Alzheimer’s Disease: Exploring the Role of Inflammation and Implications for Treatment

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by both structural abnormalities and inflammation in the brain. While recent research has chiefly focused on the structural changes involved in AD, understanding the pathophysiology and associated inflammation of the AD brain helps to elucidate potential therapeutic and preventative options. By exploring the data supporting an inflammatory etiology of AD, we present a case for the use of existing evidence-based treatments addressing inflammation as promising options for treating and preventing AD. We present data demonstrating tumor necrosis factor alpha association with the inflammation of AD. We also discuss data supporting TNF alpha associated inflammation in traumatic brain injury, stroke, and spinal disc associated radiculopathy. We augment this previously unarticulated concept of a unifying pathophysiology of central nervous system disease, with reports of benefits of TNF alpha inhibition in many hundreds of patients with those diseases, including AD. We also assess the pathophysiologic and clinical trial evidence supporting the role of other inflammation resolving treatments in AD. In aggregate, the data from the several potentially effective therapeutic and preventative options contained within this report presents a clearer picture of next steps needed in research of treatment alternatives.

The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment

“…Inflammation characterizes MCI/AD (Fillit et al 1991; Ishii and Haga 1975; McCaulley and Grush 2015), and may also involve disruption of the blood–brain barrier, especially in APOε4 homozygotes (Bell et al 2012). In this environment, inflammatory cytokines, such as macrophage-derived tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), upregulate HIF-1α likely by mechanisms that inhibit PHD enzymes and enhance HIF-1 stability and transcriptional activity (Dehne and Brune 2009; Hellwig-Burgel et al 1999; Zhou et al 2003).…”

Tumor necrosis factor α Inhibition for Alzheimer’s Disease

“…More recent research has pivoted focus to cytokine-mediated neuroinflammation as a major contributor to the development of AD, and evidence suggests that inflammation promotes pathological processes that lead to AD 11–13. Among the cytokines involved in neuroinflammation, tumor necrosis factor α (TNF-α) is the most studied and plays an essential role in the cytokine cascade during an inflammatory response.…”

Alpha-2 macroglobulin in Alzheimer’s disease: a marker of neuronal injury through the RCAN1 pathway

“…5,6 The close association between inflammation and AD pathogenesis has led to several efforts targeting inflammation as a potential strategy for disease modification in AD. 7 Although previous clinical trials of anti-inflammatory agents in patients with established AD have failed, 8–10 there is currently renewed interest in strategies that target inflammation during the early, preclinical stages before the onset of clinical symptoms of mild cognitive impairment (MCI) and AD. 11 However, despite evidence implicating inflammation in AD pathogenesis, little is known about the association between systemic inflammation and the ‘preclinical AD pathophysiological signature.’ A comprehensive understanding of how specific inflammatory pathways are associated with AD pathogenesis, including the molecular mechanisms that may drive such associations, is critical to targeting these pathways for the prevention of AD.…”