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