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AlzRisk Risk Factor Discussion
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Risk Factor:
Risk Factor Type: Metabolic
Current Understanding:
The tables below present a modest number of reports whose results, considered collectively, do not provide consistent support for an association between elevated peripheral blood levels of inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], alpha-1-antichymotrypsin [ACT], fibrinogen, lipoprotein-associated phospholipase A2 [Lp-PLA2], interleukin-1β [IL-1β] ) and risk for Alzheimer disease (AD). Associations between higher levels of these markers and total dementia risk are more suggestive, consistent with a reported link between vascular inflammation and vascular dementia. Individual markers were significantly associated with AD in some studies, but the evidence overall was inconsistent. The ability of peripheral inflammatory markers to represent inflammation in the central nervous system (CNS) is limited, and future studies may provide more clarity on the distinction between the roles of peripheral and CNS inflammation by identifying and measuring brain-specific markers of inflammation. In addition, it is possible that measurement of an overall inflammatory profile, particularly as it unfolds over time, may provide a much better test of the inflammatory hypothesis than individual markers measured on a single occasion. In the meantime, inflammatory responses might have an impact on disease progression, and could be the basis for developing and monitoring therapeutic treatments. For a review of the putative mechanisms by which inflammatory biomarkers may be related to AD risk and detailed commentary on interpreting the findings below in a broader context, please view the Discussion. A longer review and discussion of CRP and IL-6 can be found in the related earlier published review and meta-analysis, Koyama A, O’Brien J, Weuve J, Blacker D, Metti A, Yaffe K. The role of peripheral inflammatory markers in dementia and Alzheimer’s disease: A meta-analysis (J Gerontol A Biol Sci Med Sci 2013 April;68(4):433-440).
Literature Extraction: Search strategy  * New *
Last Search Completed: 12 May 2014

Risk Factor Overview

Cite as:

O'Brien J, Weuve J, Jackson JW, Blacker D. "Inflammatory biomarkers." The AlzRisk Database. Alzheimer Research Forum. Available at: http://www.alzrisk.org. Accessed [date of access]*.

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Introduction

The tables on the Risk Factor Overview present a modest number of reports whose results, considered collectively, do not provide consistent support for an association between elevated peripheral blood levels of inflammatory markers and risk for Alzheimer disease (AD). Of the range of inflammatory markers possibly involved in AD pathogenesis (Wyss-Coray, 2006; Brosseron et al., 2014), six have been examined in studies that meet our inclusion criteria: C-reactive protein (CRP), interleukin-6 (IL-6), and alpha-1-antichymotrypsin (ACT), fibrinogen, lipoprotein-associated phospholipase A2 (Lp-PLA2), and interleukin-1β (IL-1β). Some markers have been evaluated in only one or two studies, and where there are more studies, the results are generally inconsistent. There is some suggestion of an effect, however, for total dementia as an outcome, at least for some markers.

It should be noted that certain markers (e.g., fibrinogen, lipoprotein-associated phospholipase A2 [Lp-PLA2], interleukin-1β [IL-1β]), were not included as terms in our search strategy, but they were included in our review because did appear in papers that reported on other biomarkers (e.g., CRP, IL-6). These and similar terms will be integrated into the search strategy for future updates (for more information see the Search Strategy Page).

Please see the related published earlier review and meta-analysis, Koyama A, O’Brien J, Weuve J, Blacker D, Metti A, Yaffe K. The role of peripheral inflammatory markers in dementia and Alzheimer’s disease: A meta-analysis (J Gerontol A Biol Sci Med Sci 2013 April;68(4):433-440) for a more detailed discussion of CRP and IL-6 in relation to AD and total dementia risk.


