Inflammatory Cytokines Linked to Alzheimer's Risk

BOSTON, May 30 -- There's more evidence to support the inflammatory hypothesis of Alzheimer's disease, a finding that emerged from the Framingham Heart study cohort.

Higher levels of inflammatory cytokines produced by peripheral blood cell suggested they are a risk marker for dementia, reported Zaldy S. Tan, M.D., M.P.H., of Harvard, and colleagues, in the May 29 issue of Neurology

In a study of 691 cognitively intact seniors who were part of the Framingham cohort, those in either the middle third of spontaneous production of interleukin 1 (IL-1), and the top third of tumor necrosis factor-? had a more than 2.5-fold risk for incident Alzheimer's,

"Clinical observations on the potential role of inflammation in Alzheimer's disease have yielded inconsistent results," they wrote. "Whereas several community-based studies have linked anti-inflammatory interventions to a lowered risk of developing Alzheimer's disease, a randomized, placebo-controlled clinical trial failed to demonstrate a beneficial effect of nonsteroidal anti-inflammatory drugs on the progression of Alzheimer's disease."

Other studies attempting to link various markers of systemic inflammation with an Alzheimer's risk have found either positive correlations, negative correlations, or no association between cytokine levels in patients with Alzheimer's disease versus controls, they noted.

To see whether serum cytokines and/or spontaneous production of cytokines by peripheral blood mononuclear cells might be associated with the risk for Alzheimer's disease, the authors followed 691 cognitively intact community-dwelling adults who were part of the longitudinal Framingham cohort.

The participants, 62% women, had a mean age of 79. All had taken part in the 22nd Framingham Study examination cycle, which ran from 1990 to 1994, and were cognitively normal at that examination. The patients all had available measurements from that cycle of C-reactive protein, IL-1, TNF-? and the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1RA).

The investigators assessed whether spontaneous production of IL-1 and TNF- ? by peripheral blood mononuclear cells and/or serum levels of C-reactive protein and IL-6 could be related to risk of incident Alzheimer's disease. All patients identified as having Alzheimer's dementia met he National Institute of Neurological and Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for definite, probable, or possible Alzheimer's.

They created Cox proportional hazard regression models for each of the inflammatory markers, adjusting for clinical covariates, including age, gender, for age, the apoliprotein-E4 allele, history of stroke, education, homocysteine levels, current smoking, body mass index, and statin use.

They found that after adjusting for clinical covariates, patients in the top two tertiles of peripheral blood mononuclear cells production of IL-1, and in the top tertile of TNF-? production, had significantly higher risks for developing Alzheimer's disease. For patients in the middle tertile of IL-1, the hazard ratio compared with the lowest tertile was 2.84 (95% confidence interval, 1.09 to 7.43; P=0.03, and for the top tertile was 2.61 (95% CI 0.96 to 7.07; P=0.06).

For TNF-?, the adjusted hazard ratio for the middle tertile was 1.30, (95% CI 0.53 to 3.17; P=0.57 and for the top tertile was 2.59 (95% CI. 1.09 to 6.12; P=0.031) compared with those in the lowest tertile.

Neither C-reactive protein nor serum IL-6 levels were related to the risk of Alzheimer's in any of the models. The authors noted that although high plasma levels of C-reactive protein and IL-6 have been associated with poor cognitive performance at baseline and a greater risk of cognitive decline over two years, there was no link between C-reactive protein and decreased cognitive function in an analysis from the Women's Health Study.

"Higher spontaneous production of interleukin 1 or tumor necrosis factor-? by peripheral blood mononuclear cells may be a marker of future risk of Alzheimer disease in older individuals," they wrote. "These data strengthen the evidence for a pathophysiologic role of inflammation in the development of clinical Alzheimer's disease."

The authors acknowledged that their study was insufficiently powered to determine whether there might be a modest association between circulating cytokines and Alzheimer's disease risk, and that their population of almost exclusively European background limits generalizability of results.