Missing Memories

Doctors are all too familiar with the final stages of Alzheimer's disease, when neurodegenerative plaques and tangles spread throughout the brains of their patients, robbing them of memory, dignity and finally their lives. But what if there were a way to halt this terrifying decline? What if scientists developed a treatment that could somehow stop Alzheimer's disease in its tracks and prevent any further deterioration? Chances are you'd want to treat folks as soon as possible, in the earliest stages of the disease, long before devastating brain damage had occurred.

Researchers at Washington University School of Medicine in St. Louis, Mo., last week disclosed what may be an important step toward that goal. No, they didn't announce a new therapy that can stem the ravages of Alzheimer's disease. Instead, in a study that was published in the March issue of the Archives of Neurology, they provided compelling evidence that a condition called mild cognitive impairment, or mci, which is characterized by repeated lapses in short-term memory, is in fact in many patients the earliest stage of Alzheimer's disease.

Should the Washington University findings hold up, they could eventually provide drug companies with another target for treating or even preventing Alzheimer's. Perhaps more immediately, however, the results could trigger all sorts of financial and legal headaches if, for example, insurance companies start labeling mild cognitive impairment as a pre-existing condition that disqualifies patients from long-term health-care coverage. This is apart from the emotional trauma of patients realizing that they probably have an incurable disorder.

In any event, the research underscores the fact that as scientists increase their knowledge about the earliest manifestations of Alzheimer's disease, more questions are being raised than can be answered. For instance, what exactly do researchers mean when they talk about mild cognitive impairment? "There are lots of conditions that can be subsumed under the term," says Dr. John Morris, lead author of the study. MCI could stem from the side effects of taking too many medications, a blow to the head or the lassitudes of depression. But what Morris and others are focusing on is repeated problems with short-term memory that are often first noticed by a close friend or relative.

This clinical view of MCI deals with distinct changes in forgetfulness over a period of a year or two--changes that can be verified with psychological testing. "People start at different points," says Neil Buckholtz, chief of the dementias branch at the National Institute on Aging. "Everybody forgets where they put their keys. But if you forget what keys are for, that could be a concern."

There is also preliminary evidence suggesting that a diagnosis of MCI can be confirmed with a magnetic-resonance scan of the brain. Typically, in cases of what turns out to be pre-Alzheimer's mci, these images will reveal that the hippocampus, a central portion of the brain associated with short-term memory, is somewhat smaller than normal or even rather shrunken in appearance.

Of course, when Morris and his colleagues at Washington University set out on their study 10 years ago, they didn't have even this much information to guide them. Instead, they pulled together a group of 404 men and women between the ages of 45 and 103 and gave them a battery of psychological and memory tests. Nearly 230 study subjects had various levels of what we would now recognize as MCI. The rest had normal scores for their age and served as the control group.

Over the course of the study, 42 people died and donated their brains for autopsy--the only foolproof method of diagnosing Alzheimer's disease. To the researchers' surprise, 21 of the 25 people who had originally shown signs of mci proved to have Alzheimer's disease at autopsy--many more patients than they had anticipated.

Still, the Washington University study does not prove that all mci is an early stage of Alzheimer's disease. Participants were not chosen at random but had volunteered to be part of the trial. Because a family member or someone close to them had already noticed a change in their mental acuity, the results of the trial may have been skewed. In addition, it's not easy to know where normal forgetfulness ends and clinically significant impairment begins. The Food and Drug Administration invited a panel of experts to Washington last week to try to tackle the problem. The National Institutes of Health has scheduled another meeting in the fall to see if they can come up with a more rigorous definition of mild cognitive impairment.

In the meantime, at least five therapies are now being studied around the world for their potential in treating mci. Among the candidate treatments are vitamin E, anti-inflammatory medications called cox-2 inhibitors and the Alzheimer's drug Aricept. The first results aren't expected for three to four years.

Until then, doctors are likely to proceed fairly cautiously. They want to make sure they're helping their mci patients without unnecessarily stigmatizing them with the Alzheimer's label. Still, there's hope, says Dr. Ronald Petersen, director of the Alzheimer's Researcher Center at the Mayo Clinic in Rochester, Minn. "These people are really quite functional." For if mci is indeed the earliest stage of Alzheimer's disease, and if it's possible to slow its progression, patients might be able to delay the onset of full-blown Alzheimer's and preserve a fairly decent quality of life.