New Biomarker May Predict Diabetes, Alzheimer's Disease Sooner

Evaluating levels of autotaxin, an enzyme found in the fluid around the brain and spine, may be useful in identifying those at risk of cognitive decline and type 2 diabetes, Iowa researchers find.

Written by Kathleen Doheny

Measuring levels of an enzyme found in the fluid around the brain and spine can accurately predict whether a person is at risk for memory impairment, Alzheimer's disease (AD), and type 2 diabetes (T2D),1 according to study author Auriel Willette, PhD, assistant professor of neurology at the University of Iowa in Iowa City, and his research fellow. 

What the researchers found were higher levels of autotaxin in those individuals with mild cognitive impairment and Alzheimer's disease than in the mentally fit participants.

Every 1-point increase in the autotaxin levels translated to 3.5 times higher risk of mild cognitive impairment (MCI) and 5 times higher risk of Alzheimer's disease.1 The higher the levels of autotaxin, the more likely the participants were to have fewer and smaller cells in the frontal and temporal lobes, regions linked with memory and executive function.2

In earlier research, Dr. Willette confirmed a strong link between insulin resistance and memory loss and other detrimental neurological outcomes,suggesting an increased risk for Alzheimer's disease. However, he said that insulin resistance presented limitations because the way enzymes and hormones are processed in the body do not necessarily occur similarly in the brain. 

The research, to be published in the Journal of Alzheimer's Disease, represents a good initial step toward predicting dementia risk, according to Keith Fargo, PhD, director of scientific programs and outreach for the Alzheimer's Association, who commented on the study for EndocrineWeb.

While neuroimaging research is progressing as an effective method for identifying early Alzheimer’s disease progression, these procedures are expensive and not widely available, he said.

"Finding a reliable and accurate diagnostic test using cerebrospinal fluid or blood would be a major step forward in the fight against Alzheimer's disease," Dr. Fargo told EndocrineWeb

New Biomarker Identified; Linked to Brain and Glucose Changes

Dr. Willette and Kelsey McLimans, RDN, MS, a doctoral fellow at Iowa State University in Ames, Iowa, analyzed data from 287 men and women participating in the Alzheimer's Disease Neuroimaging Initiative. This partnership aims to evaluate whether imaging such as MRIs and PET scans, along with biological markers, can predict cognitive decline.

The researchers compared 86 cognitively normal people to 135 with mild cognitive impairment (MCI) and 66 individuals who were diagnosed with AD. They measured autotaxin levels from the cerebral spinal fluid. As an aside, Dr. Willette suggested that the obvious next step would be to pursue research focused on developing a blood test.

"Autotaxin is an enzyme responsible for glucose metabolism in adipose cells,'' Ms. McLimans said. "It seems to be directly related to making fat cells larger," Dr. Willette said. Overweight and obese people generally have higher levels of this enzyme present than leaner people.  

If further research confirms the findings, this enzyme may be more accurate than looking at insulin resistance, which has been linked to memory decline, to assess early disease, said Dr. Willete..   

Autotaxin: Clinically Relevant for Diabetes, Obesity?

J. Michael Gonzalez-Campoy, MD, PhD, medical director and CEO of the Minnesota Center for Obesity, Metabolism, and Endocrinology in Eagan, Minnesota, reviewed the study and put the enzyme-biomarker findings in perspective.

"Autotaxin was discovered in 1992," Dr. Gonzalez-Campoy pointed out.  "In 2003, it was found to be released from adipocytes and to play a role in stimulating pre-adipocyte differentiation. By 2008, it was well established as an adipocyte product."

In people, Dr. Gonzalez-Campoy said, "autotaxin circulating levels are directly proportional to visceral fat." This study, he told EndocrineWeb, ''raises the interesting observation that the higher the autotaxin levels in people with obesity, the higher the probability and the severity of memory loss. As a corollary to this, the authors suggest that it is visceral fat and insulin resistance that may be the real cause of the memory loss, and autotaxin is a marker for this."

"Autotaxin blockers are now under investigation," Dr. Gonzalez-Campoy says. We can look to future research to reveal whether blocking the enzyme can prevent memory loss in those who have overweight or obesity, he said.

Because autotaxin is a relatively new biomarker, more research is needed to replicate and extend the findings, Dr. Willette said, commenting on the limitations of the study. Reference levels for autotaxin as to what is normal, and what predicts cognitive decline—must be established.

If that bears out in ongoing research, someday autotaxin levels might be measured as part of a blood panel, the Iowa researchers said. The test could be targeted to older people and those with pre-diabetes or diabetes to assess their cognitive functioning. Depending on the results, "it might prompt more active intervention," Dr. Willette says.

Currently, he says, those diagnosed with diabetes may know they are at higher risk for cardiovascular problems but figure that will happen years later. The test results, he says, might drive home that ''the effects on your brain are acute and are happening right now."

According to Dr. Gonzalez-Campoy, "For now, the practical take-home message is that obesity is a chronic disease, and increasing visceral fat may be linked to progressive memory loss. Aggressive treatment of overweight and obesity as early in life as possible is highly recommended for all patients."

To learn more about the Alzheimer’s Disease Neuroimaging Imitative, watch this video.

Sources

1. McLimans K, Willette AA. Autotaxin is related to metabolic dysfunction and predicts Alzheimer’s disease outcomes. J Alzheimers Dis. Published online December 1, 2016. Accessed on: January 9, 2017. Available at: http://content.iospress.com/articles/journal-of-alzheimers-disease/jad160891.

2. Castagna D, Budd DC, Macdonald SJF, Jamieson C, and Watson AJB. Development of autotaxin inhibitors: An overview of the patent and J Med Chem. 2016;59(12):5604–5621.

3.  Ferry G, Tellier E, Try A, et al. Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity. J Biol Chem. 2003;278(20):18162-9. 

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