Midlife Peripheral Inflammation May Drive Later Cognitive Decline

A decades-long study of more than 12,000 participants suggests that midlife inflammation drives cognitive decline in old age. Scientists led by Rebecca Gottesman, Johns Hopkins Medicine, Baltimore, report in the February 13 Neurology that having more markers of inflammation during middle adulthood leads to worse memory, language, and executive function 20 years later. The findings suggest systemic inflammation might drive cognitive decline in the decades leading up to older adulthood, the authors suggest.

  • Scientists studied more than 12,000 people in the 20-year ARIC study.
  • Systemic inflammation in midlife predicted worse cognition in old age.
  • Memory declined the most, followed by language and executive skills.

“This large, longitudinal study adds strong evidence to the existing literature supporting an important role of inflammation in cognitive decline or Alzheimer’s disease,” wrote Yian Gu, Columbia University, New York, to Alzforum. Gu was not involved in the study.

The Atherosclerosis Risk in Communities (ARIC) cohort study has been ongoing for more than 30 years. Between 1987 and 1989, researchers enrolled more than 15,000 adults aged 45 to 65 from cities around the U.S. More than half the participants in this population-based study are women and almost a third are black. Recently, researchers reported that in this cohort, systemic inflammation in midlife predicts faster loss of brain volume and memory loss, as well as structural white-matter injuries in later life (Nov 2017 news; Walker et al., 2017).

In the current study, first author Keenan Walker and colleagues studied cognitive outcomes in 12,336 of the volunteers. They excluded participants who had missing biological data, a previous stroke, significant baseline cognitive impairment, or were underrepresented with regard to race for each study site. Walker correlated cognitive decline with baseline measures of inflammatory biomarkers in the blood, including fibrinogen, von Willebrand factor, factor VIII, white blood cell count, and C-reactive protein (CRP). In ARIC, the first four markers, measured since the first visit, were combined into a composite score. CRP, recognized later as a marker of cardiovascular disease, was added by the time people came for their second visit, and was accounted for separately. During 20 years of follow-up, volunteers had been tested three times on the Delayed Word Recall Test, the Digit Symbol Substitution Test, and the Word Fluency Test. Those scores were combined into a cognitive composite.

After controlling for demographic variables, comorbidities, and vascular risk factors other than the inflammatory markers, Walker found that more severe midlife inflammation associated with a steeper decline in cognition over the 20 years. Each standard deviation (SD) increase of the midlife inflammation composite translated to an additional loss of 0.035 SD on the cognitive composite after accounting for ongoing age-related decline. Volunteers with inflammatory scores in the top quartile performed 7.8 percent worse in cognitive tests than those with inflammation scores in the bottom quartile. CRP independently correlated with cognitive decline, each SD increase equating to a decline of 0.038 SDs. People in the top CRP quartile ended up with 11.6 percent more decline than those in the bottom quartile. Declines in memory were biggest, followed by language, while executive function didn’t change much. The effect of inflammation on cognitive decline was larger than for midlife hypertension, as reported in a previous ARIC study (Gottesman et al., 2014). 

While the results suggest that midlife inflammation puts a person at risk for cognitive decline later, the authors caution that systemic inflammation could be a marker, rather than a cause, of brain cell damage. They also can’t rule out inflammation as a response to neural proteopathies, such as those caused by Aβ or tau.

Previous studies of the association between systemic inflammation and cognitive impairment were mostly either cross-sectional or limited to older adults with brief follow-up. However, in keeping with the ARIC data, a 10-year study of 5,200 middle-aged French men reported that high inflammatory markers in the blood predicted cognitive decline 10 years in the future (Jul 2014 news). Similarly, the Honolulu-Asia aging study examining Japanese-American men found that those with higher CRP levels in midlife were at a threefold higher risk for dementia more than two decades later (Schmidt et al., 2002; Laurin et al., 2009). 

Most researchers interviewed for this article agreed that inflammatory markers would make poor predictive biomarkers of dementia risk, as levels can fluctuate due to many conditions. “Although we show that inflammation may be a risk factor for cognitive decline, the nonspecific nature of many of the inflammatory proteins studied thus far will likely limit their effectiveness as strong prognostic biomarkers for dementia or cognitive decline,” Walker told Alzforum. People can control their inflammation levels by treating systemic conditions, including cardiovascular and chronic inflammatory diseases, Walker said. Exercise as well as certain diets can also help reduce inflammation.—Gwyneth Dickey Zakaib

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References

News Citations

  1. Inflammation in Midlife Portends Late-Life Brain Shrinkage
  2. Inflammation in Midlife May Presage Cognitive Decline

Paper Citations

  1. Walker KA, Power MC, Hoogeveen RC, Folsom AR, Ballantyne CM, Knopman DS, Windham BG, Selvin E, Jack CR Jr, Gottesman RF. Midlife Systemic Inflammation, Late-Life White Matter Integrity, and Cerebral Small Vessel Disease: The Atherosclerosis Risk in Communities Study. Stroke. 2017 Nov 3; PubMed.
  2. Gottesman RF, Schneider AL, Albert M, Alonso A, Bandeen-Roche K, Coker L, Coresh J, Knopman D, Power MC, Rawlings A, Sharrett AR, Wruck LM, Mosley TH. Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study. JAMA Neurol. 2014 Oct;71(10):1218-27. PubMed.
  3. Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol. 2002 Aug;52(2):168-74. PubMed.
  4. Laurin D, David Curb J, Masaki KH, White LR, Launer LJ. Midlife C-reactive protein and risk of cognitive decline: a 31-year follow-up. Neurobiol Aging. 2009 Nov;30(11):1724-7. Epub 2008 Mar 7 PubMed.

Further Reading

Papers

  1. Gottesman RF, Albert MS, Alonso A, Coker LH, Coresh J, Davis SM, Deal JA, McKhann GM, Mosley TH, Sharrett AR, Schneider AL, Windham BG, Wruck LM, Knopman DS. Associations Between Midlife Vascular Risk Factors and 25-Year Incident Dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort. JAMA Neurol. 2017 Oct 1;74(10):1246-1254. PubMed.
  2. Beydoun MA, Dore GA, Canas JA, Liang H, Beydoun HA, Evans MK, Zonderman AB. Systemic Inflammation Is Associated With Longitudinal Changes in Cognitive Performance Among Urban Adults. Front Aging Neurosci. 2018;10:313. Epub 2018 Oct 9 PubMed.
  3. Marsland AL, Gianaros PJ, Kuan DC, Sheu LK, Krajina K, Manuck SB. Brain morphology links systemic inflammation to cognitive function in midlife adults. Brain Behav Immun. 2015 Aug;48:195-204. Epub 2015 Apr 14 PubMed.

Primary Papers

  1. Walker KA, Gottesman RF, Wu A, Knopman DS, Gross AL, Mosley TH Jr, Selvin E, Windham BG. Systemic inflammation during midlife and cognitive change over 20 years: The ARIC Study. Neurology. 2019 Feb 13; PubMed.

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