Summary: Autotaxin predicts type 2 diabetes and cognitive decline, a new study reports.
Source: Iowa State University.
An enzyme found in the fluid around the brain and spine is giving researchers a snapshot of what happens inside the minds of Alzheimer’s patients and how that relates to cognitive decline.
Iowa State University researchers say higher levels of the enzyme, autotaxin, significantly predict memory impairment and Type 2 diabetes. Just a one-point difference in autotaxin levels – for example, going from a level of two to a three – is equal to a 3.5 to 5 times increase in the odds of being diagnosed with some form of memory loss, said Auriel Willette, an assistant professor of food science and human nutrition at Iowa State.
Autotaxin, often studied in cancer research, is an even stronger indicator of Type 2 diabetes. A single point increase reflects a 300 percent greater likelihood of having the disease or pre-diabetes. The results are published in the Journal of Alzheimer’s Disease. Willette and Kelsey McLimans, a graduate research assistant, say the discovery is important because of autotaxin’s proximity to the brain.
“We’ve been looking for metabolic biomarkers which are closer to the brain. We’re also looking for markers that reliably scale up with the disease and have consistently higher levels across the Alzheimer’s spectrum,” Willette said. “This is as directly inside of the brain as we can get without taking a tissue biopsy.”
Willette’s previous research found a strong association between insulin resistance and memory decline and detrimental brain outcomes, increasing the risk for Alzheimer’s disease. Insulin resistance is a good indicator, but Willette says it has limitations because what happens in the body does not consistently translate to what happens in the brain. That is why the correlation with this new enzyme found in the cerebrospinal fluid is so important.
“It has a higher predictive rate for having Alzheimer’s disease,” McLimans said. “We also found correlations with worse memory function, brain volume loss and the brain using less blood sugar, which have also been shown with insulin resistance, but autotaxin has a higher predictive value.”
Physical health linked to memory
The fact that autotaxin is a strong predictor of Type 2 diabetes and memory decline emphasizes the importance of good physical health. Researchers say people with higher levels of autotaxin are more likely to be obese, which often causes an increase in insulin resistance.
Willette says autotaxin levels can determine the amount of energy the brain is using in areas affected by Alzheimer’s disease. People with higher autotaxin levels had fewer and smaller brain cells in the frontal and temporal lobes, areas of the brain associated with memory and executive function. As a result, they had lower scores for memory and tests related to reasoning and multitasking.
“Autotaxin is related to less real estate in the brain, and smaller brain regions in Alzheimer’s disease mean they are less able to carry out their functions,” Willette said. “It’s the same thing with blood sugar. If the brain is using less blood sugar, neurons have less fuel and start making mistakes and in general do not process information as quickly.”
Researchers analyzed data from 287 adults collected through the Alzheimer’s Disease Neuroimaging Initiative, a public-private partnership working to determine whether MRI and PET scans as well as biological markers can measure the progression of cognitive impairment and Alzheimer’s disease. The data came from adults ranging in age from 56 to 89 years old. Study participants completed various tests to measure cognitive function. This included repeating a list of words over various time increments.
Funding: The research was supported by an Iowa State Presidential Initiative for Interdisciplinary Research grant and a National Institutes of Health grant.
Source: Auriel Willette – Iowa State University
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Original Research: Abstract for “Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer’s Disease Outcomes” by McLimans, Kelsey E. and Willette, Auriel A. in Journal of Alzheimer’s Disease. Published online December 2016 doi:10.3233/JAD-160891
Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer’s Disease Outcomes
Background: Obesity and insulin resistance are associated with neuropathology and cognitive decline in Alzheimer’s disease (AD).
Objective: Ecto-nucleotide pyrophosphatase/phosphodiesterase 2, also called autotaxin, is produced by beige adipose tissue, regulates metabolism, and is higher in AD prefrontal cortex (PFC). Autotaxin may be a novel biomarker of dysmetabolism and AD. Methods: We studied Alzheimer’s Disease Neuroimaging Initiative participants who were cognitively normal (CN; n = 86) or had mild cognitive impairment (MCI; n = 135) or AD (n = 66). Statistical analyses were conducted using SPSS software. Multinomial regression analyses tested if higher autotaxin was associated with higher relative risk for MCI or AD diagnosis, compared to the CN group. Linear mixed model analyses were used to regress autotaxin against MRI, FDG-PET, and cognitive outcomes. Spearman correlations were used to associate autotaxin and CSF biomarkers due to non-normality. FreeSurfer 4.3 derived mean cortical thickness in medial temporal lobe and prefrontal regions of interest.
Results: Autotaxin levels were significantly higher in MCI and AD. Each point increase in log-based autotaxin corresponded to a 3.5 to 5 times higher likelihood of having MCI and AD, respectively. Higher autotaxin in AD predicted hypometabolism in the medial temporal lobe [R2 = 0.343, p < 0.001] and PFC [R2 = 0.294, p < 0.001], and worse performance on executive function and memory factors. Autotaxin was associated with less cortical thickness in PFC areas like orbitofrontal cortex [R2 = 0.272, p < 0.001], as well as levels of total tau, p-tau181, and total tau/Aβ1–42.
Conclusions: These results are comparable to previous reports using insulin resistance. CSF autotaxin may be a useful dysmetabolism biomarker for examining AD outcomes and risk.
“Autotaxin is Related to Metabolic Dysfunction and Predicts Alzheimer’s Disease Outcomes” by McLimans, Kelsey E. and Willette, Auriel A. in Journal of Alzheimer’s Disease. Published online December 2016 doi:10.3233/JAD-160891