“No way! No one else has found this. What makes you think you could?” That, according to Lee Goldstein, MD, PhD, was the general reaction to his discovery of unusual amyloid cataracts that may herald the onset of Alzheimer’s disease.
It happened quite by accident early in the research career of Goldstein, who is now Director of the Molecular Aging & Development Laboratory and Associate Director of the Center for Ophthalmic Research, both at the Brigham & Women’s Hospital in Boston, MA, and Assistant Professor of Psychiatry at the Harvard Medical School. “I was measuring hydrogen peroxide in the brains of Alzheimer’s mice,” he says, “when some previous research experience in ophthalmology came in very handy. I noticed that my mice were developing dense bilateral cataracts in their eyes—at an age when mice simply don’t get cataracts. This is very unusual. So I took a look at a few more of the Alzheimer’s mice, and they all had the same cataract.”
Healthy, wild-type control mice, on the other hand, showed no signs of similar cataracts. Goldstein then looked at eyes from people with Alzheimer’s disease, and to his astonishment, found the same unusual cataracts. He determined that the cataracts were composed of the same protein, b-amyloid, that forms sticky, tangled plaques in the brains of Alzheimer’s patients. He and his team reported their discoveries in the medical journal, The Lancet.
These were not the garden-variety cataracts that cloud people’s eyesight as they get older. Instead, they were “supranuclear” cataracts, which—because of their peripheral location in the lens behind the iris—don’t interfere with vision. This was the first time the ß-amyloid protein had been seen outside of the brain, suggesting that the disease results from a problem affecting the body’s entire system. It was an exciting discovery—and potentially a major breakthrough in the diagnosis and treatment of Alzheimer’s. Goldstein and his team strongly suspected that they had uncovered an important Alzheimer’s biomarker.
Since then, research in his lab at Brigham and Women’s Hospital has confirmed and extended the team’s initial observations. At this stage, Goldstein’s team has also created new non-invasive laser technology that can detect beta-amyloid in the eye even before the cataracts become visible. The new technology is currently being tested in human and laboratory animals. Intriguingly, they have also found that amyloid buildup appears earlier in the lens than the brain—a key finding that may have important clinical implications for diagnosing and treating Alzheimer’s.
Having a biomarker that is easily detectable early in the course of the disease is important. The Alzheimer’s process creates havoc by destroying the brain’s cells and distorting its signaling. Much of this devastation occurs before the first onset of symptoms. In fact, brain damage from Alzheimer’s disease starts years—perhaps decades—before patients first suffer memory loss and confusion. This has consequences that frustrate researchers’ attempts to develop medications that might slow or stop the disease in patients before they become symptomatic. Many of these drugs show promise, but it is impossible to test them without knowing who is likely to go on to develop full-blown Alzheimer’s. As Goldstein points out, “To effectively treat this disease, we must begin to intervene early, well before the first cognitive symptoms emerge.” He is hopeful that his team’s discoveries and their technology may allow the large number of drugs now in the pharmaceutical pipeline to be tested and eventually find their way into clinical use.
Goldstein’s research also holds promise for diagnosing other amyloid disorders, including deadly prion diseases such as Mad Cow Disease (bovine spongiform encephalopathy, BSE), chronic wasting disease (CWD) in deer, and Creutzfeldt-Jacob Disease (CJD) in humans. “Our instrument could be very useful in agri-business and animal management,” says Goldstein. “We envision using the technology for livestock screening to prevent further spread of the disease and to protect the human food.
