Metformin May Up Alzheimer's Protein if Used Alone

Metformin Beta-Amyloid Effect Raises Alzheimer's Concerns

Janis Kelly

March 16, 2009

March 16, 2009 — Diabetes mellitus is associated with increased risk for Alzheimer's disease (AD), but a new study of metformin suggests that diabetes treatments might bear some of the blame.

Yaomin Chen, PhD, from the Burnham Institute for Medical Research, in La Jolla, California, and colleagues report in the March 10 issue of the Proceedings of the National Academy of Sciences that metformin increased insulin's reduction of intracellular and extracellular beta-amyloid accumulation, but metformin by itself actually increased levels of the Alzheimer's-linked peptides.

This finding, which was observed in vitro and in animal models of AD, raises the specter of a wave of new Alzheimer's cases in diabetic patients who have been taking metformin for years. It is the most popular antidiabetic drug in the United States and 1 of only 2 oral antidiabetics on the World Health Organization List of Essential Medicines (along with glibenclamide). In 2006, there were 35 million prescriptions for generic metformin filled in the United States.

Senior author Francesca-Fang Liao, PhD, told Medscape Psychiatry that although this was an animal study, the findings are worrisome enough that physicians should promptly follow up any complaints of cognitive decline in patients taking metformin.

"Our data suggest that metformin used alone might potentially facilitate development of AD pathology," Dr. Liao said. "This raised the question of whether the increased AD risk in diabetes mellitus patients might be due to the medication itself.

"Extensive animal studies as well as epidemiological data from clinical patients should be collected and carefully analyzed to address this question." Dr. Liao was at the Burnham Institute for Medical Research when this study was done but is now at the University of Tennessee Health Science Center, in Memphis.

Safer to Use Metformin in Combination Therapy?

The upregulation of beta-amyloid generation by metformin in animal models of AD occurred at steady-state plasma levels at and even below those reported in diabetic patients.

Metformin is an insulin-sensitizing drug, and the researchers found that giving it together with insulin added to insulin's known ability to reduce beta-amyloid generation.

"Our data suggest that the potentially deleterious effects of metformin to AD patients may be avoided by using it in combination with insulin; the combination may result in a beneficial effect in treating both type 2 [diabetes mellitus] and in mitigating AD progression," the researchers write.

AD expert Michal S. Beeri, MD, from the Mount Sinai School of Medicine, in New York, told Medscape Psychiatry, "The report by Chen is very interesting and consistent with a study from our group showing that brains of diabetics who, when alive, received combination therapy (ie, insulin plus an insulin sensitizer) had 80% less neuritic plaques (1 of the hallmark lesions of AD).

"This paper is also consistent with another study published in the Proceedings of the National Academy of Sciences [De Felice FG et al. Proc Natl Acad Sci. 2009;106:1971-1976] showing that soluble beta-amyloid oligomers (precursors of neuritic plaques) promote loss of surface of insulin receptor, that this loss can be prevented by insulin, and, most interesting, that adding the insulin sensitizer rosiglitazone [Avandia, GlaxoSmithKline] to insulin potentiates this protection.

"These studies suggest that there might be some protective mechanism that is triggered when the brain is exposed to insulin and insulin sensitizers at the same time, and this in turn has therapeutic potential," she said.

Randomized Control Trials Needed

With regard to the apparent deleterious effects of metformin, Dr. Beeri is more cautious, noting that large, placebo-controlled, double-blind trials will be required to establish that this happens in human patients as well as in animal models and in vitro.

"I think Chen's study is very important and strengthens the concept of diabetes medication effects on Alzheimer's neuropathology, but at this point I do not think that there is clinical evidence for clinicians to be concerned when treating their diabetic patients with metformin," she said.

The study was supported by National Institutes of Health grants, the Alzheimer's Association, and a Zenith Award. The authors report no conflicts of interest.

Proc Nat Acad Sci 2009;106:3907-3912. Abstract