CHICAGO – A postmortem analysis of subjects with both Alzheimer's disease and diabetes found up to 80% fewer amyloid beta plaques in the brains of those who took both insulin and oral diabetic medication while alive.
The finding might shed some light on a discrepancy that has puzzled Alzheimer's researchers: Epidemiologic studies confirm a significantly increased risk of Alzheimer's and other dementias among subjects with diabetes, but their brains generally appear less physically ravaged by the disease, Michal Schnaider Beeri, Ph.D., said at the International Conference on Alzheimer's Disease.
“It appears that medication might be one explanation for this apparent discrepancy between epidemiologic and neuropathology studies,” said Dr. Beeri of the Mount Sinai School of Medicine, New York. “It also suggests that diabetes medications may beneficially influence neurologic pathways involving Aβ [amyloid beta] processing and Aβ-related brain lesions.”
The study involved 148 brains from the Mount Sinai School of Medicine Brain Bank. All were from subjects with Alzheimer's disease, half of whom also had diabetes. The subjects were matched for age (mean age 81 years), sex (57% female), and dementia severity (mean clinical dementia rating score 2.4).
Dr. Beeri and her colleagues divided the subjects into categories according to the use of diabetic medications. Of the 124 subjects with diabetes, 49 were taking insulin only, 28 were taking oral diabetes medications only, 18 were taking a combination of agents, and 29 were on no medications. All of these groups were compared against one another, and against the subjects without diabetes.
No significant associations were seen between medication and the presence of tau neurofibrillary tangles. But they found a very strong interaction between medication and Aβ42 plaques in the entorhinal cortex, hippocampus, and amygdala.
Plaque presence was rated from 0 (none) to 2 (severe). Subjects without diabetes had a rating of about 1.5, as did those with diabetes who were taking only oral medications. Subjects with diabetes who took no diabetes medications had a rating of about 1.25. Subjects taking insulin had a lower, but not significantly lower, plaque rating (1, considered sparse), compared with those without diabetes, those with diabetes who were not taking medications, and those who took only oral agents, Dr. Beeri said.
The largest differences were found between subjects on combination therapy (insulin and oral medications) and those who took only oral agents and subjects without diabetes. Combination therapy subjects had a plaque rating of about 0.25, or 80% lower than in the subjects in the other two groups. Those who had taken combination therapy also had far fewer plaques than did those who took no medications, as well as those who took only insulin, she said.
“The results of this study suggest that combination of insulin with other diabetes medication is associated with a substantial reduction in brain neuritic plaque density consistent with the effects of both on the neurobiology of insulin,” Dr. Beeri said at the meeting, presented by the Alzheimer's Association. “Insulin and insulin sensitizers (oral hypoglycemics) are designed to target organs at the periphery, but they also seem to have also an effect on the brain. This suggests the possibility of therapeutic targeting of insulin signaling pathways of the brain for the reduction of Aβ-associated neuropathology of Alzheimer's.”
Brains exposed to both insulin and oral hypoglycemic drugs showed fewer amyloid plaques (white arrows) than those of without diabetes, but no fewer neurofibrillary tangles (black arrows). COURTESY DR. VAHRAM HAROUTUNIAN