Potential Mechanism of Action

Although the primary function of the immune system is to defend the body against foreign substances and remove debris, any inflammatory response has the potential to damage healthy tissue as well (McGeer and McGeer, 1998). There are a variety of mechanisms through which inflammatory processes within the brain and central nervous system (CNS) could contribute to the neurodegeneration observed in AD. Neurofibrillary plaques and tangles, the pathological hallmarks of AD, initiate an inflammatory response, and the ensuing inflammatory cascade damages tissues and may contribute to irreversible AD pathology and ultimately cell death (Akiyama et al., 2000). In addition, inflammation and other local insults (e.g., oxidative stress, mechanical damage, exposure to toxins, hypoxia) in the CNS could act additively in promoting neuronal degeneration (Maccioni et al., 2009). It is also possible that acute-phase proteins involved in the inflammatory response disrupt the removal of Aβ, the main constituent of amyloid plaques, and that this interruption is a factor in the pathogenesis of AD (Eikelenboom et al., 2006).

Inflammatory molecules generated in the periphery might also be directly toxic to the brain if they can cross the blood-brain barrier (BBB). Moreover, peripheral inflammatory markers might be indicators of more global inflammatory processes that may relate indirectly to AD risk via their role in the development and progression of cardiovascular disease (e.g., Casserly et al., 2004), diabetes (e.g., Pradhan et al., 2001) and related conditions (Viswanathan et al., 2009; AlzRisk review of diabetes).

While all the inflammatory markers may share some of these mechanisms, they also have distinct roles that may influence their potential impact on AD. CRP is an acute-phase reactant that activates the classic complement systems leading to cell lysis and phagocytosis of pathogens. IL-6 is a multifunctional cytokine that is released by cells at the site of an injury and stimulates the production of acute-phase proteins (including CRP). It influences the inflammatory response by affecting central nervous system cell growth and differentiation. While usually considered destructive in the CNS, it should be noted that IL-6 may also have anti-inflammatory properties (e.g., regulation of neuronal survival and differentiation) (Akiyama, 2000). ACT is a protease inhibitor and also an acute-phase reactant (Akiyama et al., 2000). It has been shown to reinforce β-amyloid deposits (Zhang and Janciauskiene, 2002), and to be involved in tau phosphorylation and tangle formation (Padmanabhan et al., 2006). Fibrinogen, an acute-phase protein, has been linked to inflammatory processes in a variety of pathologic conditions (Davalos and Akassoglou, 2012). Fibrinogen also has key hemostatic properties, and is a determinant of plasma viscosity and endothelial function. Elevated levels could reduce blood flow and enhance atherogenesis (Ernst and Resch, 1993). Lp-PLA2 is an enzyme produced by inflammatory cells, and is recognized as a marker of vascular inflammation (Ahmed et al., 2011). IL-1β, a proinflammatory cytokine, is upregulated in the AD brain and promotes neurotoxic activity (Liu and Chan, 2014).

Consistent with a role of the inflammatory response in AD, several of the "top 10" genes associated with Alzheimer's disease identified by AlzGene (REF), along with many of the proteins identified in a recent biomarker study that used multiplex (xMAP) assays to identify candidate blood plasma biomarkers for Alzheimer’s disease severity and progression (Hye et al., 2014), are involved in inflammation.


Methodological Issues

Exposure

Peripheral vs. Central Measurement. The studies reviewed here measured CRP, IL-6, ACT, fibrinogen, Lp-PLA2, and IL-1β in peripheral blood rather than within the brain. Studies that use these measures cannot directly address the question of whether damage due to inflammation originates within the brain because peripheral measurements may not reflect intracerebral levels. First, ACT and CRP do not appear to cross the BBB, so peripheral measurement reflects peripheral levels only. IL-6 is capable of crossing the BBB (Banks et al., 1996), but intracerebral levels may be overshadowed by peripheral inflammatory processes (e.g., vascular inflammation, major infection, rheumatoid arthritis). In healthy states, fibrinogen does not cross the BBB, but there can be deposition of fibrinogen in the CNS in conditions where the BBB is disrupted or damaged (e.g., hemorrhagic stroke, spinal cord injury, MS, AD) (Davalos and Akassoglou, 2012). In addition, levels of inflammatory biomarkers are readily influenced by the presence of other diseases unrelated to dementia, or may even increase because of the normal ageing process itself (Krabbe et al., 2004).

