Insulin resistance in brain contributes to cognitive decline in Alzheimer’s

A new study has found that insulin resistance in the brain precedes and contributes to cognitive decline above and beyond other known causes of Alzheimer’s disease. Insulin is an important hormone in many bodily functions, including the health of brain cells. Researchers from the Perelman School of Medicine at the University of Pennsylvania identified extensive abnormalities in the activity of two major signaling pathways for insulin and insulin-like growth factor in non-diabetic people with Alzheimer’s disease. These pathways could be targeted with new or existing medicines to potentially help resensitize the brain to insulin and possibly slow down or even improve cognitive decline. This is the first study to directly demonstrate that insulin resistance occurs in the brains of people with Alzheimer’s disease. “Our research clearly shows that the brain’s ability to respond to insulin, which is important for normal brain function, is going offline at some point. Insulin in the brain not only modulates glucose uptake, but also promotes the health of brain cells -- their growth, survival, remodeling, and normal functioning. We believe that brain insulin resistance may be an important contributor to the cognitive decline associated with Alzheimer’s disease,” said senior author, Steven E. Arnold, MD, professor of Psychiatry and Neurology. The investigators used samples of postmortem brain tissue from non-diabetics who had died with Alzheimer’s disease, stimulated the tissue with insulin, and measured how much the insulin activated various proteins in the insulin-signaling pathways. There was less insulin activation in Alzheimer''s cases than in tissue from people who had died without brain disease. Other proteins linked to insulin action in the brain were abnormal in Alzheimer’s disease samples. These abnormalities were highly correlated with episodic memory and other cognitive disabilities in the Alzheimer''s disease patients. In tissue from people with Alzheimer’s disease and mild cognitive impairment (MCI), researchers found that changes to a protein called insulin receptor substrate-1 (IRS-1 pS636/639 and pS616) in brain cells were linked to the severity of memory impairments regardless of age, sex, diabetes history, or apolipoprotein E (APOE) gene status. Levels of IRS-1 were also significantly associated with, but not likely to affect, the presence of amyloid beta plaques and neurofibrillary tangles, the signature markers of Alzheimer''s disease. This suggests that insulin resistance contributes to cognitive decline independent of the classical pathology of Alzheimer’s disease. Researchers noted that three insulin-sensitizing medicines are already approved by the FDA for treatment of diabetes. These drugs readily cross the blood-brain barrier and may have therapeutic potential to correct insulin resistance in Alzheimer''s disease and MCI. “Clinical trials would need to be conducted to determine the impact the drugs have on Alzheimer''s disease and MCI in non-diabetic patients,” said Dr. Arnold. The study is now online in the Journal of Clinical Investigation.