Resistance to Insulin Increases Risk for Alzheimer’s Disease

The fact that obesity increases the risk of cardiovascular disease and some cancers is well known. But a new Iowa State University study adds to the growing evidence that memory loss should also be a top concern.

The study, published in the Journal of the American Medical Association Neurology, found a strong association between insulin resistance and memory function decline, increasing the risk for Alzheimer’s disease. Auriel Willette, a research scientist in the Department of Food Science and Human Nutrition at Iowa State, says insulin resistance is common in people who are obese, pre-diabetic or have Type 2 diabetes.

Willette and co-author Barbara Bendlin, with the Wisconsin Alzheimer’s Institute, examined brain scans in 150 late middle-aged adults, who were at risk for Alzheimer’s disease, but showed no sign of memory loss. The scans detected if people with higher levels of insulin resistance used less blood sugar in areas of the brain most susceptible to Alzheimer’s. When that happens, the brain has less energy to relay information and function, Willette said.

“If you don’t have as much fuel, you’re not going to be as adept at remembering something or doing something,” he said. “This is important with Alzheimer’s disease, because over the course of the disease there is a progressive decrease in the amount of blood sugar used in certain brain regions. Those regions end up using less and less.”

Willette’s work focused on the medial temporal lobe, specifically the hippocampus – a critical region of the brain for learning new things and sending information to long-term memory. It is also one of the areas of the brain that first show massive atrophy or shrinkage due to Alzheimer’s disease, Willette said.

Cognitive decline can have immediate impact

This is the first study to look at insulin resistance in late middle-aged people (average age was 60), identify a pattern of decreased blood sugar use related to Alzheimer’s and link that to memory decline, Willette said. Participants were recruited through the University of Wisconsin-Madison and Wisconsin Registry for Alzheimer’s Prevention study, an ongoing study that examines genetic, biological and lifestyle factors that contribute to dementia.

This image shows the location of the hippocampus in the human brain.

The research focused on the medial temporal lobe, specifically the hippocampus – a critical region of the brain for learning new things and sending information to long-term memory. It is also one of the areas of the brain that first show massive atrophy or shrinkage due to Alzheimer’s disease. Image is for illustrative purposes only.

The link between insulin resistance and Alzheimer’s disease is important for prevention, but the risk is much more immediate, Willette said. Problems regulating blood sugar may impact cognitive function at any age. Testing for insulin resistance in obese patients and taking corrective action, through improved nutrition and moderate exercise, is a crucial first step, he said.

“We are terrible at adjusting our behavior based on what might happen in the future,” Willette said. “That’s why people need to know that insulin resistance or related problems with metabolism can have an effect in the here and now on how they think, and it’s important to treat. For Alzheimer’s, it’s not just people with Type 2 diabetes. Even people with mild or moderate insulin resistance who don’t have Type 2 diabetes might have an increased risk for Alzheimer’s disease because they’re showing many of the same sorts of brain and memory relationships.”

Understanding the progression of cognitive decline will take additional research. Willette says following those who are at-risk through the different stages of dementia and Alzheimer’s will offer insight as to what happens as their cognitive function declines.

About this Alzheimer’s disease research

Erika Starks, Alex Birdsill, Sterling Johnson, Bradley Christian, Ozioma Okonkwo, Asenath La Rue, Bruce Hermann, Rebecca Koscik, Erin Jonaitis, Mark Sager and Sanjay Asthana all contributed to this study.

Source: Auriel Willette – Iowa State University
Image Credit: The image is in the public domain.
Original Research: Abstract for “Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle–Aged Adults at Risk for Alzheimer Disease” by Auriel A. Willette, PhD; Barbara B. Bendlin, PhD; Erika J. Starks, BS; Alex C. Birdsill, PhD; Sterling C. Johnson, PhD; Bradley T. Christian, PhD; Ozioma C. Okonkwo, PhD; Asenath La Rue, PhD; Bruce P. Hermann, PhD; Rebecca L. Koscik, PhD; Erin M. Jonaitis, PhD; Mark A. Sager, MD; and Sanjay Asthana, MD in JAMA Neurology. Published online July 27 2015 doi:10.1001/jamaneurol.2015.0613


Abstract

Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle–Aged Adults at Risk for Alzheimer Disease

Importance Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18–labeled positron emission tomography (FDG-PET).

Objectives To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle–aged participants at risk for AD and to examine whether insulin resistance–predicted variation in regional glucose metabolism is associated with worse cognitive performance.

Design, Setting, and Participants This population-based, cross-sectional study included 150 cognitively normal, late middle–aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) study, a general community sample enriched for AD parental history. Participants underwent cognitive testing, fasting blood draw, and FDG-PET at baseline. We used the homeostatic model assessment of peripheral insulin resistance (HOMA-IR). Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. We used a voxelwise analysis to determine whether HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, apolipoprotein E ε4 genotype, AD parental history status, and a reference region used to normalize regional uptake.

Main Outcomes and Measures Regional glucose uptake determined using FDG-PET and neuropsychological factors.

Results Higher HOMA-IR was associated with lower global glucose metabolism (β = −0.29; P < .01) and lower regional glucose metabolism across large portions of the frontal, lateral parietal, lateral temporal, and medial temporal lobes (P < .05, familywise error corrected). The association was especially robust in the left medial temporal lobe (R2 = 0.178). Lower glucose metabolism in the left medial temporal lobe predicted by HOMA-IR was significantly related to worse performance on the immediate memory (β = 0.317; t148 = 4.08; P < .001) and delayed memory (β = 0.305; t148 = 3.895; P < .001) factor scores.Conclusions and Relevance Our results show that insulin resistance, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral insulin resistance to maintain neural metabolism and cognitive function.

“Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle–Aged Adults at Risk for Alzheimer Disease” by Auriel A. Willette, PhD; Barbara B. Bendlin, PhD; Erika J. Starks, BS; Alex C. Birdsill, PhD; Sterling C. Johnson, PhD; Bradley T. Christian, PhD; Ozioma C. Okonkwo, PhD; Asenath La Rue, PhD; Bruce P. Hermann, PhD; Rebecca L. Koscik, PhD; Erin M. Jonaitis, PhD; Mark A. Sager, MD; and Sanjay Asthana, MD in JAMA Neurology. Published online July 27 2015 doi:10.1001/jamaneurol.2015.0613

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