Walker KA, Hoogeveen RC, Folsom AR, Ballantyne CM, Knopman DS, Windham BG, Jack CR Jr, Gottesman RF. Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study. Neurology. 2017 Nov 28;89(22):2262-2270. Epub 2017 Nov 1 PubMed.

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  1. This project identified association between a panel of inflammatory markers, which were assessed in midlife, and regional brain volumes on MRI and memory, both of which were measured 24 years later in life. The findings add another piece of data supporting the negative role that inflammation plays in brain aging and cognitive function.

    Given the unique long-term follow-up of the study, it also demonstrates the importance that factors from midlife play in late-life brain changes. Recently, similar results have been reported for midlife blood pressure and midlife diabetes. Taken together, these studies suggest that interventions aimed at preventing late-life brain changes may need to target individuals earlier in life than previously appreciated.  

    View all comments by Tom Mosley

  2. This study measured plasma levels of four acute phase proteins (fibrinogen, albumin, von Willebrand factor and Factor VIII) and white cell count in a mixed-race, middle-age group of 1,633 subjects with later assessment of episodic memory and 3T MRI brain volumetric studies. A composite score of these five inflammatory markers at one time point was shown to be associated with greater ventricular volumes and smaller hippocampi in these subjects 24 years later.

    Clearly this study needs to be replicated, but the findings make a lot of sense. Thus, it follows what we know of genetic risk, with the majority of the genetic risk factors in late-onset AD being involved in innate and adaptive immunity (the majority of these risk factors having peripheral as well as central effects). The standard midlife chronic inflammatory markers used in this study are known markers for cardiovascular disease and other inflammatory diseases in later life, which are also known risk factors for AD. So an association makes sense. But is it causal? It would be interesting to assess whether these peripheral inflammatory markers are also detected in the brain, and thus potentially reflecting an impairment or vulnerability of the blood-brain barrier integrity.

    The authors mention the relationship between these inflammatory markers and the peripheral cytokines IL6 and TNFα as a possible link with the CNS inflammation. Indeed these links are already in the clinical literature but not mentioned. Thus, Marsland et al.., 2008, have shown that peripheral IL6 levels are associated with smaller hippocampi on imaging in later life. Our own and others’ research shows that systemic inflammation, highlighted by an increase in TNFα, is associated with cognitive decline in AD (Holmes et al., 2009). Blockade of TNFα is associated with reducing cognitive decline in established AD (Butchart et al., 2015) and a reduced risk of developing AD (Chou et al., 2016). These findings and this new study point to causality. Hopefully this study will reawaken interest in peripheral inflammation as a viable treatment target. 

    References:

    Marsland AL, Gianaros PJ, Abramowitch SM, Manuck SB, Hariri AR. Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults. Biol Psychiatry. 2008 Sep 15;64(6):484-90. PubMed.

    Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009 Sep 8;73(10):768-74. PubMed.

    Butchart J, Brook L, Hopkins V, Teeling J, Püntener U, Culliford D, Sharples R, Sharif S, McFarlane B, Raybould R, Thomas R, Passmore P, Perry VH, Holmes C. Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. Neurology. 2015 May 26;84(21):2161-8. Epub 2015 May 1 PubMed.

    Chou RC, Kane M, Ghimire S, Gautam S, Gui J. Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case-Control Analysis. CNS Drugs. 2016 Nov;30(11):1111-1120. PubMed.

    View all comments by Clive Holmes

  3. This work is a window to expand what we know about the pathophysiology of AD. It is good work and deserves credit. Based on this article and previous findings, I think focus should be directed to: 

    1. In-depth understanding of inflammation mechanisms.
    2. A better search about upregulation of growth factors such as Neuregulin-1 and ErbB1-4 family, atherosclerotic factors at large (e.g., Apo E4, insulin or lack of its usage due to familial diabetes).
    3. Coagulative factors such as factor 8 mentioned in the article.
    4. Beta-catenin/wnt versus axin-2 cascades.
    5. The immune factors by themselves, as there are connections between neurodegeneration, for example Parkinson's disease, and coagulative factors. The relationship between certain cancers and neurodegenerative disorders goes back to the ’70s. An example is the relationship between PD and acute myeloid leukemia.

    We now know that factors contributing to blood, bone marrow, and gut cancers are involved in certain neurodegenerative diseases, such as MS and PD. The authors suggested IL-6 involvement in neurodegeneration, as was expected.

    There are few studies looking at albumin as a definitive marker for neurodegeneration. It makes sense to consider it as an indirect factor. Looking at Albumin combined with ApoE , LDL, VLDL, cholesterol, and immune factors such histamine would be an interesting path of research.

    Enjoyed reading the article and thank you to Alzforum for bringing it to the fore. 

    View all comments by Petra Katebi Kashi

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  1. Inflammation in Midlife Portends Late-Life Brain Shrinkage