Marked Brain Changes Afflict Even Senior Citizens Who Have Escaped Alzheimer's Disease

Neuroscientists have recently discovered that the region of the brain that stores episodic memories -- those for specific events and their context -- was less engaged in older people, particularly those who have a common variant of a particular gene. Researchers also have determined that senior citizens who suspect that their sense of direction is declining are astute observers of a newly discovered age-related mental change.

According to two other studies, older people are at risk for developing Alzheimer's if their blood levels of cholesterol are too high and if they are physically inactive.

Findings on aging such as these have been made possible by the application of such advanced imaging technologies as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), which enable scientists to "see" the areas of the brain that are active when an individual's memory is tested.

In an fMRI study at the National Institute of Mental Health (NIMH), Daniel Weinberger, PhD; Venkata Mattay, PhD; and colleagues linked age-related changes in the brain's memory storage area, the hippocampus, to the gene for brain-derived neurotrophic factor (BDNF), which protects and supports cell growth in the brain.

Their results indicate that senior citizens who have two normal copies of BDNF may be more resilient to age-related changes in the hippocampus than those older individuals who have either one or two mutated versions of this gene.

Weinberger and Mattay focused on the BDNF gene because previous studies of young people had associated a mutation in this gene with the individual variability in cognition and intelligence that characterizes the human population.

A total of 125 healthy volunteers, age 20 to 80, participated in the NIMH study. To measure brain activity in the study participants' hippocampus, Weinberger and Mattay asked them to perform a simple declarative memory task that required encoding and retrieval of complex, novel scenes, while fMRI images were made of their brains.

"We found that there was a main effect of age, with the elderly showing relatively decreased hippocampal engagement," says Weinberger. Their study also revealed that individuals with the BDNF mutation "showed a steeper age-related decline in hippocampal engagement" when compared with the study participants without the gene mutation.

They point out that cognitive aging is likely influenced by multiple genes, not just BDNF. Identifying these genes not only will improve scientific knowledge about the molecular basis of aging, but also could lead to cognitive gene screening tests of people approaching middle age.

"It is possible that through early identification of susceptible individuals, early intervention through lifestyle changes and other interventions could be facilitated to increase an individual's resilience to the effects of aging," Weinberger says.

In virtual environment (VE) tests, older individuals remembered landmarks along roadways as well as their younger counterparts. But they had a poorer sense of direction. And, while the younger participants in the study ignored irrelevant environmental cues presented during the VE tasks, the older individuals paid as much attention to the meaningless landmarks as they did to directional ones at intersections.

These findings came from a study by Scott Moffat, PhD, at Wayne State University in Detroit. He tested 127 men and women from 18 to 92 years of age with a VE spatial navigation task. The VE featured a series of interconnected roadways, some leading to dead ends, and others ultimately leading to the goal point.

Appearing on the roadways were landmarks that the study participants could use to decide whether to move forward, backward, left, or right. Although about 50 percent of these landmarks occurred at critical decision points, the remainder appeared in straight portions of the roadways, where the study participants did not have to make a directional decision.

After traveling through the VE, the participants were shown photos of the landmarks from multiple perspectives. They were then asked to identify the direction they would travel (forward, backward, left, or right) if they were in that location.

Both young and old subjects remembered about 90 percent of the landmarks. However, the older individuals performed worse than their younger counterparts in identifying the correct direction associated with each landmark.

"Older people are very good at remembering particular landmarks but they have great difficulty linking those locations with the correct orientation," says Moffat.

Unlike the younger individuals in the study, the older participants did not ignore irrelevant environmental cues that were presented during the VE task.

"A landmark that occurs at a critical decision point on a traveled route, such as at an intersection, is very important, whereas one that merely whizzes by the car window is not as critical," he says.

Moffat cautioned that although the sense of direction of the older participants in his study was poor, some of the older individuals performed just as well as their younger counterparts. "This variability among older people is quite characteristic of all aspects of aging," he says.

Two of the major risk factors for heart disease and stroke -- high blood levels of cholesterol and a physically inactive lifestyle -- also may increase an older individual's chances for developing Alzheimer's disease.

In one PET study, cognitively normal people with high cholesterol levels had lower-than-normal cell activity in brain regions typically damaged by Alzheimer's. Cell activity also was low in the brain areas that are impaired by normal aging. In an fMRI study, the brain regions responsible for making decisions and for inhibiting distracting informaton were strongly activated in older people who were very physically fit. In individuals who were not physically fit, these brain regions were much less activated.

The PET study was conducted at the Banner Alzheimer's Institute in Phoenix, where Eric Reiman, MD, and his research colleagues studied 117 healthy people who were in their 50s and 60s and who had different levels of genetic risk for Alzheimer's.

The scientists evaluated the blood cholesterol levels based on whether the patient was a non-carrier or a carrier of a common Alzheimer's susceptibility gene known as APOE4. The correlation between high blood cholesterol levels, APOE4, and reduced activity was significant.

"Our findings raise the possibility that higher cholesterol levels conspire with other risk factors to trigger Alzheimer's," says Reiman. "They support the possibility that cholesterol-lowering treatments might promote brain health and reduce the risk of Alzheimer's disease as people grow older."

Prompted in part by laboratory animal studies suggesting that frequent physical activity encourages new brain cells to develop, many people have taken up jogging, walking, swimming, and other forms of regular exercise to improve and preserve their cognitive abilities as well as their cardiovascular health.

However, few studies have been conducted to examine how a person's cognitive performance and its neurophysiological correlates are influenced by the individual's overall motor status.

At Jacobs University in Bremen, Germany, Ben Godde, PhD, and his colleague Claudia Völcker-Rehage, PhD, used behavioral tests and fMRI to analyze the relationship between motor status and performance in the cognitive functioning of 89 people, 61 to 79 years old.

The fMRI images revealed that the brain regions responsible for making decisions and directing specific attention were still strongly activated in the older people who were very physically fit. In the individuals who were not physically fit, these brain regions were much less activated.

"Our findings for the first time confirm the assumption that, besides cardiovascular training, other forms of physical activity, training motor balance, coordination, and speed, might positively influence cognitive performance in older adults, both on the behavioral and the neurophysiological level," says Völcker-Rehage.

She adds that their research showed that tasks requiring muscle strength and flexibility were not related to cognitive abilities.

"Our findings add important further insights to the question of whether and how lifestyle factors such as social activities, intellectual engagement, or physical activity influence cognitive vitality across the lifespan," she says.