As a medical student, Zachary Cordner was struck by a study co-authored by Peter Rabins indicating that spouses of Alzheimer’s disease patients were at a twofold risk of developing the condition themselves.

“The spouses were facing an incredible amount of stress day in and day out providing care,” says Cordner, “but exactly how that led to an increased risk of Alzheimer’s disease was entirely an open question.” Then, when he joined Johns Hopkins’ M.D./Ph.D. program and the lab of stress expert Kellie Tamashiro a couple of years later, he quickly realized that the effects of stress on the aging brain were things he could address through research using mouse models.

Lab mice live for about two years, says Cordner. To simulate the unpredictable stressors faced by spousal caregivers of Alzheimer’s disease patients, he and Tamashiro exposed young adult and aged (18 months) mice to two weeks of chronic variable stress—one day the lights might be left on overnight, or another day, they might be placed in an overcrowded cage. Memory tests given to the mice after the two-week period demonstrated that while stress exposure led to some cognitive impairment in all of the mice, the aged mice were profoundly more affected.

The work, published in Translational Psychiatry, also found that stress exposure was associated with increased expression of a gene called beta-secretase, or Bace1, which is involved in the development of plaques that build up in the brain during Alzheimer’s disease. In young mice, there was a 1.5- to twofold increase of Bace1 in the hippocampus, the center of learning and memory; in aged mice, Bace1 was increased not only in the hippocampus, but also in the prefrontal cortex and amygdala, areas that regulate thoughts, actions and emotional behavior. In addition, the researchers noted that increased expression of Bace1 was associated with decreased addition of chemicals or methyl groups in the promoter region of DNA for Bace1.

“Our work suggests that the aging brain appears to be more susceptible to the cognitive effects of stress, and stress may increase the risk of Alzheimer’s disease, especially in aging individuals,” says Cordner, now a psychiatry intern at Johns Hopkins Bayview Medical Center.

In a second set of experiments, Cordner and Tamashiro exposed two additional groups of young adult and aged mice to environmental enrichment—such as increased bedding, toys to play with or tunnels to crawl through—a week before and during a two-week chronic variable stress period. “What we found was we were able to prevent all of these negative effects of stress on learning and memory through environmental enrichment,” says Cordner.

There is a fair amount of interest in enriched environments—including exercise, brain training and social activity—in people, Cordner notes, and some data to suggest those activities help prevent adverse consequences in late life. “The tricky part is there is probably a lot going on in the brain from environmental enrichment, and exactly how that prevented the effects of stress in our study is a big question,” he says. Studying this is his next step.