Elsevier

Brain, Behavior, and Immunity

Volume 95, July 2021, Pages 178-189
Brain, Behavior, and Immunity

Peripheral inflammatory biomarkers predict the deposition and progression of amyloid-β in cognitively unimpaired older adults

https://doi.org/10.1016/j.bbi.2021.03.015Get rights and content

Highlights

  • IL-6 predicts conversion from cognitively unimpaired to mild cognitive impairment.

  • IL-6, CRP associated with longitudinal change in amyloid-β in non-demented elders.

  • Systemic inflammation differentially predicts amyloid-β based on preclinical disease.

  • Those with preclinical Alzheimer’s disease more susceptible to systemic inflammation.

Abstract

Introduction

Systemic inflammation has been increasingly implicated in the pathogenesis of Alzheimer’s disease (AD), yet the mechanistic and temporal specificity of this relationship is poorly understood. We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and Aβ deposition in oldest-old cognitively unimpaired (CU) adults.

Methods

A large sample of 139 CU older adults (mean age (range) = 85.4 (82–95)) underwent neuropsychological testing, Pittsburgh compound-B (PiB)-PET imaging and structural MRI. Hierarchical regression models examined associations between circulating inflammatory biomarkers (Interleukin-6 (IL-6), soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFr1 and sTNFr2), soluble cluster of differentiation 14 (sCD14), C-reactive protein (CRP)), cognition, and global and regional Aβ deposition at baseline and over follow-up. Indices of preclinical disease, including pathologic Aβ status and hippocampal volume, were incorporated to assess conditional associations.

Results

At baseline evaluation, higher concentrations of IL-6 and sTNFr2 were associated with greater global Aβ burden in those with lower hippocampal volume. In longitudinal models, IL-6 predicted subsequent conversion to MCI and both IL-6 and CRP predicted greater change in global and regional Aβ deposition specifically among participants PiB-positive at baseline. These relationships withstood adjustment for demographic factors, anti-hypertensive medication use, history of diabetes, heart disease, APOE ε4 carrier status, and white matter lesions.

Discussion

In a large prospective sample of CU adults aged 80 and over, peripheral inflammatory biomarkers were associated with and predictive of the progression of Aβ deposition. This was specific to those with biomarker evidence of preclinical AD at baseline, supporting recent evidence of disease-state-dependent differences in inflammatory expression profiles. Chronic, low-level systemic inflammation may exacerbate the deposition of Aβ pathology among those with emerging disease processes, and place individuals at a higher risk of developing clinically significant cognitive impairment.

Introduction

Alzheimer’s disease (AD) is the most prevalent cause of dementia and is pathologically defined in the brain by aggregated amyloid-beta (Aβ) plaques and hyperphosphorylated tau tangles (NFTs). These neurodegenerative processes commence many years before clinical symptoms manifest, with Aβ plaques considered the first detectable change in the preclinical stage of AD (Jack et al., 2018, Sperling et al., 2011). Along with Aβ and NFTs, it is now widely recognized that both the onset and the progression of AD likely involves a complex network of processes that interact to provoke a cycle of cellular dysfunction, injury, and death (Musiek and Holtzman, 2015, Wang et al., 2017). The development of timely and targeted interventions requires an enhanced understanding of the mechanisms that predict or perpetuate these neurodegenerative changes, particularly early in the course of disease onset. While inflammation has been increasingly implicated in AD pathogenesis (Canter et al., 2016, Heneka et al., 2015), the mechanistic and temporal specificity of this relationship is not well understood.

