The neuromodulatory fragility hypothesis of Alzheimer's disease pathogenesis

Abstract

Sporadic Alzheimer's disease (AD) is associated with numerous risk factors, yet its precise cause remains unclear. Here, we describe a novel framework for AD pathogenesis, whereby diverse risk factors converge on neuromodulatory subcortical systems to confer AD risk or resilience. Neuromodulatory projection neurons are uniquely fragile due to their large size, sparse myelination, and high basal metabolic demands. We propose that the increased prevalence of AD in older adult populations likely reflects a universal weakness within these projection systems, which is increasingly exposed as cellular transport and maintenance mechanisms deteriorate with age. The key insight of this "neuromodulatory fragility hypothesis" is that neuromodulatory system dysfunction is sufficient to explain both tau hyperphosphorylation and amyloid beta plaque formation, the two pathological hallmarks of AD. We therefore predict that strengthening or preserving the endogenous functions of these systems in midlife represents the most effective strategy for preventing AD.

Keywords: Alzheimer's disease; acetylcholine; amyloid beta; dopamine; neuroinflammation; neuromodulatory subcortical systems; neuronal resilience; neuronal vulnerability; noradrenaline; orexin; pathogenesis; risk factors; serotonin; tau.

FIGURE 1

Flowchart of the proposed neuromodulatory fragility hypothesis of AD pathogenesis. Risk factors confer vulnerability or resilience to NSSs either directly or indirectly through disproportionate consequences in whole brain health. Due to disruptions in cell maintenance in distal axons, tau becomes hyperphosphorylated and misfolded, causing axonal instability and reduced cortical neuromodulatory tone. This causes nebulous early symptoms (sleep disruption, mood instability, attention deficits) and disrupts microglial homeostasis, impairing amyloid clearance. Misfolded tau spreads transneuronally from NSS cells, while Aβ appears in increasingly widespread cognitive regions. When Aβ and tau interact (typically in inferior temporal cortex), tau spread, and associated neurodegeneration are exacerbated, and cognition declines rapidly, eventually leading to dementia. Aβ, amyloid beta; AD, Alzheimer's disease; NSS, neuromodulatory subcortical system.

FIGURE 2

Schematic depiction of the emergence of Aβ plaques and tau tangles due to neuromodulatory dysfunction. The left image depicts a healthy neuromodulatory projection system with good neuromodulatory tone across the entire neocortex. The middle panel depicts the emergence of tau dysfunction due to the convergence of lifetime‐accumulated risk factors. This dysfunction (shown in red) occurs first in the most distal, and therefore most vulnerable, branches of the axonal tree. The image also depicts the emergence of tau tangles in the cell bodies. The right panel shows how regions where tau was disrupted become destabilized and dysfunctional (depicted by thin gray lines in the place of red areas in the middle panel). This instability gives rise to reduced neuromodulatory tone, microglial dysregulation, and impaired clearance of Aβ oligomers, resulting in the emergence of Aβ plaques. At this stage, tau tangles are abundant in the neuromodulatory neuron cell bodies. Aβ, amyloid beta; AD, Alzheimer's disease.