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

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.

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

“…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 order to explain the approach, we first made two suggestions for a cognitive framework that we believe are essential if we are to better understand the mechanistic underpinnings of dementia and attempt to intervene in the disease process. The first suggestion was that we should separate late‐onset or “sporadic” AD from early‐onset familial AD 4 . Though they both have historically been labeled as forms of AD due to shared neuropathological hallmarks at autopsy, these are completely different diseases with respect to their risk factors and disease course.…”

“…The four remaining asterisked lifestyle medicine pillars (sleep, healthy diet, mental wellbeing and toxin exposures) can either support (3) or inhibit (4) the brain's capacity to upregulate function in the face of increased cognitive demand, with any resulting increases in function then preventing cognitive decline (5). Adapted from Turknett and Wood, 4 and made with Biorender.com…”

“…This hampers the ability to dissect the relevant contributions of different lifestyle factors, including cognitive demand, on the risk of ARCD and ARD. However, novel trial methodologies could be employed to sequentially alter individual risk factors to determine the relative contributions of cognitive demand 4,56,57 . Additional work could also be done in preclinical experiments such as in rodent models.…”

“…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.…”