With commentary by study author Laura Ekblad, MD, a researcher at the University of Turku in Finland
Insulin resistance is a somewhat silent condition in that you can have it for years with no noticeable symptoms. Now a Finnish study has identified a significant symptom—but only for women. And it may signal a greater risk for Alzheimer’s.
“We showed that higher levels of insulin resistance were strongly associated with poorer verbal fluency performance in women, but not in men,” says lead study author Laura Ekblad, MD, a researcher at the University of Turku in Finland. Verbal fluency is a measure of executive function, she explains, a form of higher thinking that involves working memory, planning, and problem solving. Together with memory, it is often among the first cognitive deficits to show up early on in Alzheimer’s disease.
In the study, published in the journal Diabetologia in July, Dr. Ekblad and her team analyzed the health of 6,000 Finnish men and women aged 30 to 97, testing their verbal fluency by asking them to name as many animals as they could in 60 seconds. They then measured their insulin resistance and also checked to see if they carried the gene APOEε4, which has been linked to Alzheimer’s disease.
What they found was that women with higher insulin resistance scored very low in verbal fluency, which makes sense based on where these skills are located in the brain. “Previous research using MRIs has tied insulin resistance to reduced brain volume in the temporal lobes,” Dr. Ekblad explains, which is where verbal fluency function happens. “We think that the effect of insulin resistance on these specific brain regions is the cause for our findings.”
But why did the same dynamic not hold true for men? The exact mechanism is still unclear, but insulin resistance is known to affect women more than men. “We suspect that this gender difference could be, at least partly due to vascular changes in the brain such as white matter lesions, which have been shown to be more common in women than in men,” she says, adding, “there might be some underlying factors that we were unable to detect that would explain the level of verbal fluency for men.”
This dynamic may partly explain why two-thirds of patients with Alzheimer’s disease are women, according to the Alzheimer’s Association. But it’s also true that women live longer than men, and Alzheimer’s risk rises with age. Lastly, cardiovascular risk factors are also risk factors for Alzheimer´s disease, Dr. Ekblad says, and men with these risk factors tend to die more often than women of cardiovascular disease between ages 45 and 65, so they’re just not around to develop Alzheimer’s disease at the same rate.
One finding in this study that seems somewhat counterintuitive was that women participants who had both higher insulin resistance and the APOEε4 gene didn’t score as low on verbal fluency tests as non-carriers of the gene with higher insulin resistance. It would seem like the odds ought be stacked against this group, since they have two risk factors instead of one.
But in fact, the same gene that bestows the disease—some 65% of patients with Alzheimer’s disease are carriers—also seems to grant a measure of protection. Recent evidence shows that the genotype regulates the effect of insulin resistance on the brain. “Even new treatments that are being tested for Alzheimer’s disease are significantly modulated by the APOEε4 genotype,” Dr. Ekblad says. For example, only Alzheimer’s disease patients who were non-carriers of APOEε4 showed improved memory after treatment with rosiglitazone (a drug used for type 2 diabetes). “We suspect that our findings regarding the APOE genotype could be explained by the fact that non-carriers of the APOEε4 genotype seem to be more sensitive to the negative effect of insulin resistance on the brain,” Dr. Ekblad says.
Because this study is cross-sectional, it can’t show cause and effect—only a correlation. But it still makes clear that for women, whether you carry the APOEε4 genotype or not, higher insulin resistance, which often leads to type 2 diabetes, can spell trouble for your cognition. “Type 2 diabetes is already an acknowledged risk factor for cognitive decline and Alzheimer’s disease,” Dr. Ekblad says. “Recent evidence suggests that insulin resistance would be the most important mechanism behind this risk and that insulin resistance would play an important role in the development of Alzheimer’s.”
The risk hasn’t yet been confirmed in large epidemiological studies, mainly because insulin resistance is not commonly measured in clinical practice. But indirectly, Dr. Ekblad says, evidence is accumulating that metabolic syndrome, which is closely associated with insulin resistance, increases the risk for cognitive impairment.
And before you shrug off the risk as a problem for senior citizens, keep in mind that the mean age of participants in this study was 52.5 years, which means that the findings apply to middle-aged and even younger adults. But your fate is not sealed.
Dr. Ekblad views the findings as a kind of call to action for young adults who already have insulin resistance, including those who are obese or who have metabolic syndrome or type 2 diabetes. “It’s likely that simple lifestyle interventions such as physical exercise and a healthier diet will have a positive effect on cognitive skills and possibly even reduce the risk for dementia,” she says.