Is the lack of appropriate cognitive demand the primary driver of dementia risk?

Abstract

Is the lack of appropriate cognitive demand the primary driver of dementia risk?With the general trend of increasing lifespan alongside populationlevel success in reducing the mortality from cardiovascular and cerebrovascular diseases, the population burden of Alzheimer's disease (AD) has steadily accelerated. In the United States, the mortality rate due to AD has increased from less than 0.5 per 100,000 in 1980 to approximately 30 per 100,000 in 2019. 1 Worldwide, the number of individuals with dementia is expected to at least triple by 2050, 2 with some reports suggesting that AD has the potential to bankrupt healthcare systems. 3 At the same time, the development of, and investment in, multiple pharmacological agents directed toward modifying the pathological "hallmarks" of AD have yielded disappointing results.Existing pharmaceuticals offer modest symptomatic benefits, at best, without modifying the course of the disease. Taken together, these factors highlight the urgent need for a critical reappraisal of the underlying risk factors for AD and potential interventions.In an attempt to reframe potential preventative and therapeutic approaches to AD, we recently proposed a model that suggests demand-function coupling in the brain is the critical upstream factor driving long-term cognitive function. 4 In this model, we describe how the health and function of any tissue, including the brain, is shaped by the demands placed upon it. In the setting of increased demand, demand-function coupling drives increases in growth and function, but also upregulates processes of cellular repair and regeneration. The result is a tissue that is more resilient, plastic, and with a greater capacity for increased work output in the face of increased requirements. In this way, we propose that the structure and function of the brain are driven by the demands placed upon it, much as cardiac and skeletal muscles respond to exercise. And as muscle or cardiovascular function decline with bed rest or detraining, the structure and function of the brain decline in a coupled manner when adequate demands are not placed upon it. Cognitive decline is then essentially an expression of "frailty" of the brain -defined as lacking additional capacity to function above basic requirements -as a result of reduced demand. Although it may appear subtle, this reframing of the cascade may be critical in understanding the disease process and intervening as healthcare providers. Whereas the prevailing explanations to date have described cognitive activity as a mitigating force; in this model, we propose that cognitive demand instead impacts the primary pathogenetic process. In fact, given the established phenomenon of demand coupling in neu-This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.