P1–209: Relations of serum inflammatory markers and monocyte production of cytokines to the risk for Alzheimer's disease: The Framingham study

Substantial experimental and epidemiological evidence implicates inflammation in the pathogenesis of Alzheimer's disease (AD). However, prior studies relating serum proinflammatory cytokines to the risk of developing AD have yielded conflicting results. The measurement of cytokine production by peripheral blood mononuclear cells (PBMC) may be an attractive alternative marker of the proinflammatory response that antedates AD. To examine whether serum cytokines (interleukin–6 [IL–6]; C–reactive protein [CRP]) and the spontaneous production of proinflammatory interleukin–1 (IL–1), tumor necrosis alpha (TNF–α) and anti–inflammatory IL–1–receptor antagonist (IL–1RA) by PBMC are associated with the risk of incident AD. We followed 691 cognitively intact, community–dwelling participants (mean age 79, 62% women) with available measures of PBMC cytokine production and CRP for the development of incident AD.Using Cox proportional hazards regression adjusted for age, gender, ApoE4 allele status, prior stroke, education, homocysteine, smoking, body mass index and statin use, we evaluated the relations of serum cytokines (CRP and IL–6) levels and spontaneous production of IL–1, IL–1RA and TNF–α by PBMC to the risk of incident AD. After 10 years of follow–up, 44 participants (25 women) developed AD. After adjusting for all covariates, individuals in the top two tertiles (T2 and T3) of PBMC production of IL–1 or the top tertile (T3) of PBMC production of TNF–α were at increased risk of developing AD (multivariable–adjusted hazards ratio [HR] for IL–1 T2=2.84, 95% confidence interval [CI] 1.09–7.43; P=0.033 and T3=2.61, 95% CI 0.96–7.07; P=0.059; for TNF–α, adjusted–HR for T2=1.30, 95% CI 0.53–3.17; P=0.569 and T3=2.59, 95% CI 1.09–6.12; P=0.031) compared to those in the lowest tertile (T1).Participants who had 2 out of 3 or all 3 markers of enhanced inflammation (>T1 IL–1, >T2 TNF–α, or <T2 IL–1RA) had an even greater risk of developing AD (adjusted HRs=2.85 (1.08–7.50); P=0.034 and 3.83 (1.81–8.09); P=<0.001, respectively). PBMC production of IL–1RA alone and serum cytokines were not significantly associated with incident AD. Higher spontaneous production of IL–1 or TNF–α by PBMC may be a marker of future risk of AD in older individuals.These data strengthen the evidence for a pathophysiologic role of inflammation in the development of clinical AD.