(08-09-09) Obesity-Driven Diabetes to Play Key Role in Rising Alzheimer?s Cases

VIENNA (EGMN) ? The rising tides of Alzheimer?s disease and obesity could join in the next 40 years to create a flood of dementia associated with type 2 diabetes.

The outlook may be dire, researchers said at the International Conference on Alzheimer?s Disease. If the trends in child and adolescent obesity continue unabated, by 2040, one-third of the 81 million expected Alzheimer?s cases worldwide may be a direct result of obesity-driven diabetes, Mary Haan, Ph.D., said at the meeting.

?We need to identify the contributions to this increase in dementia and
figure out how to decrease this burden,? Dr. Haan said. ?In the settingof
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/m2. More than half had metabolic syndrome.

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,? she said. Instead, the most effective method is probably to prevent obesity and insulin resistance ? the two factors that most strongly influence the development of diabetes.

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 signalling,? 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 was administered before the oligomeric Abeta, the dendritic spines were protected.?

The study, published in February, concluded that insulin receptor signalling downregulated the oligomeric binding sites. The addition of 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 signalling. 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, which travels directly into the central nervous system along the olfactory and trigeminal vasculature. Cognition was tested 15 minutes after each treatment.
?We saw a 50% improvement in memory compared to baseline with the highest dose,? Dr. Craft said (J. Alz. Dis. 2008;13:323-31).

Insulin also affects vascular function in the brain. ?It?s very well known
that insulin resistance is accompanied by peripheral vascular dysfunction, but the understanding that this may also manifest in the brain is very new and potentially important.?

In insulin resistance, there is a downregulation of the phosphoinositide-3 (PI3) kinase pathway, which mediates vascular relaxation. But the mitogen-activated protein (MAP) kinase pathway, which mediates vasoconstriction, is driven by high levels of insulin and thus, does not downregulate with insulin
resistance. ?You get a reduction in vasodilation and hyperactivation of
vasoconstriction,? Dr. Craft said. ?This imbalance is thought to underlie many of the vascular dysfunctions associated with insulin resistance.?

She saw this in a recent study of 196 brains (71 with dementia). The brains were divided into four groups: normal; diabetic without dementia; diabetic with dementia; and dementia without diabetes (Arch. Neuro. 2009;66:315-22).

?We saw a surprising pattern when we looked at plaques and tangles: the brains of the patients with dementia but no diabetes had a high load, as anticipated, but the brains of diabetic patients with dementia had a plaque load that was similar to the normal controls.?

The patients with both dementia and diabetes did, however, show high levels of microvascular lesions, which were absent in the other groups. ?The volume of the lesions is small, so they are almost certainly not directly responsible for the cognitive impairment, but this finding may point to some broader based vascular dysfunction,? Dr. Craft said.

Source: univadis.it

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