The acute inflammatory response to brain injury or infection is a well-established and adaptive defense system. Mediated by microglial cells, the inflammatory cascade serves to restore tissue health and benefit the affected neural environment (Calsolaro and Edison, 2016, Rubio-Perez and Morillas-Ruiz, 2012). However, in AD, perturbations in the inflammatory response occur. Abundant animal work shows that the presence and accumulation of Aβ causes microglial cells to remain in a state of chronic activation, resulting in prolonged pro-inflammatory signaling that exacerbates the neurodegenerative processes observed in AD, including the generation and progression of Aβ species (for review, see Bronzuoli et al., 2016, Dá Mesquita et al., 2016, Heneka et al., 2015, Kinney et al., 2018, Spangenberg and Green, 2017). Consistent with this, translational work in humans shows that activated microglia localize to Aβ plaques in post-mortem tissue (Calsolaro and Edison, 2016, Strauss et al., 1992), and in vivo evaluations using Positron Emission Tomography (PET) imaging confirm that neuroinflammatory signaling is elevated among those with AD (Chandra et al., 2019) as well as those in the preclinical and prodromal phases (Bradburn et al., 2019, Chandra et al., 2019, Parbo et al., 2018, Zou et al., 2020). While the precise mechanisms remain a matter of debate, these studies suggest that neuroinflammatory processes are initiated early in the disease course and may peak or become particularly relevant during distinct timepoints of disease development.

The pathogenic role of inflammation in AD may not be restricted to immune cells originating in the brain, with several lines of evidence supporting the dynamic involvement of peripheral inflammatory processes. Vascular risk factors that result in a sustained, pro-inflammatory state (e.g., hypertension, midlife obesity, insulin resistance, and high cholesterol) represent well-established risk factors for AD (Barnes and Yaffe, 2011, Kamer et al., 2008, Kivipelto et al., 2001, Welty et al., 2016). Moreover, hypertension (Hughes et al., 2014b), arterial stiffness (Hughes et al., 2014a), elevated triglycerides (Choi et al., 2016), and genetic markers of cholesterol transport (Hughes et al., 2014b) have independently been associated with elevated cortical Aβ burden in preclinical and prodromal populations. Efforts to characterize the relationship between peripheral inflammatory biomarkers and Aβ have largely involved symptomatic populations (Brosseron et al., 2014, Lai et al., 2017, Saleem et al., 2015). However, elevations in systemic inflammatory signaling may emerge or contribute to AD pathogenesis well before symptom manifestation.

Recent hypotheses propose that systemic inflammatory processes may modify the course of disease progression, in part, by acting as an accelerator, hastening or exacerbating ongoing neurodegenerative processes (Dionisio-Santos et al., 2019, Eikelenboom et al., 2012, Wang et al., 2017, Yasuno et al., 2017). Indeed, elevated levels of peripheral pro-inflammatory biomarkers including Interleukin-6 (IL-6), C-reactive protein (CRP), and soluble cluster of differentiation 14 (sCD14), predict cognitive decline (Beydoun et al., 2019, Bradburn et al., 2018) and incident dementia (Darweesh et al., 2018, Pase et al., 2020). Elevated soluble Tumor Necrosis Factor receptor levels are associated with a higher risk of progression from mild cognitive impairment (MCI) to dementia (Buchhave et al., 2010, Diniz et al., 2010), and acute inflammatory events restricted to the periphery predict cognitive deficits (Liu et al., 2018) and hasten the trajectory of cognitive decline among those with advanced AD (Holmes et al., 2009, Simone and Tan, 2011). Mechanistically, this is supported by rodent models showing that chronically activated or primed microglial cells exhibit an enhanced sensitivity to subsequent inflammatory signaling, including from cells that originate in the periphery. Moreover, the neuroinflammatory response to Aβ aggregates includes the active transport of peripheral immune cells into the brain (Calsolaro and Edison, 2016, Dá Mesquita et al., 2016, Heneka et al., 2015, Unger et al., 2020), which intensifies the neuroinflammatory drive and further promotes the progression of neurotoxic Aβ (Heneka et al., 2015, Kyrkanides et al., 2011, MacPherson et al., 2017). Despite the emerging significance of peripheral inflammation in disease onset and progression, there is an absence of longitudinal studies and work conducted in non-demented samples using in vivo measures of Aβ burden (Janelidze et al., 2018, Magalhães et al., 2018). Thus, the potential impact of systemic inflammatory processes on the pathogenesis and progression of Aβ is not well understood, particularly prior to the onset of clinical symptoms - a time when targeted interventions may be most efficacious.

