December 10, 2007
Anne Underwood

Brad Williams, a 51-year-old radio anchor in La Crosse, Wis., used to joke that, if he ever married, he would never forget his anniversary. You wouldn’t either, with a memory like his. Ask him what day of the week Christmas fell on in 1982, and he summons the correct answer in less than two seconds—Saturday. A video that his brother posted on YouTube shows Williams rattling off the answers to such random questions as what day Egyptian President Anwar Sadat was assassinated and what tragic event happened on Nov. 18, 1978. (Oct. 6, 1981, and the Jonestown massacre, respectively.) To his colleagues, he’s a human substitute for the Internet. “It works something like this,” says news anchor Mitch Reynolds, who demonstrates on the video by opening his door and calling out, “Hey, Brad. What’s [the D.A.’s] number?” Faster than you can Google it, Williams recites the listing.

There is no magic formula for achieving such a memory, although neuroscientist James McGaugh at the University of California, Irvine, is studying Williams for clues. Most of us would be happy just to keep our mental recall from slowing with age—a process that seems to start alarmingly early. “If you’re over 25, you’re one of us—your memory is slipping,” says neurologist Scott Small of Columbia University, who is 46. But scientists now know that much of that deterioration represents a slowing of cognitive function rather than actual memory loss, and they’re busy working on interventions. No one should expect miracles soon, if at all. But the deeper scientists peer into the workings of memory, the better they understand what helps to stave off age-related declines—and the closer they come to devising potential drugs to help.

There are many hypotheses about why our powers of recall go awry over time, but it’s clear that both committing new information to memory and retrieving it become more difficult. A new memory is fragile. “It has to set, like cement or Jell-O,” says McGaugh. A small structure in the brain called the hippocampus binds information from various parts of the brain into a coherent memory, which the prefrontal cortex later pulls up for use. But the prefrontal cortex and other brain structures tend to shrink with age, as the cells’ long projections contract, taking with them some of the crucial synapses that neurons use for communication. “Paradoxically, the main result we see in brain imaging is that older people have greater brain activation, not less, probably because they’re compensating,” says Michael Rugg, director of the Center for the Neurobiology of Learning and Memory at UC Irvine. For example, young people accomplish verbal memory tasks by using the language areas on the left side of the brain, while older people tend to pull in the mirror-image areas on the right side, too. This approach gets the job done, but with less efficiency and less precision.

Where there’s a physiological problem, there are usually scientists trying to devise drugs, and memory is no exception. Some potential pills are now advancing to clinical trials. One unlikely example is a class of compounds related to nicotine. Researchers have long known that it’s easier to form memories when you’re paying greater attention—and as smokers will attest, nicotine helps. But nicotine from cigarettes and patches also has negative effects on the cardiovascular system, raising heart rate and blood pressure. Memory Pharmaceuticals Corp. has devised a compound that selectively tickles nicotine receptors in the brain. “You get rid of the bad effects and retain the good,” says chief scientific officer David Lowe. Last month the company announced the results of a small trial in 80 Alzheimer’s patients, who performed better on tests of long-term memory, working memory and speed of cognitive processing after taking the pill once a day for eight weeks. Larger trials are still needed, meaning that it could be years before the drug comes to market, if ever. In the meantime, other companies are exploring different ways to enhance memory formation—from increasing the intensity of brain signaling to prolonging the activity of genes that encode memories.

But poorer memory formation is only one frustration of aging brains. What about old memories you want to retrieve? Sometimes the crucial neurons that retain a memory are damaged. More often, scientists believe, memories simply become harder to access, as that annoying tip-of-the-tongue phenomenon suggests. In a study this year in the journal Nature, neuroscientist Li-Huei Tsai at MIT provided tantalizing evidence that some “lost” memories may be recoverable, even in the presence of neuronal damage. Tsai put mice in a specially wired cage, where they received a mild shock to their feet—nothing dangerous, just unpleasant. But it made enough of an impression that the mice would tense up in fear when they were put back in the wired cage. Memories of dangerous situations tend to be very strong, since survival hinges on recalling threats and learning to avoid them. But when Tsai triggered the degeneration of critical neurons, the mice apparently forgot their fear of the wired cage. “They no longer froze in place,” she says.

The most revealing part of the experiment came in the final step, when Tsai tried two ways of boosting synaptic formation. One was placing the mice in an “enriched environment,” with lots of new toys to engage their learning and attention. The other was administering an experimental drug that promotes synapse formation. After both, the animals exhibited the fearful behavior again, without receiving any further shocks. “If they can recover these memories, that strongly indicates these memories aren’t completely erased,” says Tsai. “Even in severe dementia, people have brief moments of clarity.” Drugs like the one she tested in mice could conceivably enhance those periods of lucidity. But only years of testing will tell, and even then, the pills may have prohibitive side effects.

That’s why many scientists are more interested in what we can accomplish naturally, without drugs. “With a reasonable amount of effort, you can improve your memory 30 to 40 percent,” says Dr. Barry Gordon, founder of the memory clinic at Johns Hopkins. In the past year, research has shed new light in particular on the benefits of both mental and physical activity. It’s been known for a while that aerobic exercise increases levels of a brain chemical called BDNF, which encourages neurons to form new synapses and strengthen existing ones. “I call BDNF brain fertilizer,” says Carl Cotman, director of the Institute for Brain Aging and Dementia at UC Irvine. But in the Proceedings of the National Academy of Sciences this year, Small at Columbia showed that exercise in 11 volunteers did even more. Aerobic exercise—an hour a day, four days a week for three months—led to changes on brain scans that seemed to indicate the birth of new neurons in the hippocampus. “My lab members are dusting off their sneakers,” he says.

Mental workouts, too, encourage the formation of neural connections. Last month Peter Penzes at Northwestern University published a study showing that brain activity boosts the function of a protein called kalirin-7, whose function had been unclear. Penzes demonstrated that kalirin enlarges and strengthens synapses. By contrast, blocking kalirin causes synapses to shrink. “The old saying was right—use it or lose it,” he says.

But the problem with traditional memory exercises has been that practicing one type of task rarely improves performance on others. Working crossword puzzles doesn’t help you remember a shopping list. That’s why a presentation last month at the Gerontological Society of America seemed so intriguing. In a study of 524 healthy adults ages 65 and over, those who worked an hour a day for eight weeks on a computer-based learning program called Brain Fitness 2.0 from Posit Science showed improvements in a variety of unrelated memory tasks. “The gains were equivalent to turning back the clock 10 years,” says lead investigator Elizabeth Zelinski of the University of Southern California. By contrast, participants who were given documentaries to watch showed only marginal improvement (although improvements of any kind are better than declines). Brain Fitness doesn’t teach memory tricks, but instead asks users to discriminate between similar sounds and follow auditory commands, in a series of increasingly difficult tests. The ultimate effect is to sharpen the brain’s systems of attention—although it’s not clear yet how long after training the benefits will last.

But the truth is, there are limits. Even Brad Williams’s memory isn’t foolproof. In 1993, acting in an amateur theater production, he blanked on the name of one of the play’s characters. “You’d think I’d be able to remember it,” he says. “It was my own name—Williams.” It’s so comforting to know he’s human, too.