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Researchers Discover Potential Clue behind Age-Related Memory Decline

Scientists from Columbia University improve memory in elderly mice after pinpointing a gene for senescent forgetfulness
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Forgetfulness is accepted as a natural part of getting older, but it might not have to be. Scientists say they have identified an important biological mechanism in the brain that underlies the sorts of memory lapses that come with age. The condition is familiar to just about anyone who has lived more than a few decades and is often marked by frustrated utterances like “Where did I park the car?” and “What am I doing here?”

The latest research, which was reported in the journal Science Translational Medicine, provides further support of the idea that this kind of forgetfulness is distinct from Alzheimer’s disease, and offers clues to how we might someday prevent or even reverse age-related memory decline.

The early stages of Alzheimer’s disease can be difficult to distinguish from the typical memory loss that accompanies aging. When a loved one starts to forget names, faces, appointments or other details, waiting for the correct diagnosis can be agonizing. The current study, led by Eric Kandel, a neuropsychiatrist at Columbia University who won the Nobel Prize in Physiology or Medicine in 2000 for his work on memory, might one day lead to a diagnostic test for common forgetfulness. The results could help to rule out Alzheimer’s disease earlier—before more unmistakable symptoms begin to appear—and “save people anxiety when they begin to have memory deficits,” Kandel says.

From a neurological point of view, Alzheimer’s disease and age-related memory decline both begin in the hippocampus, a structure in the brain that is involved in converting memory from short-term to long-term. But the problems caused by Alzheimer’s start in a section of the hippocampus called the entorhinal cortex and then spread to other parts of the brain whereas the trouble with age-related memory decline seems to affect primarily a part of the hippocampus called the dentate gyrus. Autopsy studies to date suggest that the latter is mostly untouched in Alzheimer’s patients.

In the first phase of their study Kandel and his team examined the brains of eight recently deceased people aged 33 to 88 who did not have any neurological disorders. The investigators looked for changes in gene activity that corresponded with signs of aging in the dentate gyrus but not in the surrounding tissue. After singling out 17 potentially responsible genes they found one—the gene for a protein called RbAp48—that seemed more promising than the others because levels of the protein were so much lower in the dentate gyri of the brains donated by elderly individuals.

The results of the brain tissue examination established a correlation between low RbAp48 levels and memory decline, but the researchers still could not tell if the drop was the reason behind the memory deficit in the first place, or if the presence of both was simply a matter of coincidence. To answer that question, the researchers tested the memory of mice that had been genetically engineered to be deficient in RbAp48.

Mice do not get Alzheimer’s, but they do experience memory decline as they age. The researchers found that older mice also experienced a corresponding decrease in RbAp48 protein in the dentate gyrus. Compared with nongenetically modified mice of the same age, young mice that had been genetically altered to have RbAp48 deficiencies had memory problems similar to those exhibited in older, nongenetically altered mice; they were worse at escaping from a water maze and could not differentiate novel objects from ones they had seen before.

Next, the researchers restored RbAp48 in older mice whose memory had declined naturally by giving them a virus that contained genetic material that boosted production of the protein. This time when the old mice were tested, “their memory was almost as good as the young mice,” says Scott Small, director of Alzheimer’s research at Columbia and co-author of the paper. Taken together, the results signify that “an age-related decline in RbAp48 underlies, to a certain extent, the memory loss that occurs with aging,” he says.

Part of the tragedy of Alzheimer’s is that when brain cells die, they do not return—a situation that does not appear to be the case in age-related forgetfulness. Instead of experiencing a full death, the neurons in the dentate gyrus are “sick” and “are simply not communicating as well as they should,” Small says. The experiment provides evidence that when brain cells in the dentate gyrus go offline as a result of normal aging, they might be unlocked through reintroduction of RbAp48, which could “rescue some of the memory loss,” Small says.

Not everyone is convinced that Alzheimer’s and age-related memory decline are entirely separate afflictions. Samuel Gandy, associate director of Alzheimer’s research at The Mount Sinai Hospital in New York City, thinks there could still be merit to the idea that the forgetfulness of old age and Alzheimer’s are part of a degeneration spectrum. He points to a well-known study published in 2012 in Nature, where scientists in Iceland found that a mutation in a certain gene appeared to protect against both Alzheimer’s and age-related cognitive decline. (Scientific American is part of Nature Publishing Group.)

But although Kandel agrees there could be multiple factors contributing memory decline, he says that his study provides strong evidence that a decrease in RbAp48 is a major component, and occurs in all individuals, regardless of their risk for Alzheimer’s.

In addition to clarifying the distinction between Alzheimer’s and memory decline in old age, the Columbia study opens up new avenues to explore regarding treatment for age-related memory decline. Several studies in recent years have pointed to everything from red wine to mental exercises as possible preventive measures against declining cognitive function. Still unknown: why RbAp48 decreases with age and whether these treatments may prevent that loss. But by testing the impact of, say, mental exercise on how well the dentate gyrus functions, researchers may be able to pin down more precisely what works and what does not.

And according to Small, one remedy is already available. “We can ask, is there any intervention that improves the performance of the dentate gyrus? And in fact there is something that has an effect, and it is called physical exercise,” Small says.

There may also be potential to develop pharmaceutical or nutraceutical solutions that would boost production of RbAp48 in the dentate gyrus.

As for Kandel, who was born in 1929, “I feel some decrease in memory, but I stay intellectually engaged,” he says. “I try to do new things in order to protect my cognitive capabilities.”

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