype-driven. These results provide a foundation for future research that will advance our understanding of APOE in immune signalling across neuroinflammatory and neurodegenerative diseases.
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Alzheimer’s disease Neuroinflammation Multiple Sclerosis