We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and global and regional Aβ deposition in cognitively asymptomatic older adults. Using the 2018 National Institute of Aging and Alzheimer’s Association (NIA-AA) classification guidelines (Jack et al., 2018), we further assessed whether these relationships differed between study participants with and without biomarker evidence of preclinical disease by distinguishing those with elevated Aβ deposition (PiB-negative/PiB-positive) and evidence of neurodegeneration (hippocampal atrophy). Given mechanistic findings from animal models of a feedforward relationship between pro-inflammatory processes and Aβ, we anticipated that the association between peripheral inflammatory markers and Aβ burden would be magnified among individuals already exhibiting biomarker evidence of preclinical AD. Finally, we assessed whether peripheral inflammatory markers predicted cognitive decline and the longitudinal progression of Aβ deposition.

Section snippets

Participants and procedures

Participants were a subsample of the Ginkgo Evaluation of Memory Study (GEMS; 2000–2008) (Hughes et al., 2014a, Hughes et al., 2014b, Lopez et al., 2014, Mathis et al., 2013), which began in September 2000 and concluded with a final visit between October 2007 and March 2008 (Hughes et al., 2014a, Hughes et al., 2014b, Lopez et al., 2014). During the final visit, participants completed a neuropsychological assessment and a blood draw was obtained (Hughes et al., 2014b). A mean (SD) of 10 (3)

Baseline sample characteristics

The cross-sectional sample consisted of 139 CU older adults (mean [SD] age, 85.4 [2.8] years, range 82 – 95; 60 women (43%); 14.8 [2.7] years of education). There were 27 APOE ε4 carriers (19.4%; 8 participants missing genotype data) and 64 (47%) were designated as PiB-positive (Table 1). A series of planned comparisons determined that the PiB-positive participants did not differ from PiB-negative participants in age, years of education, time from blood draw to PET imaging, history of heart

Discussion

Evolving perspectives of AD etiology have begun to consider the entire biological system, including the critical impact of peripheral health, on disease onset and progression (Dá Mesquita et al., 2016, Eikelenboom et al., 2012, Wang et al., 2017). Although systemic inflammation is increasingly implicated in disease risk, how these inflammatory processes impact the pathogenesis of AD, and when they may first start to take effect, is poorly understood (Canter et al., 2016, Cao and Zheng, 2018,

References (90)

  • Y. Gu et al.

    Circulating inflammatory biomarkers in relation to brain structural measurements in a non-demented elderly population

    Brain. Behav. Immun.

    (2017)
  • M.T. Heneka et al.

    Neuroinflammation in Alzheimer’s disease

    Lancet Neurol.

    (2015)
  • T.M. Hughes et al.

    Markers of cholesterol transport are associated with amyloid deposition in the brain

    Neurobiol. Aging

    (2014)
  • C.R. Jack et al.

    NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

    Alzheimer’s Dement.

    (2018)
  • A.R. Kamer et al.

    Inflammation and Alzheimer’s disease: Possible role of periodontal diseases

    Alzheimer’s Dement.

    (2008)
  • J.W. Kinney et al.

    Inflammation as a central mechanism in Alzheimer’s disease

    Alzheimer’s Dement. Transl. Res. Clin. Interv.

    (2018)
  • K.A. Kreuzer et al.

    A comparative study of different enzyme immunosorbent assays for human tumor necrosis factor-

    J. Immunol. Methods

    (1996)
  • K.P. MacPherson et al.

    Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice

    Neurobiol. Dis.

    (2017)
  • A.L. Marsland et al.

    Brain morphology links systemic inflammation to cognitive function in midlife adults

    Brain. Behav. Immun.

    (2015)
  • P. Parbo et al.

    Does inflammation precede tau aggregation in early Alzheimer’s disease? A PET study

    Neurobiol. Dis.

