The ‘Super-aged’ Proffer a Template

by Kayt Sukel

January 14, 2009

My great-grandmother lived to the ripe old age of 98. While many of her friends and neighbors had lost critical cognitive function decades before, requiring assistance for day-to-day activities, she somehow maintained her faculties well enough to live on her own well into her 90s. What was it about my great-grandmother’s brain—and those of others like her—that allowed her to retain these essential cognitive capabilities? Researchers at Northwestern University and elsewhere are shedding some light on the so-called “super-aged,” offering new insight into the aging brain and memory.

The brain as we age

Research has shown that the brain goes through several physiological changes as we mature.

“The brain is like any other organ in the body,” says Gary Small, director of the Center on Aging at the University of California, Los Angeles (UCLA). “With time, there’s wear and tear.”

Parts of the brain atrophy, including shrinkage in areas related to memory. “We see that the medial temporal lobe, in particular the hippocampus, shows this shrinkage,” says Ronald Petersen, director of the Mayo Clinic’s Study of Aging. “These are areas involved with memory, laying down new traces and retrieving recently encoded information.” Petersen says that research also shows some neuronal loss and changes in the myelination of neuronal axons associated with memory loss and cognitive decline. Myelin insulates neurons, helping them send signals; as the layers of myelin thin, neuronal signals can get crossed—or lost altogether.

But one of the most profound changes seen in the aged brain is the development of abnormal plaques and tangles. “Both in normal aging individuals and those with Alzheimer’s disease, you see amyloid plaques and tau tangles,” says Petersen. “These are deposits in the brain—amyloid being extracellular and the tau tangles intracellular—that result in abnormal neurologic consequences. The more you have of these things, the worse the consequences.”

Though amyloid has long been implicated in the development of neuropathologies such as Alzheimer’s disease—it is often used postmortem to verify a diagnosis of the disorder—its roles are not well understood. And many elderly people who have high concentrations of these amyloid plaques appear to have no cognitive deficits.

“We’ve studied many individuals at autopsy who had enough plaques to have been diagnosed with Alzheimer’s disease, had they shown any clinical impairment,” says Petersen. “Sure, it’s possible that had that person lived another 6 months, they would have developed dementia. But they managed to get to 85 years of age with a head full of amyloid and no ill effects. Why wouldn’t they have shown some impairment before? We just don’t know the answer.”

Tangles as a missing link?

Getting to the bottom of how the brain ages may require a slight shift in thinking, suggests Changiz Geula, a researcher at Northwestern University’s Cognitive Neurology and Alzheimer’s Disease Center. While many other researchers study the detriments of age, he and his colleagues are focusing on the “super-aged,” people over 80 who perform at the same cognitive level as those decades younger.

“Everybody looks at what is decreased with aging,” he says. “But what we are looking at is what is preserved or perhaps even increasing in these super-aged individuals compared to those who age in a more normal way.”

Geula presented research at the 2008 Society for Neuroscience annual meeting that suggested that tau tangles may play a much more influential role in aging pathology than previously thought.

“We found that, in these ‘super-aged’ individuals, the deposits of amyloid did not differ as compared to normal individuals of the same age. If anything, they were even higher,” he says. “But what was particularly interesting was that there were a lower number or even an absence of the tau tangles.”

These tangles may provide new clues to understanding aging-related brain pathologies, says Christopher Rowe, director of the department of nuclear medicine at Austin Health in Melbourne, Australia. “Once you have Alzheimer’s disease, there’s no correlation between the amount of amyloid you have and how severe your dementia is,” he says. “Instead, it may be that the amyloid sets off some type of cascade that results in the continuing brain damage. The formation of tau tangles may be the missing link.”

Next: Watching subjects longer

Geula acknowledges that his findings are very preliminary, but he argues that they suggest the “super-aged” have some type of capability that helps protect their brains from the declines of aging. He plans to focus his lab work on unraveling just what these neuroprotective elements might be.

Petersen thinks that longitudinal studies of aging populations will help provide more direction for future research. “We have a lot to learn about amyloid plaques and tau tangles and why some people can tolerate this kind of pathologic burden and still function normally,” he says. “And by following these individuals longitudinally, we may soon be able to predict who will age successfully with little to no cognitive impairment and make some recommendations to others based on those predictors.”