Insulin Resistance Linked to AD Plaque 15 Years Later

Neurology Today
2 September 2010; Volume 10(17); p 1, 20

Hurley, Dan

A prospective study spanning 15 years, from laboratory measure of insulin resistance in elderly men and women to autopsy examinations of their brains, has brought a small measure of clarity to the murky association between Alzheimer disease (AD) and diabetes.

The study, from researchers at the Graduate School of Medical Sciences at Kyushu University in Fukuoka, Japan, found that higher readings on diabetes-related factors, including two-hour post-load plasma glucose, were related to an increased risk of having neuritic plaques upon autopsy 10 to 15 years later, but not of neurofibrillary tangles.

While many studies have established an association between clinically defined type 2 diabetes and dementia, the new paper is among the first to use direct measurements of insulin and glucose levels more than a decade before death, and then to connect those measurements with brain pathology, said the author of an editorial accompanying the study in the Aug. 31 issue of Neurology.

“There have been very few studies correlating laboratory measures of diabetes and insulin resistance to pathology findings consistent with Alzheimer disease,” said José A. Luchsinger, MD, MPH, associate professor of medicine and epidemiology at Columbia University Medical Center, who wrote an accompanying editorial on the study in the same issue of Neurology. “The question has always been whether the association is with Alzheimer disease or just with vascular causes of dementia.”

The study involved 135 residents of the town of Hisayama (74 men and 61 women) who were among 2,520 community members who underwent a measurement of fasting insulin and 75-g oral glucose tolerance test in 1988, and whose autopsies were performed between 1998 and 2003 (autopsy rate: 73.8%). No clinical signs of dementia were present in the participants during the initial assessment, when their mean age was 67 years.

Among those who had neuritic plaques at autopsy, two-hour post-load glucose levels were significantly higher (p=0.03), as were fasting insulin levels (p=0.03), although no dose-response effect was seen. For each one standard deviation increase in post-load glucose, the odds ratio of having any amount of neuritic plaque at autopsy was 1.66 (95% CI, 1.04-2.63; p=0.03). The odds ratio of neuritic plaque associated with a one standard deviation increase in fasting insulin was 1.61 (95% CI, 1.04-2.48; p=0.03). The associations remained significant after controlling for likely confounders.

By genotyping for apolipoprotein E (APOE), the researchers were able to show that the coexistence of hyperglycemia and APOE-4 significantly increased the risk for neuritic plaques.

In an e-mail to Neurology Today, the senior author of the paper noted that only 21 of the 88 study participants who had evidence of neuritic plaque at autopsy had been diagnosed with Alzheimer's dementia prior to death. “It is difficult to determine the risk of clinical cognitive decline” based solely on the current study's measures, said Kensuke Sasaki, MD, assistant professor in the department of neuropathology in the Neurological Institute at Kyushu University's Graduate School of Medical Sciences.

However, he added, “Our colleagues on the Hisayama study have found that post-load hyperglycemia that is caused by insulin resistance increased the risk of Alzheimer's dementia.” A paper on that finding is being prepared, he said.

While mechanisms have been proposed to explain how insulin resistance can interfere with the clearance of amyloid beta, thereby increasing the risk of developing neuritic plaques, Dr. Sasaki said there may be more to the story.

“We have other data [not yet published] showing that hyperlipidemia is also associated with neuritic-plaque pathology,” he said, “which indicates that Alzheimer disease is related not only to diabetes but more extensively to the ‘metabolic syndrome.’”

Other investigators who have been examining the relationship between diabetes and Alzheimer disease offered measured praise of the new study.

“It's an interesting observation — but observation is the key,” said Scott Small, MD, associate professor of neurology at Columbia University Medical Center. “It's nice to see a relationship between a premortem measurement and a postmortem measurement. It's interesting they find a correlation more with neuritic plaques than neurofibrillary tangles. But to really make a causal claim, you need a true experiment.”

DR. JOSE A. LUCHSINGER said while many studies have established an association between clinically defined type 2 diabetes and dementia, the new paper is among the first to use direct measurements of insulin and glucose levels more than a decade before death, and then to connect those measurements with brain pathology.

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The researcher who coined the term “type 3 diabetes” to characterize the role of insulin resistance in AD emphasized that no study has yet to demonstrate a causal, mechanistic relationship between the two disorders.

“Type 2 diabetes doesn't cause Alzheimer disease — they are co-occurring,” said Suzanne de la Monte, MD, MPH, professor of pathology and medicine and neurology at Brown University Medical School in Providence, RI. “The two diseases may have similar etiologies. We know diabetes will typically make Alzheimer disease worse. But there's no evidence that if you have type 2 you will necessarily develop Alzheimer disese.”

Dr. de la Monte took particular interest in the Japanese study's finding of an association between insulin resistance and neuritic plaques, but not of neurofibrillary tangles.

“Most of us recognize that plaques are not correlated with neurodegeneration,” she said. “They have something to do with it, but what you want to look at is the neurofibrillary tangles.”

Another researcher, however, said the findings did not surprise her.

“The studies that focus on insulin resistance have consistently shown a closer relationship with the amyloid beta side of the story than with tau,” said Suzanne Craft, PhD, professor of psychiatry and behavioral sciences at University of Washington School of Medicine and acting director of the Geriatric Research, Education and Clinical Center at the Veteran's Administration Puget Sound. “We've seen similar patterns in our studies.”

Dr. Luchsinger is participating in other clinical trials seeking to determine if reducing insulin resistance will improve cognitive outcomes. One, now midway toward completion, is a phase 2 trial in which the insulin-sensitizing agent metformin will be given to a planned 90 patients with mild cognitive impairment.

Investigators reported that higher readings on diabetes-related factors, including two-hour post-load plasma glucose, were related to an increased risk of having neuritic plaques upon autopsy 10 to 15 years later, but not of neurofibrillary tangles.

A twice-daily aerosolized nasal spray of insulin significantly improved memory in 104 patients with Alzheimer disease or mild cognitive impairment, according to a study presented in July at the International Conference on Alzheimer's Disease.

The Study of Nasal Insulin to Fight Forgetfulness (SNIFF-120) was a four-month trial involving two doses of insulin (20 or 40 IU daily) or placebo. The trial excluded diabetics, yet demonstrated either preservation or improvement on measures of cognitive function and functional status. Improvements in a CSF biomarker — the ratio of amyloid-beta 40 to amyloid-beta 2 — were also seen over the course of the trial among patients on insulin, but not among those receiving the placebo spray. PET imaging also showed preservation of activity in the posterior cingulate, known to be an AD-critical brain region.

“When you have high circulating levels of insulin, as you do in type 2 diabetes, there is a reduction of transport of insulin into the brain,” said the study's senior author, Suzanne Craft, PhD, professor of psychiatry and behavioral sciences at University of Washington School of Medicine and acting director of the Geriatric Research, Education and Clinical Center at the Veteran's Administration Puget Sound. “We need to do a much longer trial in order to see whether or not this holds up and whether it increases over time, but we're encouraged. It does have a potential to offer a considerable therapeutic benefit to patients.”

She emphasized, however, that neither neurologists nor their patients should consider the use of intranasal insulin sprays unless and until the treatment has been more rigorously tested and approved by the FDA.

Matsuzaki, T., Sasaki K, Iwaki T,et al., Insulin resistance is associated with the pathology of Alzheimer's disease: the Hisayama Study. 2010. 75:764-770.

Luchsinger JA. Editorial—Insulin resistance, type 2 diabetes, and AD: Cerebrovascular disease or neurodegeneration? 2010; 75:758-759.