    (2018)
  • R.T. Perry et al.

    The role of TNF and its receptors in Alzheimer’s disease

    Neurobiol. Aging

    (2001)
  • B.L. Rosario et al.

    Inter-rater reliability of manual and automated region-of-interest delineation for PiB PET

    Neuroimage

    (2011)
  • E.E. Spangenberg et al.

    Inflammation in Alzheimer’s disease: Lessons learned from microglia-depletion models

    Brain. Behav. Immun.

    (2017)
  • R. Sperling et al.

    The evolution of preclinical Alzheimer’s disease: Implications for prevention trials

    Neuron

    (2014)
  • R.A. Sperling et al.

    Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease

    Alzheimer’s Dement.

    (2011)
  • M.S. Unger et al.

    CD8+ T-cells infiltrate Alzheimer’s disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice

    Brain. Behav. Immun.

    (2020)
  • K.A. Walker et al.

    Association of peripheral inflammatory markers with connectivity in large-scale functional brain networks of non-demented older adults

    Brain. Behav. Immun.

    (2020)
  • W.Y. Wang et al.

    Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease

    Ann. Transl. Med.

    (2015)
  • F.K. Welty et al.

    Targeting inflammation in metabolic syndrome

    Transl. Res.

    (2016)
  • M. Wu et al.

    A fully automated method for quantifying and localizing white matter hyperintensities on MR images

    Psychiatry Res. - Neuroimaging

    (2006)
  • H. Zhang et al.

    The relationship between inflammatory markers and voxel-based gray matter volumes in nondemented older adults

    Neurobiol. Aging

    (2016)
  • J. Zou et al.

    Microglial activation, but not tau pathology, is independently associated with amyloid positivity and memory impairment

    Neurobiol. Aging

    (2020)
  • D. Aderka et al.

    Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors

    J. Exp. Med.

    (1992)
  • D. Aderka et al.

    Shedding kinetics of soluble tumor necrosis factor (TNF) receptors after systemic TNF leaking during isolated limb perfusion. Relevance to the pathophysiology of septic shock

    J. Clin. Invest.

    (1998)
  • D.E. Alley et al.

    Three-year change in inflammatory markers in elderly people and mortality: The Invecchiare in Chianti study

    J. Am. Geriatr. Soc.

    (2007)
  • S. Bradburn et al.

    Association of peripheral interleukin-6 with global cognitive decline in non-demented adults: A meta-analysis of prospective studies

    Aging Neurosci. Front.

    (2018)
  • M.R. Bronzuoli et al.

    Targeting neuroinflammation in Alzheimer’s disease

    J. Inflamm. Res.

    (2016)
  • F. Brosseron et al.

    Body Fluid Cytokine Levels in Mild Cognitive Impairment and Alzheimer’s Disease: a Comparative Overview

    Neurobiol. Mol.

    (2014)
  • R.G. Canter et al.

    The road to restoring neural circuits for the treatment of Alzheimer’s disease

    Nature

    (2016)
  • Cao, W., Zheng, H., 2018. Peripheral immune system in aging and Alzheimer’s disease 11 Medical and Health Sciences 1109...
  • Capuron, L., Miller, A.H., 2011. Immune system to brain signaling: Neuropsychopharmacological implications. Pharmacol....
  • A. Chandra et al.

    Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer’s disease and mild cognitive impairment

    Hum. Brain Mapp.

    (2019)
  • T.V. Clendenen et al.

    Temporal reliability of cytokines and growth factors in EDTA plasma

    BMC Res. Notes

    (2010)
  • Dá Mesquita, S., Ferreira, A.C., Sousa, J.C., Correia-Neves, M., Sousa, N., Marques, F., 2016. Insights on the...
  • S.I. Dev et al.

    Peripheral inflammation related to lower fMRI activation during a working memory task and resting functional connectivity among older adults: a preliminary study

    Int. J. Geriatr. Psychiatry

    (2017)
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