July 24, 2025

Targeting Inflammation in Alzheimer’s Disease: Insights Into Pathophysiology and Therapeutic Avenues-A Comprehensive Review

Key Points

Alzheimer's disease is characterized by cognitive decline, including memory and executive function deficits, primarily affecting adults over 65.
Neuroinflammation plays a critical role in AD, with altered microglial responses linked to increased Aβ risk and neuronal damage.
Astrocytes contribute to neuroprotection, but Aβ can induce reactivity leading to toxic effects and impaired Aβ clearance.
Current therapeutic approaches focus on slowing AD progression through targeting amyloid-beta and tau, with a growing emphasis on addressing neuroinflammation.

Abstract

Alzheimer’s Disease (AD) is the most common dementia, affecting mainly older adults, particularly over 65. Characterized by progressive cognitive decline—including deficits in memory, executive functions, and language, alongside behavioral disturbances—AD arises from complex pathophysiological mechanisms. These include neurotransmitter imbalances, cholinergic deficits, amyloid-beta (Aβ) toxicity, tau protein hyperphosphorylation, oxidative stress, synaptic dysfunction, and neuroinflammatory processes. Growing evidence highlights the protective role of microglia in AD pathology through their immune functions, phagocytic clearance of Aβ proteins, and trophic support to promote tissue repair and maintain cerebral homeostasis, as alterations in their response to Aβ are linked to an increased risk of AD. However, disruptions in homeostasis or tissue alterations may trigger microglial activation, leading to detrimental effects such as increased inflammatory activity, impaired microglial-mediated clearance, synapse loss, and neuronal damage. Astrocytes, a distinct type of glial cell with homeostatic functions, also exhibit neuroprotective effects. However, the presence of Aβ may result in astrocyte reactivity, leading to neurotoxic effects associated with disturbances of calcium levels, activation of proinflammatory pathways, gliotransmission, altered tau metabolism, and impaired clearance of Aβ. Despite substantial research, AD remains challenging to diagnose early and lacks effective treatments. Given its multifactorial nature, therapeutic approaches primarily aim to slow progression and remain limited in achieving a definitive cure. While most current strategies focus on mitigating the toxic effects of Aβ and tau proteins, growing interest has emerged in addressing neuroinflammation as a potential means to delay or prevent neurodegeneration. Targeting neuroinflammation could open new therapeutic avenues for the treatment of AD.

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