Elevated levels of inflammation biomarkers in midlife may be associated with loss of brain volume later in life, researchers found.

In an analysis of data from the prospective ARIC study, each standard deviation increase in a composite score of inflammation was tied to smaller hippocampal and occipital lobe volume about a quarter century later, Keenan Walker, PhD, of Johns Hopkins University, and colleagues reported online in Neurology.

Greater inflammation in midlife was also tied to a smaller Alzheimer’s disease signature region volume, and a larger ventricular volume down the road, the researchers said.

“These results suggest that inflammation in midlife may be an early contributor to the brain changes that are associated with Alzheimer’s disease and other forms of dementia,” Walker said in a statement. “Because the processes that lead to brain cell loss begin decades before people start showing any symptoms, it is vital that we figure out how these processes that happen in middle age affect people many years later.”

Walker and colleagues assessed data on 1,633 people (average age 53, 60% female, 27% African American) enrolled in the Atherosclerosis Risk in Communities (ARIC) study, creating composite scores for each participant based on levels of five blood-based markers of inflammation: fibrinogen, albumin, white blood cell count, von Willebrand factor, and Factor VIII.

A higher inflammation composite score at baseline was associated with older age, female sex, African-American race, and increased levels of a number of cardiovascular risk factors.

Patients, who enrolled in their 40s and 50s, were followed for an average of 24 years. At that time, the researchers found that each standard deviation increase in inflammation composite score at baseline was associated with a:

  • 532 mm3 smaller AD signature region volume (P=0.008)
  • 519 mm3 smaller occipital lobe volume (P=0.009)
  • 110 mm3 smaller hippocampal volume (P=0.013)
  • 1,788 mm3 larger ventricular volume (P=0.013)

They noted that each standard deviation increase in inflammation composite score on occipital lobe, ventricular, and hippocampal volume was “similar to the effect associated with possession of a single APOE e4 allele in our multivariable regression analyses.”

No link was found between midlife inflammation and total brain, frontal lobe, temporal lobe, or parietal lobe volume, they noted.

Late-life episodic memory was reduced among those with higher levels of the inflammation composite score; each standard deviation increase was associated with a -0.08 decrease in performance on the delayed word recall (DWR) test after adjustment (P=0.046), and a higher number of elevated inflammatory markers at baseline was tied to reduced DWR performance (P=0.009).

Walker told MedPage Today that primary analyses excluded patients who met criteria for various forms of dementia, but secondary analyses that involved patients with dementia at the time of MRI and memory assessments didn’t change the findings.

As suggested by prior cross-sectional studies in older non-demented adults, the association between midlife inflammation and late-life brain volume was modified by age and marginally by race, whereby younger participants and white participants with higher levels of systemic inflammation during midlife were more likely to show reduced brain volumes subsequently. However, this study did not support the previously reported interaction with sex, the authors noted.

While it is too early to recommend any dramatic changes in practice, Walker said the team’s findings “do suggest that reducing the burden of diseases known to cause chronic inflammation should be a priority for dementia prevention throughout adulthood. It is my hope that these findings will direct future research efforts for dementia prevention and treatment.”

Limitations included the use of some inflammatory markers that may be involved in other closely related physiologic processes such as hemostasis, which could impact brain volume, and by the fact that it relied on single measurements of inflammation, which may not paint a complete picture of inflammatory profile.

Elisabeth Lucassen, MD, of Penn State University, who wasn’t involved in the study, said although the results aren’t surprising, the study “allows a previously known association of variables to be viewed as a cause/effect that is more concrete.”

She said the researchers were thorough in looking at covariates, though “I would have been interested to know if diet may have played a role … I also think that they could have been more thorough in their cognitive testing, as the DWR only tests one aspect of dementia (episodic memory), and I do not think one can make a diagnosis of dementia based on this one test alone. An MMSE or MoCA at least would have tested more cognitive domains and are tests that are used clinically, giving clinicians a better perspective of what this data really mean.”

Share the knowledge