Thirty Risk Factors for Alzheimer’s Disease Unified by a Common Neuroimmune–Neuroinflammation Mechanism

Abstract

One of the major obstacles confronting the formulation of a mechanistic understanding for Alzheimer’s disease (AD) is its immense complexity—a complexity that traverses the full structural and phenomenological spectrum, including molecular, macromolecular, cellular, neurological and behavioural processes. This complexity is reflected by the equally complex diversity of risk factors associated with AD. However, more than merely mirroring disease complexity, risk factors also provide fundamental insights into the aetiology and pathogenesis of AD as a neurodegenerative disorder since they are central to disease initiation and subsequent propagation. Based on a systematic literature assessment, this review identified 30 risk factors for AD and then extended the analysis to further identify neuroinflammation as a unifying mechanism present in all 30 risk factors. Although other mechanisms (e.g., vasculopathy, proteopathy) were present in multiple risk factors, dysfunction of the neuroimmune–neuroinflammation axis was uniquely central to all 30 identified risk factors. Though the nature of the neuroinflammatory involvement varied, the activation of microglia and the release of pro-inflammatory cytokines were a common pathway shared by all risk factors. This observation provides further evidence for the importance of immunopathic mechanisms in the aetiopathogenesis of AD.

Overlapping Receptor-Based Pathogenic Cascades in Degenerative Disease: Implications Ranging from Tumor Targeting to Aging and Dementia Therapeutics

“…Young adults who suffer moderate to severe head trauma also have a greater-than-two-fold increased risk of developing Alzheimer's disease or a related dementia later in life. As a result, early (or even proactive) drug targeting toward a major SAA receptor, implicated in SAA-mediated cell signaling processes leading to normal aging brain alterations [67] and/or dementia [71], may provide an effective preventive and therapeutic strategy.…”