As this storyline emerges, a raft of clinical trials are testing diabetes drugs among patients with Alzheimer disease or other forms of age-related cognitive impairment. A few studies are also looking at whether metabolism-boosting lifestyle interventions like dietary modifications or exercise might delay or reduce cognitive impairments.

So far, results from diabetes drug trials have been mixed. Investigators stopped a phase 3 trial of the blood glucose–lowering drug pioglitazone in 2018 after an interim analysis failed to show that it delayed the onset of mild cognitive impairment due to Alzheimer disease. But insulin—which is essential for brain energy metabolism—and other therapies might be more promising.

Suzanne Craft, PhD, who directs Wake Forest’s Alzheimer’s Disease Research Center, presented 18-month results from a phase 2 and 3 study of nasal insulin at the Alzheimer’s Association International Conference last July. The trial tested 2 different intranasal insulin delivery devices; patients who used one model appeared to benefit, whereas patients who used another did not.

“What we’ve learned is that not all devices are created equal,” said Craft, who also co-directs the Sticht Center for Healthy Aging and Alzheimer’s Prevention at Wake Forest. She and her colleagues are currently testing intranasal insulin devices to ensure delivery into the brain, a necessary component for a planned phase 3 trial.

Luchsinger, meanwhile, is studying whether the diabetes drug metformin can keep people with mild cognitive impairment from progressing to Alzheimer disease. The drug helps to control glucose and increase insulin sensitivity and has a long track record of safety among individuals without diabetes. Other researchers are interested in the GLP-1 analogue liraglutide, which in a small 2016 trial stabilized glucose levels in patients with Alzheimer disease. Results from a larger study are expected soon.

With a dearth of treatment options, Craft and others are also turning to lifestyle interventions that may have beneficial metabolic effects in both the body and brain. Craft recently published results of a pilot crossover trial comparing a modified version of the ketogenic diet incorporating Mediterranean diet elements with a low-fat diet among patients with memory complaints or mild cognitive impairment.

Six weeks after completing the modified ketogenic diet, patients had improved Alzheimer disease biomarkers in their cerebrospinal fluid. “With the ketogenic diet, we are moving the β-amyloid in a healthier direction,” Craft said. Patients also had better blood flow to the hippocampus and improved body-wide insulin sensitivity. A larger trial of the modified ketogenic diet is now under way.

Craft is also exploring the benefits of exercise, which has been shown to improve cognition and insulin sensitivity in other populations, as a therapy for patients with Alzheimer disease. In Luchsinger’s view, there isn’t enough evidence yet to recommend lifestyle modifications for Alzheimer disease treatment, although he noted that a recent Finnish trial provided proof of concept that lifestyle interventions may benefit those at risk for dementia.

“I certainly think that having healthy habits, eating in a way that you keep a healthy weight, doing physical activity—it’s going to be good even if it doesn’t necessarily change Alzheimer disease,” he said. “It’s more likely to make the brain more resilient to the effects of aging.”

But Craft emphasized that a healthy lifestyle that boosts the brain’s resilience could potentially delay the onset of dementia. “There’s a lot that can be done to, at the very least, push the onset of these disorders back in time,” she said. “It would mean people have lived a good life for much longer.”