Neuroinflammation goes hand in hand with dementia, but it remains unclear which comes first. Epidemiologic research reported in the July 2 Neurology now links elevated peripheral cytokines in midlife to later cognitive decline, strengthening the case that inflammation may contribute to neurodegeneration. Researchers led by Archana Singh-Manoux at INSERM, Paris, retrospectively analyzed data from more than 5,200 cognitively healthy participants in a longitudinal study, and found that those with the highest plasma levels of the inflammatory protein IL-6 had the lowest cognitive scores at baseline and also experienced the steepest drop in mental abilities over the next 10 years. Although the effect size was modest, it nonetheless accelerated age-related cognitive decline by about four years, the authors calculated.
Holly Soares at Bristol-Myers Squibb, Wallingford, New Jersey, called the data intriguing. “It is consistent with the literature showing there are blood-based signatures that flag people who are progressing to dementia. The next step would be a prospective study to see how robust this finding is,” she told Alzforum. Soares was not involved in the research.
In elderly populations, high plasma levels of several inflammatory proteins associate with an increased risk of developing Alzheimer’s disease or vascular dementia (see, e.g., Engelhart et al., 2004; Tan et al., 2007). Few studies have looked at midlife, however, leaving it unclear whether inflammation represents a cause of dementia or merely an early symptom. A Dutch study hinted at the former, reporting that middle-aged children of AD patients, who have higher risk for the disease, had elevated levels of several cytokines (see van Exel et al., 2009).
To look more closely at middle-aged populations, Singh-Manoux and colleagues turned to the U.K. Whitehall II study. Participants were former London office workers, predominantly white, male, and well-educated, with an average age of 56 at baseline. The authors focused on two inflammatory proteins that have been consistently linked to dementia risk: the cytokine interleukin-6 (IL-6) and C-reactive protein (CRP), which is released by the liver in response to inflammation. The authors averaged plasma levels from two measurements taken a few years apart to arrive at baseline values, thus lessening the effect of any aberrant readings from temporary challenges to the immune system, such as infections. At baseline, participants at the highest third of IL-6 levels scored modestly worse on tests of reasoning and verbal fluency. Although the difference only amounted to approximately one-tenth of the baseline standard deviation in this population, it equaled an acceleration in age-related cognitive decline of about two years, the authors claim.
Over the next 10 years, the cognitive performance of all participants dropped by about one-third of the baseline standard deviation. Those with the highest IL-6 again fared worse than their peers in reasoning tests, with their losses corresponding to an additional two years of cognitive aging, for a total difference of four years. In addition, this group was almost twice as likely as peers to experience a drop of three points or more on the Mini-Mental Status Examination. However, people with high IL-6 did fine on short-term memory tests. Because speech and reasoning problems commonly occur in vascular dementia, whereas memory loss better characterizes AD, the data support other studies that have linked inflammatory markers more strongly to vascular dementia than AD, the authors note (see Schmidt et al., 2002; Sundelöf et al., 2009).
Although participants with high CRP levels showed a trend toward lower baseline cognition and faster decline, it was not significant after adjusting for confounding factors such as age, sex, and education. In an accompanying editorial, Mario Di Napoli at San Camillo de Lellis General Hospital, Rieti, Italy, and Jeremy Silverman at Icahn School of Medicine, Mount Sinai, New York, point out that IL-6 directly affects processes such as lipid metabolism that might contribute to cognitive decline, whereas CRP is activated downstream of IL-6 and thus may not become a factor until later in life. Some neuroimaging studies show that IL-6 associates more closely with brain volume loss than does CRP (see Jefferson et al., 2007; Fornage et al., 2008; Satizabal et al., 2012).
Commentators agreed that more research is needed to tease out the effect inflammation might have on the brain. Soares wondered whether these markers associate specifically with dementia, or rather might be general risk factors for many neurodegenerative diseases. Sid O’Bryant at the University of North Texas Health Science Center, Fort Worth, noted that he would like to see a follow-up study looking at a panel of inflammatory markers. Researchers also noted that because plasma cytokine levels fluctuate greatly, these molecules probably would be poor biomarkers. “Measurement of IL-6 in midlife is highly unlikely to be useful in clinical practice on an individual level,” Di Napoli and Silverman concluded.—Madolyn Bowman Rogers
- Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, Stijnen T, Hofman A, Witteman JC, Breteler MM. Inflammatory proteins in plasma and the risk of dementia: the rotterdam study. Arch Neurol. 2004 May;61(5):668-72. PubMed.
- Tan ZS, Beiser AS, Vasan RS, Roubenoff R, Dinarello CA, Harris TB, Benjamin EJ, Au R, Kiel DP, Wolf PA, Seshadri S. Inflammatory markers and the risk of Alzheimer disease: the Framingham Study. Neurology. 2007 May 29;68(22):1902-8. PubMed.
- van Exel E, Eikelenboom P, Comijs H, Frölich M, Smit JH, Stek ML, Scheltens P, Eefsting JE, Westendorp RG. Vascular factors and markers of inflammation in offspring with a parental history of late-onset Alzheimer disease. Arch Gen Psychiatry. 2009 Nov;66(11):1263-70. PubMed.
- 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.
- Sundelöf J, Kilander L, Helmersson J, Larsson A, Rönnemaa E, Degerman-Gunnarsson M, Basun H, Lannfelt L, Basu S. Systemic inflammation and the risk of Alzheimer's disease and dementia: a prospective population-based study. J Alzheimers Dis. 2009 Jan 1;18(1):79-87. PubMed.
- Jefferson AL, Massaro JM, Wolf PA, Seshadri S, Au R, Vasan RS, Larson MG, Meigs JB, Keaney JF, Lipinska I, Kathiresan S, Benjamin EJ, Decarli C. Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study. Neurology. 2007 Mar 27;68(13):1032-8. PubMed.
- Fornage M, Chiang YA, O'Meara ES, Psaty BM, Reiner AP, Siscovick DS, Tracy RP, Longstreth WT Jr. Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study. Stroke. 2008 Jul;39(7):1952-9. Epub 2008 Apr 24 PubMed.
- Satizabal CL, Zhu YC, Mazoyer B, Dufouil C, Tzourio C. Circulating IL-6 and CRP are associated with MRI findings in the elderly: the 3C-Dijon Study. Neurology. 2012 Mar 6;78(10):720-7. Epub 2012 Feb 22 PubMed.
- Singh-Manoux A, Dugravot A, Brunner E, Kumari M, Shipley M, Elbaz A, Kivimaki M. Interleukin-6 and C-reactive protein as predictors of cognitive decline in late midlife. Neurology. 2014 Jul 2; PubMed.
- Di Napoli M, Silverman JM. How predictive of dementia are inflammatory biomarkers in late midlife?. Neurology. 2014 Jul 2; PubMed.