Midlife Insulin Resistance Affects Brain Function
Insulin resistance is associated lower brain glucose metabolism and poorer memory in late-middle-aged adults at risk for Alzheimer's disease (AD), a new study indicates.
"While we have known for several years that people with type 2 diabetes are at increased risk for developing AD, the exact mechanisms underlying increased risk are still elusive," Barbara B. Bendlin, PhD, from University of Wisconsin School of Medicine and Public Health and Wisconsin Alzheimer's Disease Research Center in Madison, told Medscape Medical News.
"Our findings suggest that insulin resistance, a central feature of diabetes, could increase risk for AD by altering the way the brain uses glucose, the primary fuel for the brain."
The study was published online July 27 in JAMA Neurology.
Window of Opportunity
Participants included 150 cognitively normal adults with a mean age of 60.7 years who underwent cognitive testing, fasting blood draw, and fludeoxyglucose F 18–labeled positron emission tomography of the brain at baseline. They are part of the Wisconsin Registry for Alzheimer's Prevention (WRAP), a community sample enriched for AD parental history. Of the 150 participants, 108 (72%) were women, 103 (68.7%) had a parental history of AD, 61 (40.7%) had an APOE ε4 allele, and 7 (4.7%) had type 2 diabetes.
Higher homeostatic model assessment of peripheral insulin resistance was significantly associated with lower global glucose metabolism (P < .01) and regional glucose metabolism (P < .05) "across large portions of the frontal, lateral, parietal, lateral temporal, and medial temporal lobes," the researchers report.
The association was particularly "robust" in the left medial temporal lobe, and lower glucose metabolism in this area correlated significantly with poorer performance on tests of immediate and delayed memory (P < .001 for both), they note.
"In addition to finding that people with insulin resistance have lower brain glucose metabolism, we also found that lower glucose uptake in brain regions, important for memory function, was associated with lower memory performance," Dr Bendlin told Medscape Medical News. It's important to note, she added, that the participants studied are late middle-aged, and the majority do not have diabetes. "Midlife may provide a window of opportunity for altering insulin resistance which may be protective against memory decline," she said.
"We suspect that there are optimal ranges of glucose and insulin levels that are needed for healthy brain function. Especially for individuals who are 'prediabetic', it is likely important to maintain insulin sensitivity (for example, through diet and exercise modification), for overall health, and more specifically for brain health as well," Dr Bendlin said.
"Although this paper reiterates a known observation (decrease in brain metabolism associated with APOE4 genotype and the link with the metabolic syndrome), it extends this relationship to middle-aged people with increased risks for AD," Claude Messier, MD, PhD, from the University of Ottawa School of Psychology in Ontario, Canada, who wasn't involved in the study, told Medscape Medical News.
"Although it does not prove that there is a causal relationship between type 2 diabetes (or the metabolic syndrome) and AD, it demonstrates convincingly that insulin sensitivity is associated with decreases in metabolic activity in brain regions most sensitive to AD," he said.
It is now "pretty clear," Dr Messier added, that being diabetic will "hasten cognitive decline and interact with other disease states (vascular disease and AD) to hasten their progression." At this point, it's fair to say that if "you can avoid diabetes through lifestyle changes, you are probably reducing your odds of early AD."
Laura D. Baker, PhD, from the University of Washington School of Medicine in Seattle, told Medscape Medical News that these new findings "build on the work of others who have helped shift our scientific focus to midlife health status as a potent predictor of those who are likely to develop AD down the road."
Dr Baker, who wasn't involved in the study, said it also expands on previous work conducted by her group that uncovered "striking similarity in brain glucometabolic signatures of older insulin-resistant adults and patients with early AD. The [new] findings indicate that this similarity extends to middle-aged adults and thus makes the important point that increased AD risk may be linked to glucometabolic dysfunction, regardless of when it occurs in adulthood," she said.
"At a time in history when type 2 diabetes is diagnosed in progressively younger adults, the [new] findings have important implications for age of AD onset — with symptoms that will be increasingly reported by adults in their 50s and even possibly even in their 40s. These and other findings that highlight the importance of middle-age health status for AD risk have important implications for when interventions to prevent or slow the disease must be initiated," Dr Baker said.
The study had no commercial funding. The authors have disclosed no relevant financial relationships.
JAMA Neurol. Published online July 27, 2015. Abstract