Demand Coupling Drives Neurodegeneration: A Model of Age-Related Cognitive Decline and Dementia
Open Access
- 7 September 2022
- Vol. 11 (18), 2789
- https://doi.org/10.3390/cells11182789
Abstract
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.This publication has 151 references indexed in Scilit:
- Alzheimer’s Disease: Analyzing the Missing HeritabilityPLOS ONE, 2013
- The Hallmarks of AgingCell, 2013
- Post-Hospital Syndrome — An Acquired, Transient Condition of Generalized RiskThe New England Journal of Medicine, 2013
- Education and Dementia in the Context of the Cognitive Reserve Hypothesis: A Systematic Review with Meta-Analyses and Qualitative AnalysesPLOS ONE, 2012
- Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blueProgress in Neurobiology, 2012
- Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasisNature, 2012
- Acquiring “the Knowledge” of London's Layout Drives Structural Brain ChangesCurrent Biology, 2011
- Exercise training increases size of hippocampus and improves memoryProceedings of the National Academy of Sciences of the United States of America, 2011
- Recovery of functional and structural age-related changes in the rat primary auditory cortex with operant trainingProceedings of the National Academy of Sciences of the United States of America, 2010
- Computer-based Cognitive Training for Mild Cognitive ImpairmentAlzheimer Disease & Associated Disorders, 2009