THE IMMUNE SYSTEM IN ALZHEIMER’S DISEASE: INNATE AND ADAPTIVE IMMUNITY, NEUROINFLAMMATION, AND THERAPEUTIC APPROACHES

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized pathologically by extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Beyond these hallmark lesions, a growing body of evidence indicates that the immune system plays a pivotal role in AD pathogenesis. Neuroinflammatory processes – driven by both the brain’s innate immune cells (e.g. microglia, astrocytes) and components of the adaptive immune system (e.g. T and B lymphocytes) – are now recognized as key mediators of neuronal injury and disease progression. Genetic risk factors for late-onset AD notably include several genes associated with immune functions, underscoring the connection between immunity and neurodegeneration. Microglial activation in response to Aβ and tau can be double-edged: acutely, microglia may phagocytose Aβ and protect neurons, but chronic activation leads to release of pro-inflammatory cytokines, complement components, and other neurotoxic factors that exacerbate synaptic dysfunction and neuronal loss. Similarly, peripheral immune cells infiltrating the aging or diseased brain – including CD8⁺ and CD4⁺ T cells, natural killer cells, neutrophils, and others – have been implicated in amplifying neuroinflammation and modulating AD pathology. This review provides a comprehensive overview of the role of the immune system in AD, covering innate immunity (microglial activation states, inflammasome signaling, complement cascade, astrocyte-mediated responses), adaptive immunity (T cell and B cell responses within the central nervous system), the interplay between chronic neuroinflammation and AD pathogenesis, cytokine profiles in AD patients, disruption of the blood-brain barrier and immune trafficking, and the influence of peripheral immune factors. We also discuss emerging immune-based therapeutic strategies for AD – ranging from anti-amyloid immunotherapies and vaccines to approaches aiming to temper detrimental inflammation or boost beneficial immune responses. Understanding the multifaceted role of immunity in AD offers promising avenues for intervention and biomarkers. Therapeutic modulation of the immune system – carefully calibrated to suppress harmful inflammation while preserving or enhancing clearance of pathological proteins – may hold the key to altering the course of AD.