O2‐13‐05: CSF Markers of Inflammation and Alzheimer's Disease Pathogenesis in the Cognitively Intact Prevent‐Ad Cohort

The decades-long pre-symptomatic stages of AD offer a window of opportunity for evaluation of candidate interventions that may slow disease progression and defer onset of symptoms. Among such potential interventions are anti-inflammatory treatments. We therefore investigated the relationship of 45 inflammatory markers in CSF with a common metric for AD pathogenesis. We recruited >350 cognitively intact persons aged 60+ with a parental history of AD-like dementia (confers ∼3-fold increased risk of AD). From this “PREVENT-AD” cohort, we enrolled 210 into INTREPAD, a two-year placebo-controlled cognitive- and biomarker-endpoint trial of naproxen-sodium 220mg b.i.d. as a potential AD preventive. Among these, 107 participants agreed to serial lumbar punctures at baseline, 3, 12, and 24 months. In pilot work with 20 CSF samples, we assayed baseline CSF for 45 inflammatory markers using both the Luminex “Milliplex” and MesoScale Discovery (MSD) platforms. Using Innotest ELISA kits, we assayed the same CSF samples for Aβ42, total-tau (t-tau) and P-tau. The Luminex and MSD assays produced generally consistent results for 21 overlapping inflammatory markers (Figure 1C shows results for IP-10), although ceiling effects may limit MSD for some markers (Figure 1D). We analyzed the association of these and other markers with the ratio of CSF total-tau (t-tau) to Aβ42, a widely used index of disease progression. Even in this limited sample, we observed significant correlation (p <0.05) between IL-1β, IL-8, IP-10, MCP-1, or TNF-α (all measurable using both platforms) and log t-tau/Aβ42 (e.g., Figure 1A, 1B). MCP-4 and TARC were also correlated with log t-tau/Aβ42, but were measurable by MSD only. Changes in markers of AD progression may be used in high-risk populations to assess potential of candidate preventive interventions. The importance of inflammatory processes in AD pathogenesis is suggested by a strong association between several inflammatory markers and an established index of AD progression. Our results suggest a rationale for testing anti-inflammatory treatments as potential preventives that may delay onset of AD symptoms – now under investigation in INTREPAD. The longitudinal pattern of individual inflammatory markers and their response to NSAID treatment may reveal much about the etio-pathogenesis of AD.

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