Demand Coupling Drives Neurodegeneration: A Model of Age-Related Cognitive Decline and Dementia.

The societal burden of Alzheimer's Disease (AD) and other major forms of dementia continues to grow, and multiple pharmacological agents directed towards modifying the pathological "hallmarks" of AD have yielded disappointing results. Though efforts continue towards broadening and deepening our knowledge and understanding of the mechanistic and neuropathological underpinnings of AD, our previous failures motivate a re-examination of how we conceptualize AD pathology and progression. In addition to not yielding effective treatments, the phenotypically heterogeneous biological processes that have been the primary area of focus to date have not been adequately shown to be necessary or sufficient to explain the risk and progression of AD. On the other hand, a growing body of evidence indicates that lifestyle and environment represent the ultimate level of causation for AD and age-related cognitive decline. Specifically, the decline in cognitive demands over the lifespan plays a central role in driving the structural and functional deteriorations of the brain. In the absence of adequate cognitive stimulus, physiological demand-function coupling leads to downregulation of growth, repair, and homeostatic processes, resulting in deteriorating brain tissue health, function, and capacity. In this setting, the heterogeneity of associated neuropathological tissue hallmarks then occurs as a consequence of an individual's genetic and environmental background and are best considered downstream markers of the disease process rather than specific targets for direct intervention. In this manuscript we outline the evidence for a demand-driven model of age-related cognitive decline and dementia and why it mandates a holistic approach to dementia treatment and prevention that incorporates the primary upstream role of cognitive demand.