Abstract
Despite remarkable advances, research into neurodegeneration and Alzheimer Disease (AD) has nonetheless been dominated by inconsistent and conflicting theory. Basic questions regarding how and why the brain changes over time remain unanswered. In this work, we lay novel foundations for a consistent, integrated view of the aging brain. We develop neural economics—the study of the brain’s infrastructure, brain capital. Using mathematical modeling, we create ABC (Aging Brain Capital), a simple linear simultaneous-equation model that unites aspects of neuroscience, economics, and thermodynamics to explain the rise and fall of brain capital, and thus function, over the human lifespan. Solving and simulating this model, we show that in each of us, the resource budget constraints of our finite brains cause brain capital to reach an upper limit. The thermodynamics of our working brains cause persistent pathologies to inevitably accumulate. With time, the brain becomes damaged causing brain capital to depreciate and decline. Using derivative models, we suggest that this endogenous aging process underpins the pathogenesis and spectrum of neurodegenerative disease. We develop amyloid–tau interaction theory, a paradigm that bridges the unnecessary conflict between amyloid- and tau-centered hypotheses of AD. Finally, we discuss profound implications for therapeutic strategy and development.
Highlights
Despite remarkable advances, research into neurodegeneration and Alzheimer Disease (AD) has been dominated by inconsistent and conflicting theory
As we describe applying neural economics on the macro-level provides an explanation of brain aging, unifying pathogenesis to provide a unique lens on neurodegenerative disease as well as promising directions for therapeutic intervention
We considered the pathogenesis of neurodegeneration through the lens of neural economics
Summary
Research into neurodegeneration and Alzheimer Disease (AD) has been dominated by inconsistent and conflicting theory. The need for pollution control as well as the impact of accumulated pathology in turn determine the brain’s resource budget (endowment) available to either develop brain capital as investment or clear short-term pathology as pathology control. The complete ABC (Aging Brain Capital) model (Box 2, Table 1) elegantly ties together essential coevolving processes within the brain—the generation and maintenance of brain capital, the impact of its deployment on the production of pathology, the clearance and persistence of pathology, pathology-mediated damage, and the brain’s resource budget (Fig. 1A).
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