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Evidence conflicting on effect of diabetes on cognitive decline
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Research has shown that diabetes may be associated with dementia in patients with and without Alzheimer’s disease. Diabetes has also been found to increase the risk for developing Alzheimer’s disease by at least 50% in various studies. However, the exact relationship between the two remains unknown.
Therefore, there was much interest in the results of a recent French study in which researchers claimed that diabetes was found to be associated with a slower rate of cognitive decline in Alzheimer’s disease.
Although many experts said research looking at the link between diabetes and cognitive decline in Alzheimer’s disease is to be commended, the results seemed unexpected. In fact, they disputed the accuracy of the study and said endocrinologists should use caution in applying the data.
“We must interpret these results carefully,” said J. Matthew Neal, MD, endocrinologist and director of the internal medicine residency program at Ball Memorial Hospital, Muncie, Ind. Neal, similar to many of the experts whom Endocrine Today spoke with, said although the researchers’ findings may be statistically significant, the clinical significance is uncertain without further evidence.
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“I also question the practical implications of these findings,” Neal said. “There was a study in 1997 linking nicotine usage to decreased progression of dementia, and we certainly would not recommend patients take up smoking.”
Endocrine Today spoke with experts in the field to take a closer look at the relationship between diabetes and Alzheimer’s disease, including the terminology of “type 3 diabetes.”
According to the researchers at INSERM, the French National Institute for Health and Medical Research in Toulouse, there are a lack of studies that examine the effect of diabetes on the progression of Alzheimer’s disease. In 2002, they conducted the Réseau sur la maladie d’ Alzheimer Français (REAL.FR) multicenter cohort study on patients with Alzheimer’s disease and their caregivers. The results of the study were published in the Oct. 27 issue of Neurology.
During the four-year study, researchers examined 608 patients with a probable diagnosis of Alzheimer’s disease and a Mini-Mental State Examination (MMSE) score between 10 and 26. Mean follow-up was 26 months.
However, during the course of the study, 94 patients died, 65 were lost to follow-up and 76 withdrew consent. When other reasons for discontinuing were included, only 198 patients remained at the end of the study.
Results showed that 63 patients (10.4%) had diabetes at baseline. In a mixed model adjusted for sex, age, education level, dementia severity, cholinesterase inhibitor use and vascular factors (hypertension, atrial fibrillation, coronary heart disease and hypercholesterolemia), there were no differences between the groups in MMSE baseline scores (–0.75; P=.20), but cognitive decline was slower in the group with diabetes (0.38; P=.01).
The conclusion that patients with Alzheimer’s disease and diabetes were found to have a slower cognitive decline than patients with Alzheimer’s disease and no diabetes opposes what previous research has stated, the experts said.
“My research does not show the origins of this slow cognitive decline,” Caroline Sanz, MD, lead researcher of the study, told Endocrine Today.
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“This may be caused by medications, but the theory I’m most convinced by is the neurohistological differences between people with and without diabetes (mixed-brain dementia),” said Sanz, of the department of diabetology, metabolic disease and nutrition at the Institut National de la Santé et de la Recherche Médicale, Toulouse, France.
A specific neuropathologic process that contributes to dementia seems to be promoted by diabetes, and these differences in brain lesions could explain the slower rate of cognitive decline, Sanz said. Histopathologic markers of vascular disease were associated with dementia, and amyloid-beta burden was lower in patients with diabetes compared with those without diabetes.
“These associations lead to a mixed-brain pathology, and patients with a mixed-brain pathology (Alzheimer’s disease with cerebrovascular disease) have a slower decline than patients with Alzheimer’s disease,” Sanz said.
Interpreting the results
Because diabetes is a strong risk factor for atherosclerotic disease, there is also a risk factor for vascular dementia, which can complicate Alzheimer’s disease, Neal said.
“But a study demonstrating decreased cognitive decline with diabetes is interesting,” Neal said. However, “the rate of cognitive decline in the diabetic group was only 0.38 points (on a 30-point scale) less than the control group — very small. And there is some inherent error possible in any metric — especially one such as the MMSE, which is more subjective than, say, an HbA1c.”
