Neuroinflammation in Alzheimer’s disease: glial crosstalk, pathological modulation, and therapeutic implications

Alzheimer’s disease (AD) remains a major therapeutic challenge despite the availability of amyloid-targeting disease-modifying therapies for selected patients with early symptomatic disease. These therapies have shown that disease modification is possible, but their benefits are modest and constrained by amyloid confirmation, safety monitoring, infusion delivery, access, and eligibility requirements.

Neuroinflammation is increasingly viewed as a context-dependent modifying process that interacts with β-amyloid (Aβ), tau pathology, metabolic stress, and vascular dysfunction, rather than as an unequivocally established primary initiating driver. This review provides a selective, glia-centered synthesis of AD neuroinflammation focused on microglia, astrocytes, and their reciprocal crosstalk.

We examine how microglial and astrocytic responses can support Aβ handling, plaque containment, tissue homeostasis, and synaptic protection, while chronic or poorly resolved glial signaling can amplify cytokine and complement responses, metabolic and oxidative stress, and neuronal vulnerability. Representative signaling nodes, including NF-κB, AMPK/mTOR, and PI3K/Akt, are discussed as organizing mechanisms linking inflammatory transcription, proteostatic stress, glial metabolism, and neuronal injury, rather than as equivalently validated therapeutic targets.