OHSU Researchers Reveal Genetic Ties To Anxiety

05/25/05    Portland, Ore.

Increased anxiety occurs in approximately 70 percent of Alzheimer's patients, correlates with impaired activities of daily living.

While it is a less heralded and less understood behavioral change associated with Alzheimer's disease, it also is the most common reason why Alzheimer's patients are institutionalized by their families. For years, clinicians and scientists have been aware that in many cases, Alzheimer's patients suffer from a high level of anxiety. Now Oregon Health & Science University scientists believe they have uncovered a genetic link behind it. The results of their research are published in the latest edition of the journal Neurobiology of Aging.

 "Increased anxiety may occur in up to 70 percent of Alzheimer's patents during the course of their disease," explained Jacob Raber, Ph.D., an associate professor of behavioral neuroscience and neurology in the OHSU School of Medicine, and an affiliate associate scientist in the Division of Neuroscience at the OHSU Oregon National Primate Research Center. "Most pharmacological treatments for controlling behavioral changes are associated with deterioration in mental performance and motor function. This research recognizes the need to gain a better understanding of factors contributing to anxiety in dementing illnesses."

Studying both mice and suspected Alzheimer's patients, Raber and colleagues observed the impacts of two closely related human genes called apoE3 and apoE4. In the past, apoE4 has been linked to increased risk of developing Alzheimer's disease. As part of their research, the scientists studied mice without mouse apoE, and with or without either form of the human apoE.

Behavioral studies of the animals completely lacking mouse apoE or possessing the human apoE4 showed them to be more anxious than wild strain mice. In addition, when given a choice, these mice chose sheltered dark areas versus open areas, to a larger extent, than wild strain mice. As mice consider themselves to be more vulnerable and are more anxious in these open spaces but are curious to explore them, measures in the open areas can be used to assess the anxiety levels of the mice. The mice in these two groups were also showed an increased startle response following an acoustic stimulus. Finally, brain damage in the portion of the brain called the amygdala, which plays an important role in the regulation of anxiety, was found in these two groups of mice. In comparison, mice bred with apoE3 responded much like normal wild mice and did not display significant brain damage.

To confirm these results, researchers analyzed anxiety scores in probable Alzheimer's disease patients. The researchers then compared these test results to the patients' genetic profiles.

"What we learned was that the human data matched the mouse data in that patients with only apoE4 showed higher anxiety scores than those with only apoE3," explained Raber. "The human studies also revealed a sex-linked difference associated with people with apoE3 and apoE4. While females with apoE3 and apoE4 showed anxiety scores comparable to females with only apoE4, males with apoE3 and apoE4 showed anxiety scores comparable to males with only apoE3."

The research was funded by the National Institute on Aging, a component of the National Institutes of Health; the OHSU General Clinical Research Center; the Ellison Medical Foundation; the Medical Research Foundation of Oregon; and a VA Career Development Award. 

The ONPRC is a registered research institution inspected regularly by the United States Department of Agriculture. It operates in compliance with the Animal Welfare Act and has an assurance of regulatory compliance on file with the National Institutes of Health. The ONPRC also participates in the voluntary accreditation program overseen by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).