VIENNA – If current trends in child and adolescent obesity continue, by 2040, one-third of the 81 million expected Alzheimer's cases worldwide may be a direct result of obesity-driven diabetes, according to researchers at the International Conference on Alzheimer's Disease who labeled the outlook as “dire.”
“We need to identify the contributions to this increase in dementia and figure out how to decrease this burden,” said Mary Haan, Ph.D., said at the meeting. “In the setting of diabetes and Alzheimer's, this means we need to think about intervening earlier in the process and treating across the life span. Our focus should be prevention, which is probably more effective when begun at younger ages.”
Dr. Haan is the primary investigator on the Sacramento Area Latino Study on Aging (SALSA), a prospective cohort study that has been ongoing since 1997. SALSA consists entirely of Mexican-Americans, whose high rates of type 2 diabetes, metabolic syndrome, and hypertension create an ideal population in which to study the impact of these disorders on cognition.
At the meeting, Dr. Haan of the University of California, San Francisco, presented 9 years of follow-up data on this group of 1,789 men and women (mean baseline age, 72 years). At study entrance, 33% of the group had type 2 diabetes and 40% had a body mass index of more than 25 kg/m
Over 9 years, 158 incident cases of dementia or nondementia cognitive impairment developed. After controlling for age, gender, girth, diabetes treatment, fasting insulin, and C-reactive protein, Dr. Haan said the presence of diabetes at baseline more than doubled the risk of dementia or cognitive impairment. “This translates into a population attributable risk of 19%,” she said. “Nineteen percent of all these dementia cases were the direct result of type 2 diabetes.”
When carried forward in accordance with the projected increases in obesity, that 19% figure means that by 2040, 24 million cases of dementia could be directly tied to type 2 diabetes, Dr. Haan said. Unfortunately, “there are no randomized controlled trials that support the notion that we should be treating [cognitive impairment] with an antidiabetic drug.” Instead, the most effective method is probably to prevent obesity and insulin resistance.
Suzanne Craft, Ph.D., agreed. “The concern is this current epidemic of diabetes associated with insulin resistance, in conjunction with a rapidly aging population, foreshadows an epidemic of Alzheimer's.” And while it makes sense to investigate the impact that diabetes treatment might have on cognition, an incredibly effective intervention already exists.
“Exercise is the most potent insulin-sensitizing agent we have,” said Dr. Craft, a geriatrician and Alzheimer's researcher at the Veterans Administration Puget Sound Health Care System, Seattle. “A single bout of aerobic exercise improves insulin sensitivity for 24 hours. It's much more potent than any medication. Caloric restriction also lowers hyperinsulinemia and improves insulin sensitivity.”
A large body of work now suggests that insulin resistance increases the risk of Alzheimer's by multiple mechanisms, Dr. Craft said. Far from being active only in the periphery, insulin readily crosses the blood-brain barrier and binds to receptors located throughout the brain–especially in areas of strategic importance in cognition: the hippocampus, entorhinal cortex, and frontal cortex. Once in the brain, insulin interacts with amyloid beta in several ways, increasing its intracellular clearance through insulin degrading enzyme and apparently even protecting neurons from the protein's toxic effects.
“This has been known for some time, but recent research has shown that amyloid beta may have its own independent effects on insulin signaling,” Dr. Craft said. A series of experiments by William L. Klein, Ph.D., concluded that soluble oligomers of amyloid beta can remove insulin receptors from the dendritic plasma membranes of hippocampal neurons. However, Dr. Craft said, “If insulin were administered before the oligomeric Abeta, the dendritic spines were protected.”
The study concluded that insulin receptor signaling downregulated the oligomeric binding sites. Adding rosiglitazone potentiated this effect, suggesting that insulin-sensitizing agents may have some role in cognitive protection (Proc. Natl. Acad. Sci. U.S.A. 2009;106:1971–6).
“Insulin appears to mitigate many of the negative effects of amyloid and regulates its clearance, while beta amyloid appears to reduce insulin signaling. So high levels of insulin in the brain can induce a brain insulin-resistance by removing the insulin receptors from the nerve cell membranes,” Dr. Craft said.
She recently investigated insulin's effect on memory in a group of 33 patients with Alzheimer's or mild cognitive impairment and 59 elderly controls. The patients received placebo or five escalating doses of intranasal insulin. Cognition was tested 15 minutes after each treatment. “We saw a 50% improvement in memory compared with baseline with the highest dose,” Dr. Craft said (J. Alz. Dis. 2008;13:323–31).