Ageing research reviewsJul 25, 2026

Targeting a Key Immune Trigger in Alzheimer's Disease: Understanding How It Works and New Treatment Approaches

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 26, 2026

Abstract

Aberrant NLRP3 activation is closely associated with amyloid-β deposition, tau pathology, glial reactivity, and cognitive decline in Alzheimer's disease.

Neuroinflammation is identified as an early and sustained driver of Alzheimer's disease.
Evidence from human brain tissues, cerebrospinal fluid, and animal models supports the role of the NLRP3 inflammasome in Alzheimer's pathology.
Microglia are highlighted as the principal effector cells involved in inflammasome-associated pathology.
Pathological interactions between amyloid-β and tau activate the NLRP3 inflammasome through various interconnected mechanisms.
Downstream effects of NLRP3 activation include increased levels of IL-1β, IL-18, and gasdermin D, which may enhance neuroinflammation and neuronal injury.

Simplified

Alzheimer's disease (AD) is the leading cause of dementia, yet current therapies provide limited clinical benefit. Neuroinflammation, as an early and sustained driver of AD, places the NLRP3 inflammasome at the center of pathological and therapeutic focus. In this review, we synthesize recent advances in the structure, assembly, and activation of the NLRP3 inflammasome, and evaluate its contribution to AD using evidence from human brain tissues, cerebrospinal fluid, and diverse AD animal models. Available data consistently support aberrant NLRP3 activation in AD brain, where it is closely associated with amyloid-β (Aβ) deposition, tau pathology, glial reactivity, and cognitive decline. We further discuss the cell-type-specific roles of microglia and astrocytes, highlighting microglia as the principal effector cells in inflammasome-associated pathology. Mechanistically, Aβ and tau converge on NLRP3 activation through interconnected pathways involving K⁺ efflux, lysosomal rupture, mitochondrial dysfunction, and impaired autophagy. Downstream IL-1β, IL-18, and gasdermin D amplify neuroinflammation and neuronal injury. We summarize emerging therapeutic strategies directly targeting its core components or downstream effectors, as well as anti-AD agents with indirect NLRP3 modulation including endogenous molecules, repurposed drugs, and natural products. Collectively, this review regards NLRP3 inflammasome as a critical inflammatory hub and a promising target for disease-modifying therapy in AD, and provide useful perspectives on AD pathogenesis and inform the development of more rational therapeutic strategies.

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PubMed

Targeting a Key Immune Trigger in Alzheimer's Disease: Understanding How It Works and New Treatment Approaches

Abstract

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