Adipokines: a link between obesity and dementia?

Abstract

Being overweight or obese, as measured with body-mass index or central adiposity (waist circumference), and the trajectory of body-mass index over the life course have been associated with brain atrophy, white matter changes, disturbances of blood-brain barrier integrity, and risk of all-cause late-onset dementia and Alzheimer's disease. This observation leads us to question what it is about body-mass index that is associated with health of the brain and dementia risk. If high body-mass index and central adiposity represent an increase in adipose tissue, then the endocrine function of adipose tissue, mediated by adipose tissue hormones and adipokines, could be a clue to mechanisms that underlie the association with dementia and Alzheimer's disease. Hundreds of adipokines have been identified, creating a complexity that is a challenge to simplify. Nonetheless, adipokines are being investigated in association with clinical dementia outcomes, and with imaging-based measures of brain volume, structure, and function in human beings and in preclinical models of clinical dementia.

Figure 1

Anthropometric measures and corresponding cutpoints of overweight and obesity in adults.

Figure 2

WAT is an endocrine organ that secretes hundred of adipokines that influence multiple physiological processes to maintain homeostasis and respond to injury. WAT exists as subcutaneous, visceral and retroperitoneal depots, and has a stromal layer containing ADSCs. Amount of WAT is measured crudely in humans as BMI. BMI, on average, exhibits a dynamic trajectory with ageing. This trajectory is characterized by an adult life increase, followed by later life decrease. Generally, higher BMI or BMI increase is associated with the vascular risk that is common among overweight and obese adults. BMI decrease is associated with ageing and neurodegeneration. This reverse association is reflected in changing risk associations commonly observed between BMI and dementia/AD over the life course.

Figure 3

The trajectory of BMI over the life course by chronological age and potential roles of adipokines. Observational data suggest that higher levels of adult BMI may increase risk for late-onset dementia. Mid-life inflammatory cytokine levels measured in blood are higher in relationship to dementia. A null association with blood leptin levels has been reported. The BMI-dementia association changes direction later in life. BMI declines such that lower levels of BMI are observed among those with dementia compared to those without. During this period, lower blood leptin levels have been reported and reports on other adipokines are mixed. Other BMI trajectories have been observed, suggesting perhaps different adipokine-related mechanisms underlying the evolution of aging and dementia, as well as heterogeneity in the dementia outcome.