In a surprising finding, elevated levels of two inflammatory proteins were associated with slower cognitive decline in older adults.

Higher plasma levels of pro-inflammatory cytokine interleukin-12 p70 (IL-12p70) were associated with less cognitive decline in people with a significant burden of amyloid-beta, reported Rudolph Tanzi, PhD, of Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues. Elevated IL-12p70 levels also were associated with fewer tau tangles in these people.

Moreover, higher levels of another pro-inflammatory cytokine, interferon-gamma (IFN-γ), were associated with slower cognitive decline independently of amyloid burden, they wrote in Alzheimer’s & Dementia.

“These are totally unexpected results,” Tanzi said in a statement.

Previous meta-analyses of case-control and prospective cohort studies showed that cytokines and inflammatory markers — like interleukin-6 (IL-6), C-reactive protein (CRP), and others — are elevated in Alzheimer’s dementia cases and predicted incident all-cause dementia.

While it seems counterintuitive that people with high levels of inflammation-inducing proteins are protected against cognitive decline, it may be that their immune systems are better primed to fight infection, Tanzi observed.

This would fit with the antimicrobial protection hypothesis of Alzheimer’s that Tanzi helped developed, which postulates that amyloid-beta aggregation can be triggered by subacute microbial infection in the brain. Having high levels of IL-12 and IFN-γ “may nip infections in the bud, before they can leak into the brain and induce Alzheimer’s pathology,” he said.

Tanzi and colleagues measured nine cytokines in the baseline plasma of 298 older adults who were cognitively unimpaired and followed longitudinally in the Harvard Aging Brain Study. Mean baseline age was 72; 62% were female and 81% were white. Participants were followed an average of 4.3 years.

The researchers first looked to see whether the cytokines were associated with cognitive decline — alone or synergistically with amyloid-beta — then examined associations between cytokine levels and neuroimaging biomarkers of amyloid, tau, and neurodegeneration.

Neither IL-12p70 nor IFN-γ was associated with age, sex, or APOE4 carrier status (all P>0.05). Immunosuppressant medication use did not affect baseline IL-12p70 or IFN-γ levels. Concentrations of IL-12p70 and IFN-γ from the same individual remained stable on repeat measures up to several years apart.

Higher IL-12p70 was associated with slower cognitive decline in the setting of higher amyloid-beta (false discovery rate=0.0023). Higher IFN-γ was associated with slower cognitive decline independent of amyloid burden (false discovery rate=0.013).

Higher IL-12p70 was associated with less neocortical tau on PET and hippocampal neurodegeneration in people with a higher amyloid-beta burden. IFN-γ was not correlated with tau or neurodegeneration.

“Greater IL-12/IFN-γ axis activation may be protective against cognitive decline and early-stage Alzheimer’s disease progression,” Tanzi and colleagues wrote.

The study had several limitations, the researchers acknowledged. Associations between IL-12p70 and neuroimaging markers of tau and neurodegeneration were cross-sectional, not longitudinal. The study enrolled cognitively unimpaired people who mainly were white and findings may not extend to other older adults.

Moreover, the effect sizes of IL-12 and IFN-γ in predicting cognitive decline were statistically significant, but small. “These cytokines should be considered ancillary biomarkers rather than stand-alone prognostic indicators,” Tanzi and colleagues wrote. Further validation and mechanistic studies are needed to translate the findings into clinical use.