WASHINGTON, DC—Intranasal insulin may improve memory in patients with Alzheimer’s disease and amnestic mild cognitive impairment but who lack apolipoprotein E (APOE) ε4, which can result in insulin abnormalities. Results from two studies “provide further evidence for APOE-related differences in insulin metabolism in Alzheimer’s disease,” according to Suzanne Craft, PhD.

“There’s growing evidence that insulin plays an important role in a number of brain functions,” said Dr. Craft, Professor of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine in Seattle. “Of great relevance to Alzheimer’s disease, insulin has recently been shown to modulate levels of the beta-amyloid protein as well as to modulate expression and activity of insulin-degrading enzyme, a protease that is known to play a role in the clearance of beta-amyloid.” Dr. Craft made her presentation at the 2005 Alzheimer’s Association International Conference on Prevention of Dementia.

Dysregulation of insulin’s functions—in particular, insulin resistance—has been associated with an increased risk of Alzheimer’s disease. The insulin resistance syndrome typically comprises two components—persistent high levels of plasma insulin and a reduced ability of insulin to carry out its daily functions. “Interestingly, this relationship may be stronger for a genetic subgroup of patients: that is, patients without the APOE ε4 allele, who comprise approximately 50% of all patients with sporadic late-onset disease,” said Dr. Craft, who is also Associate Director of the Geriatric Research, Education, and Clinical Center of the Veterans Affairs Puget Sound Medical Center, Seattle.

One way of increasing insulin levels in healthy adults is via intravenous infusion, which has been shown to enhance memory at optimal doses. However, peripherally administrated insulin is unrealistic as chronic therapy due to the risk of hypoglycemia and the potential for perpetuating insulin resistance.

“An interesting alternative is the intranasal administration of insulin,” said Dr. Craft. “Intranasal insulin will raise insulin levels in the cerebrospinal fluid and affect memory performance in young, healthy adults, and animal models have shown that insulin-like peptide signals are measurable in rat hippocampus amygdala as soon as 30 minutes after entering intranasal administration. So this is really a very rapid process.”

INTRANASAL INSULIN AND COGNITIVE IMPAIRMENT

The two studies were conducted to determine whether intranasal insulin administration produced a pattern of cognitive facilitation similar to that observed with acute intravenous insulin administration, and whether the effects would differ according to dose or APOE genotype. In the first study, 26 memory-impaired patients and 35 healthy controls underwent three intranasal treatment conditions consisting of saline or insulin 20 or 40 IU in randomized order at least one week apart. Of those patients with memory impairment, 13 had early Alzheimer’s disease, and 13 had amnestic mild cognitive impairment; 12 had the APOE ε4 allele, and 14 did not. The memory-impaired patients were well matched for age, education, body mass index, and cognitive status, and all were at the very early stages of disease.

After a 12-hour fast, subjects arrived at the clinic for a blood draw followed by one of the three treatment conditions. Fifteen minutes after treatment, a 30-minute cognitive-testing protocol was administered, followed by a final blood draw. The cognitive battery included two primary measures of declarative memory shown in previous studies to be responsive to insulin—a story recall measure and a selective reminder list measure. Change in cognitive performance was calculated for the 20- and 40-IU insulin doses versus saline.

“Patients without the APOE ε4 allele, the group we have previously described as having greater insulin regulation abnormalities, showed quite a striking improvement in memory recall at both doses of insulin,” Dr. Craft said. In contrast, memory-impaired patients with APOE ε4 and normal subjects showed no improvement in story or list recall with insulin, “a pattern that may reflect dose-response profile or a difference in metabolism that actually may have therapeutic implications.”

Subjects with APOE ε4 showed reduced performance at the 40-IU dose, indicating the optimal dose had been exceeded, Dr. Craft added, given that previous work has shown facilitation at very low insulin doses. Those with Alzheimer’s disease and mild cognitive impairment responded similarly to insulin, which did not affect other cognitive measures or plasma glucose or insulin levels.

In the second study, the protocol was identical except that two doses of insulin, 10 and 60 IU, were added. The trial included 46 healthy controls and 22 with memory impairment. There were five patients with Alzheimer’s disease and three with mild cognitive impairment without APOE ε4; there were eight with Alzheimer’s disease and six with mild cognitive impairment with APOE ε4.

For those participants without APOE ε4, a significant benefit was observed for story recall with the 10- and 40-IU insulin doses versus saline, Dr. Craft noted. No change was observed in those with APOE ε4. For the delayed list recall, those without APOE ε4 showed overall improvement, while a slight decrement in performance was found in those with APOE ε4. Overall memory was enhanced for those without APOE ε4, whereas a variable effect was observed for those with APOE e4.

FUTURE OF INSULIN THERAPY

“This is a first step,” Dr. Craft said. “Our future directions are to look at a daily administration protocol to see if we can predict more persistent effects—and there are many details to be worked out with respect to optimal dosing regimen, role of delivery—and to investigate further what is the potential cause or meaning of these differences in ε4 genotype response.” A number of studies are beginning to see differences emerge between those with and without APOE ε4; those with APOE ε4 have had better responses to donepezil and statins, for example.

“Our data would suggest we’ve got the other half of the group covered,” Dr. Craft concluded. “Patients without the ε4 allele may have insulin resistance as a specific risk and have therapeutic requirements that address that particular risk factor. These studies underscore the heterogeneity of Alzheimer’s disease and suggest that different therapeutic strategies may be beneficial for different subgroups of patients.”

NR

—Debra Hughes

Suggested Reading
Craft S. Insulin resistance and cognitive impairment: a view through the prism of epidemiology. Arch Neurol. 2005; 62:1043-1044.

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