Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study

Keenan A. Walker, Ron C. Hoogeveen, Aaron R. Folsom, Christie M. Ballantyne, David S. Knopman, B. Gwen Windham, Clifford R. Jack, Rebecca F. Gottesman

Research output: Contribution to journalArticlepeer-review

83 Scopus citations


Objective: To clarify the temporal relationship between systemic inflammation and neurodegeneration, we examined whether a higher level of circulating inflammatory markers during midlife was associated with smaller brain volumes in late life using a large biracial prospective cohort study. Methods: Plasma levels of systemic inflammatory markers (fibrinogen, albumin, white blood cell count, von Willebrand factor, and Factor VIII) were assessed at baseline in 1,633 participants (mean age 53 [5] years, 60%female, 27%African American) enrolled in the Atherosclerosis Risk in Communities Study. Using all 5 inflammatory markers, an inflammation composite score was created for each participant. We assessed episodic memory and regional brain volumes, using 3T MRI, 24 years later. Results: Each SD increase in midlife inflammation composite score was associated with 1,788 mm3 greater ventricular (p = 0.013), 110 mm3 smaller hippocampal (p = 0.013), 519 mm3 smaller occipital (p = 0.009), and 532 mm3 smaller Alzheimer disease signature region (p = 0.008) volumes, and reduced episodic memory (p = 0.046) 24 years later. Compared to participants with no elevated (4th quartile) midlife inflammatory markers, participants with elevations in 3 or more markers had, on average, 5% smaller hippocampal and Alzheimer disease signature region volumes. The association between midlife inflammation and late-life brain volume was modified by age and race, whereby younger participants and white participants with higher levels of systemic inflammation during midlife were more likely to show reduced brain volumes subsequently. Conclusions: Our prospective findings provide evidence for whatmay be an early contributory role of systemic inflammation in neurodegeneration and cognitive aging.

Original languageEnglish (US)
Pages (from-to)2262-2270
Number of pages9
Issue number22
StatePublished - 2017

Bibliographical note

Funding Information:
K. Walker, R. Hoogeveen, A. Folsom, and C. Ballantyne report no disclosures relevant to the manuscript. D. Knopman serves on a Data Safety Monitoring Board for Lundbeck Pharmaceuticals and the DIAN study; is an investigator in clinical trials sponsored by Biogen, TauRX Pharmaceuticals, Lilly Pharmaceuticals, and the Alzheimer’s Disease Cooperative Study; and receives research support from NIH. B. Windham reports no disclosures relevant to the manuscript. C. Jack Jr serves on a scientific advisory board for Eli Lilly and Company and receives research support from NIH and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Foundation. R. Gottesman is Associate Editor for Neurology® and receives research support from the NIH. Go to Neurology.org for full disclosures.

Funding Information:
The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data are collected by U01 HL096812, HL096814, HL096899, HL096902, and HL096917 with previous brain MRI examinations funded by R01-HL70825. Dr. Walker was supported by the NIA (T32 AG027668). The sponsors had no role in the design and conduct of the study; collection management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Publisher Copyright:
© 2017 American Academy of Neurology.


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