Summary: Higher circulating levels of two cytokines were linked to slower cognitive decline in older adults, according to a new study.
Source: Mass General
Although previous research has associated inflammation with Alzheimer’s disease (AD), investigators from Massachusetts General Hospital (MGH) and the Harvard Aging Brain Study (HABS) report unexpected findings about that relationship.
Published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the study finds that higher blood levels of two inflammation-related signaling proteins, known as cytokines, correlate with a slower rate of cognitive decline among older adults.
“These are totally unexpected results,” says Rudolph Tanzi, PhD, co-senior author of the study, vice chair of Neurology and co-director of the Henry and Allison McCance Center for Brain Health at MGH. He notes that these findings may eventually help identify cognitively normal people who remain at risk for AD before symptoms emerge.
Tanzi’s prior work includes the 2008 discovery of CD33, the first Alzheimer’s-associated gene tied to the immune system. Since that finding, many other AD-related genes have pointed to immune system involvement, and a growing body of evidence implicates immune dysregulation in AD. Historically, elevated cytokine levels have been reported in people with AD and other dementias.
What remained unclear was how the immune system behaves during the earliest, pre-symptomatic phase of AD—when hallmark brain changes can accumulate in apparently healthy older adults. To explore that stage, the researchers partnered with HABS to determine whether measuring cytokines in blood (a minimally invasive test) might predict later cognitive decline more feasibly than cerebrospinal fluid testing, which requires a lumbar puncture.
The study focused particularly on older adults who were cognitively normal at enrollment but whose brain PET scans showed deposits of amyloid beta, the principal component of amyloid plaques linked to AD. The central question was why some people can carry amyloid in the brain without noticeable decline while others progress to impairment.
Co-senior author Jasmeer Chhatwal, MD, PhD, a neurologist at MGH and HABS investigator, explains that combining McCance Center expertise with HABS’s long-term cohort data provided an ideal opportunity to search for blood-based biomarkers of resilient versus vulnerable brain aging.
The analysis included 298 HABS participants aged 50 to 90 who were cognitively unimpaired at baseline and received annual cognitive assessments. All participants provided blood samples at enrollment and underwent PET imaging to assess amyloid beta and tau pathology, along with other neurodegenerative changes.
Investigators measured nine cytokines in baseline plasma and tested associations between these cytokine levels and subsequent cognitive trajectories, as well as links to imaging markers of amyloid, tau, and neurodegeneration. Two cytokines stood out.
First, higher plasma concentrations of interleukin-12 (IL-12), a pro-inflammatory cytokine, were associated with markedly slower cognitive decline among participants who had a substantial amyloid burden on PET. In contrast, individuals with high amyloid but lower IL-12 showed greater cognitive decline over time. Higher IL-12 levels were also linked to fewer tau tangles and reduced neurodegeneration in amyloid-positive participants.
Second, elevated levels of interferon-gamma (IFN-γ), another pro-inflammatory cytokine, correlated with slower cognitive decline regardless of amyloid status. Together, these findings identify an IL-12/IFN-γ axis that may relate to resilience against early-stage cognitive deterioration.
At first glance, it seems counterintuitive that higher levels of inflammation-associated proteins in blood would coincide with protection from cognitive decline. Tanzi suggests a possible explanation: elevated IL-12 and IFN-γ may reflect an immune system that is better primed to prevent or control infections that could otherwise penetrate the nervous system and trigger Alzheimer’s pathology.
This idea aligns with a hypothesis Tanzi developed with the late Robert Moir, PhD, proposing that amyloid beta can act as an antimicrobial defense, trapping pathogens in the brain. Over time, however, persistent amyloid accumulation may become harmful, damaging neurons and synapses. A more responsive peripheral immune system—signaled by higher IL-12 and IFN-γ—might prevent infections from escalating and interacting with amyloid to accelerate neurodegeneration.
If validated, measuring IL-12 and IFN-γ in plasma could augment a future toolkit of blood-based biomarkers to assess brain health in cognitively normal adults—a clinical “checkup from the neck up” that currently does not exist. The researchers emphasize that further work is needed to understand the mechanisms by which these cytokines influence brain aging and to determine whether they could guide prevention strategies.
The study’s lead author, Hyun-Sik Yang, MD, notes that men and women with both high amyloid and low IL-12 experienced greater decline, reinforcing the potential importance of IL-12 in modifying disease trajectory. Moving forward, the team will explore how the IL-12/IFN-γ axis interacts with other immune and neurobiological processes linked to Alzheimer’s disease.
Rudolph Tanzi is Vice-Chair of Neurology (Research) and Co-Director of the Henry and Allison McCance Center for Brain Health at MGH and holds the Joseph P. and Rose F. Kennedy Professorship of Neurology at Harvard Medical School. Jasmeer Chhatwal and Hyun-Sik Yang are assistant professors of Neurology at Harvard Medical School and investigators affiliated with HABS.
Funding: This research was supported by the National Institutes of Health, the Cure Alzheimer’s Fund and the Doris Duke Charitable Foundation.
About this cognitive decline and aging research news
Source: Mass General
Contact: Marcela Quintanilla-Dieck – Mass General
Image: The image is in the public domain
Original Research: Closed access. “Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults” by Rudolph Tanzi et al., published in Alzheimer’s & Dementia.
Abstract
Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults
Introduction
Immune dysregulation has been implicated in neurodegeneration, and altered cytokine profiles are reported in people with dementia. It remains unclear whether baseline plasma cytokine levels can predict cognitive decline in cognitively unimpaired older adults, particularly in the context of elevated brain amyloid beta (Aβ).
Methods
The researchers measured nine cytokines in baseline plasma from 298 cognitively unimpaired, longitudinally followed older adults. They tested whether plasma cytokine levels predicted cognitive decline over time, alone or in interaction with Aβ burden on PET imaging, and examined associations with imaging markers of Aβ, tau pathology, and neurodegeneration.
Results
Higher IL-12p70 predicted slower cognitive decline among participants with higher Aβ (false discovery rate [FDR] = 0.0023), while higher IFN-γ predicted slower decline independent of Aβ status (FDR = 0.013). Elevated IL-12p70 was also linked to lower tau burden and less neurodegeneration among those with higher Aβ.
Discussion
These findings implicate immune signaling in early-stage cognitive changes and suggest that greater activation of the IL-12/IFN-γ axis may be associated with protection against cognitive decline and early progression of Alzheimer’s pathology. Further studies are needed to confirm these associations and to clarify the underlying biological mechanisms.