DIMENSIONS Winter 2006


by Rebecca Logsdon, PhD

Dr. Suzanne Craft

Dr. Suzanne Craft and her colleagues, Drs. Stennis Watson and Laura Baker are among the nation’s leading experts on the effects of insulin regulation on the development of Alzheimer’s disease (AD). For over 10 years, Craft and the Memory Wellness Program research team at the Geriatric Research, Education, and Clinical Center (GRECC) of the VA Puget Sound Health Care System and UW Department of Psychiatry and Behavioral Sciences, have been exploring the impact of insulin on memory. Many common medical conditions are related to poor insulin control, including obesity, diabetes, cardiovascular disease, and hypertension. Thanks to the Memory Wellness Program team, Alzheimer’s disease may now be added to that list. Their research is exploring how insulin is transported through the body and into the brain, and how it then affects brain chemistry. Craft has discovered that when insulin regulation is disrupted, it can have a profound effect on memory and thinking. The Craft research team suspects that when insulin is poorly controlled over a prolonged period of time (as is the case in as many as one-half of older adults who have insulin resistance or elevated blood sugar), this may trigger a series of reactions in the brain that lead to the development of AD. In this chain-reaction, insulin resistance triggers elevation of proteins in the brain that are similar to those found in senile plaques in the brains of individuals with AD. Insulin resistance is also associated with higher levels of inflammation in the central nervous system. The combination of elevated brain proteins and inflammation may be an important risk factor for development of AD.

These links between insulin and cognition provide a promising avenue for the development of strategies for treating, delaying, or preventing AD. The Memory Wellness Program is currently conducting two studies exploring the use of medications that regulate insulin activity to treat individuals with mild cognitive impairment or early stage AD.

Rosy Outlook for Rosiglitazone
Rosiglitazone is a medication that is already approved by the FDA for the treatment of diabetes. The Memory Wellness Program is evaluating whether use of rosiglitazone also improves memory in people with memory disorders. In a pilot study completed last year by Craft and colleagues, thirty participants with AD took either rosiglitazone or placebo for six months. Rosiglitazone, as has been shown in other studies, was found to be very safe. Participants who took rosiglitazone showed preserved memory and attention, while those who took placebo declined in these abilities over the six-month period. These results suggest that improving insulin sensitivity may help to slow the progression of memory problems.

Because of these promising findings, the National Institutes of Health (NIH) has funded a multi-site clinical trial that will allow Craft’s team to extend this research to people with mild cognitive impairment (MCI). Persons with MCI have noticeable changes in their memory but these changes do not affect their ability to carry out their usual daily activities. Volunteers with mild memory changes will take either rosiglitazone or placebo for 18 months, and will be given tests of thinking and memory before, during, and after their time on medication. This investigation will allow researchers to evaluate the potential long-term effects of rosiglitazone on memory in people with very mild problems. In addition, volunteers will undergo magnetic resonance imaging (MRI) brain scans before and after treatment in order to establish whether this medication produces structural changes in areas of the brain that are important for memory.

Nasal News: Insulin Nose Drops and Memory
Craft’s research team has demonstrated that when the brain receives extra doses of insulin, memory improves. However, turning this discovery into a treatment for memory disorders is more difficult than it might sound at first. The problem is that insulin typically gets to the brain through the blood. While insulin is in the blood, it can have undesirable effects on blood sugar levels. Therefore, one goal of developing an effective treatment is to deliver insulin directly to the brain without using blood as the pathway.

Recent research suggests that one way to bypass the blood supply is to place insulin drops in the nose. In another Memory Wellness Program study, volunteers who received nasal insulin drops experienced improvement in memory on three different tests of memory, while their blood sugar levels remained completely safe. Follow-up studies are helping the Craft team determine what dose of insulin is most helpful for memory and whether daily administration of an intranasal insulin spray will provide lasting beneficial effects for people with memory problems. Volunteers receive either insulin or placebo nose spray every day for three weeks, and their memory and attention are tested before, during, and after treatment. In an upcoming NIH-funded clinical trial, the research team will be expanding and continuing this important research.

PACE (Puget Sound Aging, Cognition & Exercise) STUDY
It’s possible that exercise may have a beneficial influence on memory and thinking for healthy older adults! In January, a large observational study conducted at Group Health in Seattle, reported that adults who were more physically active were less likely to develop Alzheimer’s disease. How do we explain these findings? Many scientists are now studying this connection; however there are two possible explanations that have been proposed so far. One, we know that exercise improves the body’s ability to efficiently use glucose, the fuel needed not only by the muscles but also by the brain. Second, we know that exercise protects brain cells from injury and promotes new growth in brain regions needed for complex thought. The Memory Wellness Program of the University of Washington and the VA Medical Centers is conducting a new study (the PACE study) to test whether six months of exercise will improve memory and thinking abilities for older adults with memory problems. We are also watching to see if exercise has a beneficial influence on biological processes associated with the development of Alzheimer’s disease. In the PACE study, older adults (55+ years) are assigned to an aerobic exercise or stretching program for six months under the supervision of a personal fitness trainer. During the study, subjects will receive tests to measure thinking abilities, as well as other tests of physical health. Our hope is that the results of this study will provide scientific support for a relatively simple and inexpensive intervention that improves memory and thinking abilities, as well as many of the health factors that may increase a person’s risk of developing memory problems down the road.

No Miracle Cures Yet
While results of the research on insulin resistance and its association with AD, along with potential preventive or treatment methods, are promising and exciting, the jury is still out regarding whether this will prove to be an effective treatment avenue in the future. The two randomized controlled clinical trials that are currently underway will help shed light on this question. In the meantime, this research provides yet another piece of evidence that in the body, all systems are related, and all roads lead, eventually, to the brain.

Craft and her colleagues would like to thank all of the study volunteers for their commitment to their research studies. For those interested in participating in our research projects, please contact Donna Davis at 1-888-291-7316 or Karen Hyde at 1-866-638-2213.

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