A more direct method to assess inflammation within the brain would be to measure inflammatory biomarkers in the cerebrospinal fluid (CSF). However, these measurements are relatively new (Mattsson et al., 2009), and, moreover, lumbar puncture is generally too invasive for epidemiologic studies.

Timing of exposure assessment. The timing of exposure measurement relative to dementia assessment is another key methodological issue, since elevated inflammatory markers in the periphery could reflect both causes and consequences of AD (Engelhart et al., 2004). Most of the studies evaluated here measured inflammatory profiles late in life. AD pathology commences long before the presentation of clinical symptoms, and studies with exposure assessment close to the onset age of dementia do not exclude the possibility that elevated levels of inflammatory molecules exist only in response to underlying disease and play no causal role in AD pathogenesis. The Honolulu-Asia Aging Study (Schmidt et al., 2002) recorded CRP levels 25 years before the dementia assessment, providing the only evidence that heightened levels of inflammatory biomarkers in midlife could influence the development of AD.

Assay sensitivity. The results from these studies could vary due to the sensitivity of the assays used to measure levels of inflammatory markers. For example, most studies of CRP used a high-sensitivity assay, but one used a lower-sensitivity assay, which might have contributed to the heterogeneity of results. Furthermore, the markers were measured only once, making it difficult to evaluate the possibility of measurement error or within-person variability. For instance, intercurrent illness could temporarily elevate levels of inflammatory markers, reducing the ability to detect the impact of ongoing lower levels of inflammation (Dik et al., 2005). It is especially challenging to isolate the source of any observed the inflammatory response in an elderly population with high rates of multiple medical conditions(Schram et al., 2007). However, previous studies have established that CRP levels are stable over time (Ockene et al., 2001), and that measures of inflammatory markers taken as much as five years apart are highly correlated (Ridker et al., 1999). Overall, large-scale epidemiologic studies of inflammatory markers offer the advantage of higher statistical power, which may be sufficient to detect associations attenuated by noise in the exposure measurement.

Confounding and intermediate variables

In observational studies such as the ones reported here, it remains possible that results could be partially explained by factors correlated with a person’s inflammatory profile (e.g., age, sex, education, cardiovascular disease, adiposity, smoking, physical activity). However, all the papers reported here adjusted for age, education, and sex at a minimum, and many also adjusted for cardiovascular disease, BMI, stroke history, smoking history, physical activity, hypertension, diabetes mellitus, the use of anti-inflammatory medication, and APOE genotype. In addition to the possibility of residual confounding, there may also be complex survival effects because inflammatory biomarker levels are influenced by smoking, cardiovascular disease, and other strong predictors of mortality.

Cardiovascular disease (CVD) and/or atherosclerosis could be intermediate variables in the putative relation of peripheral inflammation to AD. CRP in particular is known to be a marker for all forms of vasculopathy, including cerebral small vessel disease (van Dijk et al., 2005), which has a demonstrated role in the development of AD dementia (Farkas and Luiten, 2001). Peripheral vascular pathology could also lead to higher levels of peripheral inflammatory markers leading in turn to toxic effects on the brain. In any case, there is evidence that peripheral vascular disease is a risk factor for AD (Newman et al., 2005), and that cerebrovascular disease in the brain contributes to a greater risk of manifesting clinical dementia for a given level of AD pathology (Schneider et al., 2004).

