Figure 2.

Cognitive demand as the critical upstream determinant of cognitive function and decline. 1. Cognitive demand is increased or decreased as a result of numerous individual and societal factors that can either positively or negatively affect the entire cascade. 2. As a result of direct demand-function coupling, cellular and organ responses down/upregulate homeostatic processes that can either increase or decrease repair, autophagy, and function. 3. Critical demand–function responses such as waste clearance and plasticity occur during recovery periods, particularly sleep. 4. In the setting of low demand and/or inadequate recovery, an individual’s personal environmental, health, and genetic circumstances result in differing and heterogeneous pathological phenotypes and cellular hallmarks of dementia and cognitive decline. 5. Created with BioRender.com.