Obesity, Diabetes Trends Portend AD Wave : Most effective method of treating cognitive impairment might be preventing insulin resistance.

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.

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,” she said.

The patients with 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.

The synapse deterioration seen in AD might be tied to the loss of insulin receptors (red) on dendrites of hippocampal neurons attacked by amyloid beta oligomers (green).

Source Courtesy Fernanda G. De Felice and William L. Klein, Ph.D. (appeared in Proc. Natl. Acad. Sci. U.S.A. 2009;106:1971–6)