In addition to the impact on AD and total dementia reported in the tables, some of the studies reviewed here showed an association between certain inflammatory markers and vascular dementia (VaD) or vascular cognitive impairment (VCI) (e.g., Ravaglia et al., 2007; Schmidt et al., 2002; Engelhart et al., 2004; van Oijen et al., 2005). In the Conselice Study of Brain Aging, high levels of serum CRP in combination with elevated IL-6 predicted VaD; none of the inflammatory markers measured in the study, alone or in combination, predicted AD (Ravaglia et al., 2007). In one investigation from the Rotterdam Study, there was an association between higher levels of CRP and increased risk of vascular dementia but not AD, though ACT and IL-6 did predict AD (Engelhart et al., 2004). However, another study from that cohort did not find an association between CRP and AD or VD, although higher levels of fibrinogen were associated with increased risk of both AD and VD (van Oijen et al., 2005). In the Honolulu Asia Aging Study, which measured only CRP, CRP concentrations at midlife predicted both AD and VD. Thus, it would seem that vascular inflammation (measured well by the blood biomarkers) is important at least in VaD, while the role in AD is less clear. However, these findings must be interpreted with caution because vascular risk factors and outcomes may steer the diagnosis away from Probable AD.


Results from Other Lines of Research

Other studies have focused on the role of inflammatory markers in cognitive performance and decline, and have also had mixed results. The results for these studies are similar to those for Alzheimer’s disease and total dementia reported in the tables: a mixture of positive and negative findings with no consistent result for any one biomarker (e.g., Yaffe et al., 2003; Dik et al., 2005; Teunissen et al., 2003; Roberts et al., 2009; Noble et al., 2010; Weuve et al., 2006; Alley et al., 2008).

The inflammatory response may have a genetic component, and it is possible that a genetic predisposition to an enhanced inflammatory response could augment an individual’s susceptibility to AD via a lifelong contribution of inflammatory processes to neuronal dysfunction and death (for review, see Wan et al., 2008). Some work has been done on the distinct effects of CRP among APOE-ε4 carriers, who are at elevated risk for AD. One study found no effect of CRP on dementia risk in non-carriers, but found CRP to be protective in carriers, leading the investigators to hypothesize that a high level of serum CRP could be a marker of healthy immune system functioning among those with the ε4 allele (Haan et al., 2008). Genome-wide association studies of AD have identified genes involved in inflammation (e.g., CLU, CR1), suggesting a potential role of inflammation in AD progression (Hollingworth et al., 2011).

Further support for the role of inflammation in AD might come from studies of non-steroidal anti-inflammatory drugs (NSAIDs). However, the available evidence, which includes both multiple prospective observational studies along with a large primary prevention trial, does not support the hypothesis that use of these drugs reduce AD risk. [Alzrisk review underway, Jaturapatporn et al., 2012, ADAPT research group, 2013, Szekely and Zandi, 2010).

Other inflammatory markers (e.g., tumor necrosis factor-α [TNF-α] (Fillit et al., 1995), IL-18 (Liu et al., 2014)) have been found in the brains and plasma of people with dementia (for reviews, McGeer & McGeer, 1995, 2006; Akiyama et al. 2000). To date, there are no epidemiologic studies of these markers meeting the AlzRisk inclusion criteria. Furthermore, new technologies (e.g., proteomics, microarray studies) may allow for multiple inflammatory markers or inflammation-related genes to be investigated simultaneously. Some studies have used these techniques to develop better predictive models of AD (O’Bryant et al., 2010; Johnstone et al., 2012; Ray et al., 2007).


Discussion and Recommendations

Although individual markers were significantly associated with AD in some studies, overall the evidence for an association of AD with peripheral inflammatory biomarkers is inconsistent. While the currently available markers do not provide evidence for a role of CNS inflammation in the development of AD, this does not preclude such a role. The ability of peripheral inflammatory markers to represent CNS inflammation is limited, and the signal to noise ratio may simply be too low. It is possible that measurement of an overall inflammatory profile, particularly as it unfolds over time, may provide a much better test of the inflammatory hypothesis than individual markers measured on a single occasion. In addition, brain-specific markers of inflammation may be identified and measured. In the meantime, inflammatory responses might have an impact on disease progression, and could be the basis for developing and monitoring therapeutic treatments Certainly at present, neither this review of inflammatory markers and AD/dementia risk nor that of non-steroidal anti-inflammatory drugs suggest a role for anti-inflammatory treatments as a strategy to prevent dementia.


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