The researchers said one confounding factor is that patients with diabetes may already be taking medications, such as antiplatelet drugs, statins and antihypertensive agents, which may inhibit vascular events, and that this may account for the difference.
“This study is difficult to interpret,” said William Thies, PhD, chief medical and scientific officer of the Alzheimer’s Association. “First, only one-third of the patients at baseline completed the study. This could mean that only the people with slow progression completed the study.”
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Thies said one of his main concerns is that the study by Sanz and colleagues did not include measures of diabetes severity, which could also allow the surviving population to be biased.
“Finally, we know from other studies that prevalence of diabetes is related to density of physicians, so it may also be a marker for good medical care, which could slow progression,” Thies said.
Earl Zimmerman, MD, a neurologist at Albany Medical College, said the study suffers from poor design, and there were other confounders that were not measured, such as exercise.
“It’s a very flawed study, and I would take it with a grain of salt,” Zimmerman said. “However, we do need studies like this to continue. We’re quite desperate to find something that will make a difference in managing and preventing Alzheimer’s disease.”
Complexity of Alzheimer’s disease
Kerry Hildreth, MD, medicine geriatrician conducting research at the University of Colorado, Denver, said the results of the study were unexpected, especially given the strong association between Alzheimer’s disease and diabetes, and also that diabetes is in many ways a disease of accelerated aging.
“It seems intuitive that people with diabetes would experience a faster rate of cognitive decline than those without,” Hildreth told Endocrine Today.
“Although the results of this study did not support this hypothesis, I do not think anyone is concluding that diabetes imparts a more favorable prognosis in Alzheimer’s disease. This study really highlights the complexity of Alzheimer’s disease and how much we have yet to understand and how other conditions, such as diabetes, may influence the development and course of the disease,” she said.
Hildreth said it is possible that the patients with diabetes in the study were more likely to be on cardiovascular medications such as aspirin, antihypertensives and statins. Better control of blood pressure and lipids may also affect the course of cognitive decline in Alzheimer’s disease.
“People with diabetes also tend to be seen more frequently by their providers, so it is possible that reversible causes of cognitive decline such as medication effects, thyroid disease, vitamin B12 deficiency, were recognized and treated,” she said.
Another challenge with studies of this nature is the inherent difficulty in measuring a complex human cognition, according to Hildreth. Also, a general screening instrument such as the MMSE may mask significant differences between groups in a particular cognitive domain (eg, working memory or executive function) that would only be apparent with more sensitive and focused neuropsychological testing.
According to Hildreth, because Alzheimer’s disease is so complex and heterogenous, much is not understood about its pathogenesis and progression.
“This makes finding effective therapies incredibly challenging,” she said. “In addition, conducting clinical trials in persons with Alzheimer’s or mild cognitive impairment is challenging with regard to issues such as informed consent, capacity, confidentiality, etc.”
‘Type 3 diabetes’
Some studies have alluded to Alzheimer’s disease as being a form of diabetes, with the proposed term “type 3 diabetes.”
According to Hildreth, the notion has some fairly compelling support. She noted a 2008 review published in the Journal of Diabetes Science and Technology that concluded that the term “type 3 diabetes” accurately reflects that Alzheimer’s disease represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with type 1 and type 2 diabetes.
Hildreth said the research suggests that Alzheimer’s disease is a neuroendocrine disorder of the brain caused by impaired central nervous system insulin action with molecular and biochemical abnormalities.
Thies said the label “type 3 diabetes” is too simplistic.
“There is more to Alzheimer’s disease than just being an outcome of diabetes,” Thies said. “There are too many people without diabetes who develop Alzheimer’s disease.”
Despite similar pathogenic mechanisms, Neal also said it may be premature to call Alzheimer’s disease a subtype of diabetes.
