Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Immunology
• Gerontology

Background:

• Inflammation plays a complex role in Alzheimer's Disease (AD), potentially protecting against early amyloid deposition but worsening tau pathology later.
• The NLRP3 inflammasome, a key factor in age-related chronic inflammation (inflammaging), is implicated in AD.
• Interleukin-18 (IL-18), a marker of NLRP3 activation, was investigated for its role throughout the AD continuum.

Purpose of the Study:

• To explore the role of the IL-18 signaling cascade in Alzheimer's Disease (AD) pathogenesis.
• To investigate the association of IL-18 with aging, AD pathology (tau and amyloid-beta), synaptic damage, and cognitive function.
• To examine IL-18 in pre-symptomatic and symptomatic AD stages using longitudinal and cross-sectional data.

Main Methods:

• Utilized longitudinal data from the PREVENT-AD cohort (at-risk/pre-symptomatic AD) and cross-sectional data from the ADNI cohort (symptomatic AD and cognitively unimpaired).
• Analyzed cerebrospinal fluid (CSF) and post-mortem brain tissue for IL-18 cascade proteins, AD pathology markers (tau, Aβ42), synaptic damage markers, and cognitive scores.
• Employed general and mixed linear models, ELISA, ECLIA, OLINK assays, and mass spectrometry for analysis.

Main Results:

• CSF IL-18 levels and IL-18 mRNA in brain tissue increased with age.
• IL-18 signaling proteins were significantly associated with increased tau pathology in both CSF and brain tissue.
• A genetic variant in the IL-1 receptor gene cluster correlated with tau pathology.
• IL-18 signaling was linked to cognitive function and synaptic marker levels in the pre-symptomatic AD cohort.

Conclusions:

• The IL-18 signaling cascade is modulated by age and plays a significant role in the pre-symptomatic stages of AD.
• IL-18 signaling primarily influences tau pathology across the AD continuum, with minimal impact on amyloid-beta pathology.
• These findings may elucidate the relationship between tau pathology, synaptic degeneration, and cognitive decline in AD.