Neuroinflammation and Cognitive Decline: Molecular Crosstalk between Immune and Neural Pathways in Neurodegeneration

Abstract

Neurodegenerative disorders are associated with progressive neuronal dysfunction, synaptic loss, and cognitive decline. Increasing evidence indicates that chronic neuroinflammation contributes to these processes through sustained interactions between immune and neural pathways. This narrative review examines molecular crosstalk among glial cells, inflammatory mediators, vascular dysfunction, mitochondrial stress, and neuronal signalling in neurodegenerative disease. It focuses on mechanisms involving microglial activation, astrocyte reactivity, cytokine signalling, complement-mediated synaptic pruning, NLRP3 inflammasome activation, oxidative stress, blood-brain barrier disruption, and neuroimmune metabolic reprogramming. These pathways are considered in relation to cognitive impairment in major neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. The reviewed evidence suggests that inflammatory signalling may impair cognition not only by promoting neuronal injury but also by disturbing synaptic plasticity, neurotransmission, mitochondrial function, and neurovascular regulation. Microglia and astrocytes appear central to this process because their protective functions can shift towards sustained inflammatory activity under chronic pathological stimulation. Shared inflammatory mechanisms, including interleukin-1 beta signalling, tumour necrosis factor alpha signalling, inflammasome activation, oxidative injury, and blood-brain barrier impairment, may contribute to disease progression across neurological disorders. Emerging therapeutic strategies therefore aim to modulate neuroimmune signalling, preserve mitochondrial function, regulate glial responses, and support precision neuroimmunology. Clinical translation remains limited by disease heterogeneity, intervention timing, incomplete biomarker validation, and the complexity of immune-neural interactions. Improved understanding of neuroimmune crosstalk may support earlier diagnosis and more targeted interventions for cognitive decline in neurodegenerative disorders.