Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction

Abstract

Scientific evidence has established several links between metabolic and neurocognitive dysfunction, and epidemiologic evidence has revealed an increased risk of Alzheimer's disease and vascular dementia in patients with diabetes. In July 2015, the National Institute of Diabetes, Digestive, and Kidney Diseases gathered experts from multiple clinical and scientific disciplines, in a workshop entitled "The Intersection of Metabolic and Neurocognitive Dysfunction", to clarify the state-of-the-science on the mechanisms linking metabolic dysfunction, and insulin resistance and diabetes in particular, to neurocognitive impairment and dementia. This perspective is intended to serve as a summary of the opinions expressed at this meeting, which focused on identifying gaps and opportunities to advance research in this emerging area with important public health relevance.

Keywords: Alzheimer’s disease; Diabetes; cognition; cognitive impairment; insulin resistance; mechanism; obesity; vascular dementia.

Figure 1.. Possible mechanisms explaining the bidirectional relationship between metabolic and neurocognitive dysfunction.

The most plausible biological mechanisms (middle panel: molecular, cellular, organ and tissue-based, systemic) are shown that may explain the bidirectional relationship between metabolic (left panel: obesity, insulin resistance, prediabetes, type 2 diabetes) and neurocognitive dysfunction, including dementia (right panel: e.g., VCID, VaD, AD, other). Genetic and epigenetic mechanisms (not represented in the figure) likely trigger the pathophysiological processes underlying metabolic and neurocognitive dysfunction (represented by the innermost circle), and these disease processes, in turn, may be modified by other factors (listed under the “policy” umbrella), which may be targets to maximize health outcomes and behaviors. Finally, public policy (including health policy and health care management) is the societal tool that can serve as the ultimate modifier of these various risk factors, and will determine the success of the major effort required to prevent these common co-morbid diseases that are increasingly likely to burden our aging population.