The Interplay Between Immunometabolism and Neuroinflammation in Alzheimer’s Disease

May 27, 2026Biomolecules

How Immune System Metabolism and Brain Inflammation Interact in Alzheimer's Disease

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Abstract

Chronic neuroinflammation is a key mechanism in Alzheimer's disease, linking genetic and metabolic dysfunctions.

Alzheimer's disease is characterized by cognitive decline and the presence of amyloid-β plaques and neurofibrillary tangles.
Activated immune cells, such as microglia and astrocytes, release inflammatory substances that worsen neuronal damage.
Impaired mechanisms for clearing waste and disruptions in the blood-brain barrier contribute to sustained neuroinflammation.
Dysregulation of various metabolic pathways, including those for glucose and lipids, is associated with an inflammatory state in Alzheimer's.
Genetic variants, such as APOE4 and TREM2, influence how microglia manage lipids and respond to inflammation.
Natural compounds like polyphenols may help regulate immune and metabolic pathways, potentially offering new therapeutic strategies.

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Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and neuropathological hallmarks such as amyloid-β plaques and neurofibrillary tangles. In recent years, chronic neuroinflammation has emerged as a central mechanism linking genetic, metabolic, and immune dysfunctions in AD. Activated microglia and astrocytes release pro-inflammatory cytokines and reactive oxygen species that exacerbate synaptic and neuronal injury, while impaired clearance mechanisms and blood-brain barrier disruption further sustain inflammation. A growing body of research highlights the role of immunometabolism-the bidirectional interaction between immune activation and cellular metabolism-in shaping glial phenotypes and disease progression. Dysregulation of glucose, lipid, and amino acid metabolism, together with alterations in key metabolites such as lactate, NAD, and reactive oxygen species, promotes a maladaptive inflammatory state. Genetic factors including APOE4 and TREM2 variants affect microglial lipid handling pathways, while systemic metabolic disorders and gut microbiota alterations amplify neuroinflammatory cascades. Natural bioactive compounds, particularly polyphenols, have gained attention for their ability to modulate immunometabolic pathways. By activating AMPK and SIRT1 and inhibiting mTOR and NLRP3 inflammasome signaling, polyphenols may tune mitochondrial function, redox homeostasis, and autophagy, promoting adaptation to chronic metabolic stress. Therefore, metabolic-immune interactions represent pleiotropic therapeutic avenues for AD. Understanding how immunometabolites and nutrient-sensing pathways regulate compartmentalized inflammation in the CNS may pave the way for novel interventions that combine metabolic precision with neuroprotective efficacy. +

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The Interplay Between Immunometabolism and Neuroinflammation in Alzheimer’s Disease

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