“The big question we need to answer is if use of antidiabetic drugs may be useful in therapy of [Alzheimer’s disease] patients without diabetes,” Neal said.
Many adults with diabetes are insulin-resistant individuals with type 2 diabetes and therefore do not have absolute insulin deficiency; some predict that insulin-sensitizing drugs (eg, thiazolidinediones) may play a role in therapy, Neal said.
Synthetic amylin (pramlintide) is used for the treatment of diabetes, and the effect of this drug on Alzheimer’s dementia would be of interest, given the amyloid factor, Neal said.
“However, we need more scientific data, currently, to support treatment of Alzheimer’s disease with antidiabetic drugs,” Neal said. He noted that research has shown several drugs to have beneficial effects outside their primary role in therapy.
“We must remember that the majority of patients with Alzheimer’s disease do not have diabetes (only 10.4% in the REAL.FR study’s cohort) — this does not exclude diabetes as a risk factor for Alzheimer’s disease, but it is clear that factors other than diabetes contribute,” Neal said.
Pathways to Alzheimer’s disease
Zimmerman recently collaborated with James Desemone, MD, director of Goodman Diabetes Service and associate professor of medicine at Albany Medical College, on an editorial about the ideal management of diabetes and dementia that was published in Archives of Neurology. He said the best way to prevent cognitive dysfunction in diabetes is to prevent the disease and avoid the risks and problems with treatment, adding that until there is better research, exercise and decreasing BMI should be the main focus.
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Zimmerman said one of the most promising studies is the finalized results of the ACCORD-MIND (Action to Control Cardiovascular Risk in Diabetes — Memory in Diabetes) study. The study objective was to test whether the rate of cognitive decline and structural brain change in patients with diabetes who are treated with standard care guidelines is different than in patients with diabetes treated with intensive care guidelines.
The researchers studied 2,977 patients and concluded that higher HbA1c levels, not fasting glucose levels, are associated with lower cognitive function in patients with type 2 diabetes. Follow-up will be completed to assess the effect of glucose lowering on cognitive function.
Sanz said she is currently conducting a cohort study that includes more than 500 patients with Alzheimer’s disease. Her research team will study the effect of diabetes duration on cognitive decline with a two-year follow-up. Early results, Sanz said, have led to a slower cognitive decline associated with a longer duration of diabetes.
According to Thies, the issue is whether the link between diabetes and Alzheimer’s disease leads to a useful treatment pathway.
“The first attempt to treat Alzheimer’s disease with drugs for diabetes failed, so we need to investigate other alternatives, for example to find out if close control of glucose levels or even better prevention of type 2 diabetes in midlife prevents late-life Alzheimer’s disease,” Thies said.
Future studies
Hildreth said there is compelling evidence for abnormal insulin action in Alzheimer’s disease, and she wants to find a better understanding of the link between diabetes and Alzheimer’s disease.
“A big step is that we are starting to challenge the traditional notion that Alzheimer’s disease and vascular dementia are distinct entities and recognizing that significant overlap exists,” Hildreth said.
Neal said there are insufficient data to make recommendations to endocrinologists based on this study and the small statistical difference seen.
“Certainly, we should achieve the best possible control of diabetes, given the current evidence supporting prevention of complications. Alzheimer’s dementia is a devastating illness, and I hope that further research may provide further insight into treatment to improve the quality of life for these patients and their families,” Neal said.
“It is promising, in that if a definite association exists prevention of diabetes (via diet, exercise, and possibly medication) may prevent the onset and progression of Alzheimer’s disease. But we need more evidence to demonstrate that diabetes actually slows the progression of Alzheimer’s disease or that use of antidiabetic drugs would be useful for primary treatment of Alzheimer’s disease,” he said. – by Angelo Milone
What are the
implications of the REAL.FR study for endocrinologists?
For more information:
- De la Monte SM. J Diabetes Sci Technol. 2008;2:1101-1113.
- Sanz C. Neurology. 2009;73:1359-1366.
- Zimmerman EA. Arch Neurol. 2010;67:131-133.