The Neural Economics of Brain Aging

Human brain aging is a true spectrum across the population, ranging from minimal changes on the microscopic level to full-blown neurodegenerative disease with accumulation of pathology, neuronal loss, dysfunctional large-scale brain networks, and progressive functional decline. Although much is known about the individual mechanisms involved in brain aging, a convincing framework that ties these highly related processes together is lacking. Herein, using mathematical modeling, I sought to understand decline with brain aging by capturing the essential macro-level processes that shape how a brain changes over the lifetime. I develop ABC (Aging Brain Capital), a simple linear simultaneous-equation model that unites aspects of neuroscience, economics, and thermodynamics to explain the evolution of brain pathology and human brain capital, the infrastructure and processes that underlie brain function, over the lifespan. The results of this model suggest that aging-associated decline in brain function is inevitable, driven by the finite nature of the brain’s pathology-clearance capacity. Furthermore, age-related neurodegenerative diseases can be understood as part of this aging process, explaining the spectrum of pathology and neurodegeneration across the population. I demonstrate that several essential aspects of the pathogenesis of Alzheimer disease (AD) can be likewise explained in this framework incorporating amyloid-tau interaction, the emerging concept that amyloid pathology accelerates tau pathology. The conception of Alzheimer pathogenesis that I present not only explains and unifies the basis for familial AD, primary-age-related tauopathy (PART), and late-onset AD (LOAD), but also reconciles amyloid-centered, tau-centered, and synergistic models of AD. Finally, I describe the possible implications of these results for future therapeutic development across neurodegenerative disease.