Metabolic Disease and Alzheimer's or Dementia

The number of Americans with Alzheimer’s disease is expected to more than double over the next two decades. Although becoming older is the strongest risk factor for developing Alzheimer’s disease or a related form of dementia, there are many other common health conditions that contribute to the development of age-related cognitive problems. One of the better known risks is metabolic disease, the most common of which is type 2 diabetes, which often occurs as a consequence of poor diet and being chronically overweight. ​Additionally, the Alzheimer's disease risk gene Apolipoprotein E (APOE) has been associated with a number of different metabolic changes. For example, individuals who have inherited the E4 version of the APOE gene show lower rates of glucose uptake in the brain. Problems with metabolism affect the entire body, including the brain and the gastrointestinal tract. Recent evidence shows that the imbalance of the microorganism in the gut (known as dysbiosis) could potentially contribute to the systemic metabolic dysfunction as well as to AD pathogenesis. 

The dysbiosis is particularly more severe in the APOE4 carriers compared to the non-carriers. 

The human brain accounts for about only 2 percent of body weight, but consumes more than 20 percent of body’s energy.  

Trying to Understand Interconnectedness

Although researchers have known about a possible connection between dementia and metabolism for many years, we still do not understand how these two major health problems are linked. 

Researchers at the Sanders-Brown Center on Aging have been studying how problems with metabolism relate to the development of age-related neurologic disease and gut microbiome dysbiosis. Our hope is that by better understanding these conditions, we can develop better therapies. This is an urgent public health concern, since many Americans are overweight or obese by the time they reach middle age.

Current Research

Current research encompasses how drugs used to treat diabetes and metabolic syndrome affect the development of Alzheimer’s disease pathology in the brain, such as amyloid plaques and neurofibrillary tangles. Other research is focused on how diet impacts the gut microbiome, and how metabolites such as short chain fatty acids interact with the brain. A key area of overlapping interest for many Sanders-Brown faculty is how the key cells involved in the brain’s immune response – microglia and astrocytes –behave under conditions of altered metabolism, and how this impacts the development of dementia.

Co-morbidities such as those contributing to diabetes are known risk factors for dementia and regional decline in glucose metabolic rate is one of the earliest and most consistent features of AD. University of Kentucky researchers and those from the Sanders-Brown Center on Aging have been awarded a $10 million grant (P20GM148326/GM/NIGMS NIH HHS/United States) for developing Centers of Biomedical Research Excellence (COBRE) from the National Institutes of Health (NIH) and Medical Sciences (NIGMS). At SBCoA researchers will investigate the mechanism of how TDP-43 pathology drives the dysregulation of cerebral glucose utilization and overall brain metabolism in TDP43 proteinopathies.

Steve Estus

Michael Paul Murphy