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 framework’ is that neuromodulatory system dysfunction is sufficient to explain both tau hyperphosphorylation and b-amyloid (Ab) 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.