Alzheimer’s disease and other forms of dementia are associated with both increasing age and obesity. There are also associations between insulin resistance, type 2 diabetes, and cognitive decline. The mechanisms are not clear, but the synergy between age, obesity, and type 2 diabetes could have devastating effects as populations grow older and more obese.
“Obesity is still poorly understood in how it can be related to brain function,” said Auriel A. Willette, PhD, MS, Assistant Professor of Food Science and Human Nutrition and Co-Director of Imaging, Big Brain Initiative, Iowa State University. “What is more interesting is insulin resistance, type 2 diabetes, and the Alzheimer’s brain.”
Dr. Willette opened Dementia and Diabetes—What Are the Causes and How Do We Prevent It? on Tuesday, June 7. The session was livestreamed and can be viewed on-demand by registered meeting participants at ADA2022.org. If you haven’t registered for the 82nd Scientific Sessions, register today to access the valuable meeting content.
Obesity can lead to insulin resistance, which sets the stage for the development of beta amyloid plaques and tau tangles in the brain, both hallmarks of Alzheimer’s disease. Obesity and insulin resistance also are consistently associated with decreased brain volume and lower glucose uptake.
The associations between genetic risk for Alzheimer’s disease in the form of apolipoprotein E4 (APOE4), type 2 diabetes, and Alzheimer’s disease are better established. Individuals with APOE4 are at two to three times higher risk for developing Alzheimer’s disease, Dr. Willette explained. Individuals with type 2 diabetes are at one and a half times increased risk for developing Alzheimer’s disease. Those with both APOE4 and type 2 diabetes are at six to 10 times higher risk for developing Alzheimer’s disease.
Clinical trials have shown that walking two hours per week can improve global cognition in people with Alzheimer’s disease, Dr. Willette said. Trials of inhaled insulin (INI) also suggest potential benefits for memory and function.
The associations between diabetes and dementia are so strong that some researchers have proposed Alzheimer’s disease as type 3 diabetes, said Vera Novak, MD, PhD, Associate Professor of Neurology, Harvard Medical School. Metabolic syndrome and type 2 diabetes accelerate brain aging, degrade cognition, and slow neural networks that have a high metabolic demand.
Diabetes ages the brain by about five years.
“It may not matter that much when you are 40, but it matters a lot at 80,” Dr. Novak said. “When half of people already have some degree of dementia based on age alone, your brain is already 85.”
Early trials of INI in people with type 2 diabetes have shown improved walking speed, visuospatial memory, and verbal memory, she said. When inhaled into the upper nasal cavity, insulin can bypass the blood brain barrier by direct absorption through the olfactory and trigeminal nerves and perivascular transport.
The type of delivery device, properties of the insulin formulation, absorption enhancers, mucoadhesive agents, droplet size, duration of administration, even head position, can all make a difference in how much insulin crosses into the brain and how quickly. INI typically travels to multiple regions of the brain within 10 minutes. Cerebrospinal fluid concentrations peak at 35-40 minutes.
INI trials have not been consistent, she continued. In 94 INI trials between 2005 and 2022, insulin dosing ranged from 20 IU to 160 IU. Only 19 of those trials assessed cognition. Sixteen trials showed positive cognition outcomes; three showed negative results.
The phase 3 Study of Nasal Insulin in the Fight of Forgetfulness trial used two different INI devices and had mixed results. One device showed no difference between 20 IU twice daily versus placebo over 18 months, while the second device showed improvement in cognition and in activities of daily living.
The phase 2 Memory Advancement with Intranasal Insulin trial showed significant improvement in walking speed (p=0.002), executive function (p=0.002), and verbal memory (p=0.02) for 40 IU twice daily versus placebo over 48 weeks. A cohort with prediabetes showed similar improvements in walking, executive function, and verbal memory.
There were no serious or moderate adverse events, Dr. Novak reported. INI did not acutely change interstitial glucose levels or cause hypoglycemia in individuals with type 2 diabetes. COVID-19 disruptions caused the trial to be underpowered.
“Further validation is needed,” Dr. Novak said. “And with 90 million adult Americans and increasing numbers of young people with prediabetes, findings on benefit from INI need more attention and confirmation in a larger trial.”