YOUR DOSE OF MEDICINE
By Charles C. Chante, MD
The Philippine Star
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 maybe a direct result of obesity-driven diabetes.
We need to identify the contributions to this increase in dementia and figure out how to decrease this burden. 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.
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 of the University of California, San Francisco were presented 9 years of follow-up data on this group of 1,789 men and women (mean baseline age 72 years). At the study entrance, 33 percent of the group had type 2 diabetes and 40 percent had a body mass index of more than 25kg/m2. More than half had metabolic syndrome.
Over 9 years, 158 incident cases of dementia or non- dementia cognitive impairment developed. After controlling for age, gender, girth, diabetes treatment, fasting insulin, and C-reactive protein, it was said that 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 percent of all these dementia cases were the direct result of type 2 diabetes.
When carried forward in accordance with projected increases in obesity, the 19 percent figure means that by 2040, 24 million cases of dementia could be directly tied to type 2 diabetes. However, 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 — the two factors that most strongly influence the development of diabetes.
“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 although it make sense to investigate the impact that diabetes treatment might have on cognition, an incredibly effective intervention already exist.
Exercise is the most potent insulin-sensitizing agent we have, said 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 mechanism. Far from being active only on the periphery, insulin readily crosses the blood brain barrier and binds to receptors located throughout the brain. Once in the brain, insulin interacts with amyloid beta in several ways, increasing its intracellular clearance through insulin degrading enzyme and apparently even protecting neuros 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 in insulin signaling..”
A series of experiments concluded that soluble oligomers of amyloid beta can remove insulin receptors from the dendritic plasma membranes of hippocampal neutrons. The study concluded that insulin receptor signaling downregulated the oligomeric binding sites. The addition of rosiglitazone potentiated this effect, suggesting that insulin-sensitizing agents may have some role in cognitive protection. “Insulin appears to mitigate many of the negative effects of amyloid and regulates it 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.”
Recently investigated insulin’s effect on memory in a group of 33 patients with Alzheimer’s or mild 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 percent improvement in memory compared to baseline with the highest dose,”
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 down-regulation of the phosphoinositide-3 (PI3) kinase pathway, which mediates vascular relaxation. But the mitogen-activated protein (MAP) kinase pathway, which mediates vasoconstriction.” “This imbalance is thought to underlie many of the vascular dysfunctions associated with insulin resistance.”
This is 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.
“Saw a surprising pattern when 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 patient 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.”