Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus (2025)

Table of Contents

Introduction

  • Colocalization of immune cells with amyloid plaques is present
  • Changes in immune system owed to age are linked to:
    • Chronic expression of circulating pro-inflammtory markers
    • Senescent secretory profile of cells, releasing inflammatory mediators

Peripheral inflammation, cognitive decline and dementia

  • Meta analyses link peripheral inflammatory markers and AD and all-cause dementia.
  • Historical relevant biomarkers associated with development of AD:
    • C-reactive protein
    • IL-6
    • TNF
    • IL-1beta

Peripheral innate immunity and AD stages

  • Attempts of using inflammatory biomarkers for demarcate phases of cognitive decline got mixed results
  • Some biomarkers peak on early stages and decline in later stages of cognitive decline
  • Peripheral inflammatory biomarkers are more reliable associated to CSF levels of phosphorylated tau than wiht CSF levels of amyloid-beta
  • Remarkably, studies like Yang et. al found that IL-12p70 is associated with slower rates of longitudinal cognitive decline in asymptomatic older adults.
    • This suggest a protective effect of inflammation on early stages of disease
  • Putting aside tipical studies focused on plasma cytokine levels, studies using phenotypic functional assays on immune cells, provide a promising more reliable biomarker of cognitive decline.

Systemic inflmmatory events and clinical outcomes

  • systemic inflammatory events: acute infections, surgery, critical illness (for example, sepsis).
  • sickness behavior suggest mechanisms linking systemic inflammation and central system
  • epidemiologic studies associates chronic inflammatory events and systemic inflammatory events/infections requiring hospital treatment, with development of dementia, in the long run.
  • some studies found an inverse relation between infections and an inflammatory environment in the brain. peripheral infection might cause in the brain:
    • upregulation of anti-inflammtory genes
      • IL4R
      • CHI3L1
    • decreased expression of pro-inflammatory proteins

Correlation between peripheral and central compartments

  • CNS inflammatory response occurs early in AD
    • Inflammatory response is marker dependent and mixed, though.
    • Temporal pattern is also not linear:
      • CSF levels of inflammation are lower in stage 1 than stage 0, but markedly higher in stage 2.