Recent evidence supports Alzheimer’s disease–diabetes link

Possible association suggests need for further study.

Issue: June 2009

Findings from various recent studies have suggested a possible connection between metabolic disorders and the risk for developing Alzheimer’s disease and other forms of dementia.

Dementia is a looming public health crisis that is estimated to triple in prevalence by 2050, according to Rachel A. Whitmer, PhD, an investigator in the division of research at Kaiser Permanente Northern California.

Whitmer and colleagues recently reported that patients with type 2 diabetes and a history of severe hypoglycemic episodes are at increased risk for dementia. The findings were published in a recent issue of JAMA.

“Type 2 diabetes is a risk factor for dementia and there have been observational study findings showing that people with type 2 diabetes have a 30% to 80% greater risk for dementia — all-cause dementia, Alzheimer’s disease and vascular dementia,” Whitmer said during a news briefing.

This month, the Journal of Alzheimer’s Disease published a special issue on the association between diabetes and Alzheimer’s disease. Angelika Bierhaus, PhD, and Peter P. Nawroth, MD, both of the University of Heidelberg, Germany, noted that several pathological features have been identified as common denominators of Alzheimer’s disease and type 2 diabetes, including impaired glucose/energy metabolism, altered insulin-signaling pathways, mitochondrial dysfunction, oxidative stress and inflammation.

However, the exact etiology has yet to be determined, according to Derek LeRoith, MD, PhD, an Endocrine Today Editorial Board member.

“Findings from studies showed cognitive decline associated with obesity alone; metabolic syndrome with concomitant abnormalities such as lipids, cytokines and insulin resistance; or diabetes at the other extreme,” said LeRoith, also professor of medicine at Mount Sinai School of Medicine in New York, said during an interview.

Recent data

According to findings of a recent Diabetes study that enrolled 13,693 elderly twins, there was an increased risk for Alzheimer’s disease and vascular dementia with the presence of diabetes. The association was stronger with midlife diabetes occurrence compared with diabetes occurrence later in life.

A related study concluded that history of diabetes was associated with more rapid progression of cognitive decline in 156 patients with incident Alzheimer’s disease. Higher LDL and total cholesterol (prediagnosis) further affected the course of disease.

The data provide “further evidence for the role of vascular risk factors in the course of Alzheimer’s disease,” the researchers concluded. The results were published in Archives of Neurology.

Other studies have indicated a link between metabolic disorders, dementia and sex.

Kristine Yaffe, MD, and colleagues reported a greater association with presence of metabolic syndrome and cognitive impairment in women with metabolic syndrome when compared with women who did not have metabolic syndrome (7.2% vs. 4.1%). The four-year subgroup analysis included 4,895 women with osteoporosis. These findings were published in Archives of Neurology.

For men, results of the Health Aging and Body Composition study suggest a link between obesity and cognitive change.

“In our study of elderly men and women (n=3,054), higher levels of adiposity were associated with worsened cognitive function over time in men but not in women,” Alka M. Kanaya, MD, assistant professor of medicine at the University of California in San Francisco, told Endocrine Today.

“Differences in sex hormones and other metabolic risk factors, like diabetes and high blood pressure, did not explain this difference between men and women,” Kanaya added.

Results of a systematic review published in the Journal of Alzheimer’s Disease suggest that diabetes is likely to increase the risk for Alzheimer’s disease. Researchers reviewed 14 prospective studies conducted in 11 different populations. In all studies, the risk ratio was greater than one (median, 1.59). In four studies, the risk was statistically significant.

Glycemic control vital

“Trying to get a handle on glycemic control and how it might affect the brain in older patients is a key issue,” Whitmer said during the news briefing.

One example of the association between glycemic control and cognitive function was reported in ACCORD-MIND, which included a subset (n=2,977) of the 10,251 patients with type 2 diabetes in the ACCORD trial. Patients were randomized to therapeutic strategies to determine whether intensive interventions reduced the rate of cardiovascular events more than standard approaches. Higher HbA1c values were associated with a lower score on four different cognitive tests.

“These analyses extend previous reports of a link between cognitive decline and diabetes and are consistent with the hypothesis of a progressive relationship between the degree of chronic hyperglycemia and cognitive dysfunction,” the researchers concluded.

A study published in Proceedings of the National Academy of Sciences reported that insulin slowed or prevented damage and memory loss caused by toxic proteins in Alzheimer’s disease by shielding memory-forming synapses from harm.

While many studies have demonstrated a relationship between metabolic factors and cognition, there are many challenges ahead in understanding the association and the underlying mechanisms, Suzanne Craft, PhD, professor of psychiatry and behavioral sciences at University of Washington School of Medicine, wrote in a review published in Archives of Neurology.

“Future research aimed at identifying mechanisms that underlie comborbid associations will not only provide important insights into the causes and interdependencies of late-life dementias but will also inspire novel strategies for treating and preventing these disorders,” Craft wrote. – by Christen Haigh

For more information:

Craft S. Arch Neurol. 2009;66:300-305.
De Felice FG. Proc Natl Acad Sci USA. 2009;106:1971-1976.
Fitzpatrick AL. Arch Neurol. 2009;66:336-342.
Helzner EP. Arch Neurol. 2009;66:343-348.
Kanaya AM. Arch Neurol. 2009;66:329-335.
Kopf D. J Alzheimers Dis. 2009;16:677-685.
Whitmer RA. JAMA. 2009;301:1565-1572.
Xu W. Diabetes. 2009;58:71-77.
Yaffe K. Arch Neurol. 2009;66:324-328.