Study of Nasal Insulin to Fight Forgetfulness - Long-acting Insulin Detemir - 21 Days (SNIFF-LONG 21)

• Verbal Memory Composite [ Time Frame: Change from Baseline in Verbal Memory at 3 Weeks ] [ Designated as safety issue: No ]
  The composite will consist of the weighted sum of Immediate + Delayed Story Recall and Immediate +Delayed List Recall
  
  

• Neuropsychological Test of Executive Function 1 [ Time Frame: Change from Baseline in Executive Functioning at 3 Weeks ] [ Designated as safety issue: No ]
  Computerized Dot Counting Test (test of executive functioning)
  
  
• Glucose Tolerance [ Time Frame: Change from Baseline in Glucose Tolerance at 3 Weeks ] [ Designated as safety issue: Yes ]
  Subjects will undergo oral glucose tolerance test (OGTT) to assess glucose tolerance
  
  
• Functional Ability [ Time Frame: Change from Baseline in Functional Ability at 3 Weeks ] [ Designated as safety issue: No ]
  Subjects will have a collateral informant (i.e., spouse or friend) rate the subjects' ability to carry out activities of daily living on the Dementia Severity Rating Scale.
  
  
• Plasma biomarkers of AD [ Time Frame: Change from Baseline in Plasma Biomarkers at 3 Weeks ] [ Designated as safety issue: No ]
  Plasma Abeta (ABeta 38, ABeta 40, and Abeta 42) and Tau (total tau and phosphorylated tau) will be measured in each subject.
  
  
• Neuropsychological Test of Executive Functioning 2 [ Time Frame: Change from Baseline in Executive Functioning at 3 Weeks ] [ Designated as safety issue: No ]
  Computerized Stroop Test
  
  
• Neuropsychological Tests of Visual Working Memory [ Time Frame: Change from Baseline in Visual Working Memory at 3 Weeks ] [ Designated as safety issue: No ]
  Benton Visual Retention Test Form F&G (a test of visual working memory)
  
  

It is well-known that insulin, a hormone that is naturally secreted by the pancreas, plays an important physiological role by regulating blood sugar levels in the body. The investigators now know that insulin plays many important roles in the brain as well. Insulin seems to be especially active in the part of the brain that corresponds to learning and memory. Studies have shown that when people have insufficient insulin in the brain (which, for example, is the case with Type-II diabetes), they are increasingly at risk to develop memory problems and Alzheimer's disease. In a past study, the investigators administered intravenous insulin to participants and found that it improves their memory. However, that particular method would not be a practical intervention for people with Alzheimer's disease due to the risk of hypoglycemia or exacerbation of insulin resistance. Instead, the investigators use an "intranasal" method of administration, in which the insulin is inserted into a device, and administered intranasally. In this method, the insulin travels directly to the brain, and bypasses the body. Our past studies have also demonstrated that this can be a reliable way to improve memory, and it does not change the body's blood glucose levels.

In our past studies, the investigators have used regular insulin, which lasts about 3-4 hours and creates a similar "spike" in insulin that one would have after eating a meal. However, in normal physiology, the pancreas also releases small and more constant "pulses" of insulin throughout the day and night, establishing a base level of insulin. Accordingly, several longer-lasting types of insulin are now available that last closer to 10-12 hours, mimicking that base level of insulin. The current study uses a long-lasting type of insulin called "insulin detemir," to determine if learning and memory will benefit from a more constant supplement of insulin. the investigators want to determine whether this treatment can benefit people who already have a memory impairment—either they already have a diagnosis of Alzheimer's disease or are diagnosed with mild cognitive impairment, a condition that precedes Alzheimer's disease, and whether a lower or higher dose of insulin detemir is more effective. The investigators will examine cognition, daily function, and different markers of Alzheimer's disease that are in the blood as outcome measures.

The investigators have these specific aims:

1. The investigators will test the hypothesis that compared to placebo, three weeks of treatment with intranasal insulin detemir will improve cognition and function in adults with Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI).
2. The investigators will determine which of two doses of intranasal insulin detemir produces the greatest improvement in cognition and daily function relative to placebo for adults with AD or MCI.

To examine these hypotheses, the investigators are recruiting approximately 60 participants who have been diagnosed with AD or MCI. They will be randomly selected to take a lower dose of insulin detemir, a higher dose of insulin detemir, or saline (which is an inactive substance and will serve as a placebo). Cognition and the level of daily function will be tested before they begin the study drug, and after 3 weeks of the study drug. The investigators will also measure glucose tolerance and take blood samples to measure markers of AD in the blood.