Could Metformin be useful to prevent Alzheimer’s?

From Diabetes in Control.
July 16th, 2016
The diabetes drug may have a beneficial effect on neurodegenerative diseases.
Metformin, a biguanide, is an oral diabetes medicine used to improve blood glucose levels in people with type 2 diabetes. There have been various studies on other uses of metformin. It may be beneficial in Alzheimer’s disease, stroke and other degenerative brain cell diseases. An animal study found that metformin helps neurogenesis and enhances hippocampus, a key pathway (aPKC-CBP).

Type 2 diabetes doubles the risk of having dementia; though some studies show metformin helps reduce risk, other studies show antidiabetic medications like insulin are linked to increased risk of having dementia.

Animal studies show that metformin recruits endogenous neural stem cells and also promotes the genesis of new neurons. Metformin, however, needs to have been used for a longer period before a drastic reduction in neurodegenerative disease and its neuroprotective nature is seen.
The purpose of this study is to find a link between antidiabetic medications, especially metformin and other neurodegenerative diseases. Also, to know how long one has to be on these antidiabetics before the neuroprotective nature kicks in.

A cohort study of type 2 diabetes patients who are 55 years and above and being managed on a monotherapy antidiabetic drug of either metformin, sulfonylurea (SU), thiazolidinedione (TZD) or insulin were observed in a period of 5 years.

In the course of 5 years, dementia was identified in 9.9% of the patients. Comparing those taking metformin to those taking sulfonylurea, there was a 20% reduction in dementia in those taking metformin. The hazard ratio 0.79%, a 95% confidence interval of 0.65-0.95.

For TZD, metformin had a 23% reduction in having dementia as compared to TZD with hazard ratio of 0.77, 95% confidence interval of 0.66-0.90.

Whereas those on SU as compared to metformin had a 24% increased risk for dementia with a hazard ratio of 1.24, 95% confidence interval of 1.1-1.4.TZD had an 18% increased risk, hazard ratio of 1.18, 95% confidence interval of 1.1-1.4.

Insulin had the highest risk of 28% with hazard ratio of 1.28, 95% confidence interval of 1.1-1.6.

These findings proved that metformin use has neuroprotective benefits while insulin has an increased risk of one having dementia.
In yet another study, patients 50 years and older from Veterans Affairs, diagnosed with type 2 diabetes, were recruited. Those on insulin were followed from the time they started insulin. The exclusion criteria were neuropathy, vitamin B12 deficiency, cognitive impairment, cerebrovascular disease, renal disease, and those who took insulin for less than two thirds of the study period. The sample size after all exclusions was 6,046 patients with 90% of them being male and a median age of 5.25 years.

334 cases of dementia were diagnosed, 100 of them had Parkinson’s, 71 had Alzheimer’s disease and 19 had cognitive impairment during the follow up period. The incidence of developing neurodegenerative disease was lower (2.08) for those who never used metformin as against those who used it for less than a year, which was (2.47). Metformin usage for 4 years was 0.49, 2 to 4 years was 1.30 and 1.61 for less than 2 years. This proves that the longer one stays on metformin the better the neuroprotective benefits take effect.

This study was significant for dementia (0.567 at 2-4 years and 0.252 for more than 4 years), but for Parkinson’s and Alzheimer’s disease it was 0.038 and 0.229 respectively, which happened from four years and beyond. For future studies, a larger scale prospective cohort study is needed to approve the connection between metformin use and the risk for neurodegenerative disease.

A spatial learning maze test performed on mice showed those given metformin (200mg/kg) were significantly better to be able to learn the location of a submerged platform as compared to those given a sterile saline solution.

Other studies have also proposed that metformin could stimulate neurogenesis from human neural stem cells.
Metformin is known to cross the blood-brain barrier, and has pleiotropic effects. It is known to have other possible preventive roles in cancer and heart disease. From all these various studies, one can conclude that metformin does have a therapeutic potential for mild cognitive impairment and dementia.
Practice Pearls:
Metformin use for more than 2 years has a significant reduction in neurodegenerative disease; it is neuroprotective as well as promoting neurogenesis.
Though the mechanism between metformin and neurodegenerative disease is uncertain, it is known to cross the blood brain barrier and has pleiotropic effects.
Growing evidence suggests that neural stem cells play a role in the repair of injuries or a degenerated brain.

Shi Qian, Lui Shuqian, Foseca Vivian, et al. “The effort of Metformin Exposure on Neurodegenerative disease among Elder Adult Veterans with Diabetes Mellitus”. American Diabetes Association-76th Scientific session 2016. Web June 19 2016.
Wang Jing, et al. “Metformin Activates an Atypical PKC-CBP Pathway to promote Neurogenesis and Enhance Spatial Memory Formation”. Cell Stem Cell. Vol 11(1) July 2012. Web June 19 2016.
Knopman David S et al. “Metformin Cuts Dementia Risk in Type 2 Diabetes”. Alzheimer Association International. July 2013. Web 19 2016.