Cultured skin cells (green) from a healthy person (top) and a person with Alzheimer’s disease (bottom).
A novel test that detects enzymes that are dysfunctional in patients with Alzheimer’s disease–and that are found both in the brain and in skin cells–is about to undergo large clinical trials. Researchers at the Blanchette Rockefeller Neurosciences Institute (BRNI), in Morgantown, WV, who developed the diagnostic have also garnered approval from the Food and Drug Administration to test in humans an experimental drug that activates the enzymes–a mechanism that represents a new therapeutic approach to Alzheimer’s.
In preliminary clinical trials, the skin test could accurately predict which patients had Alzheimer’s disease. Last month, BRNI announced a partnership with Inverness Medical Innovations, a medical diagnostics company based in Waltham, MA, that will fund a larger clinical trial of thousands of patients that is necessary to commercialize the diagnostic.
Currently, Alzheimer’s disease can only be definitively diagnosed on autopsy. Physicians diagnose the disease in patients with a combination of cognitive tests to assess mental function, a neurological exam, and brain scans to rule out other problems, such as stroke or brain tumors. But it can be difficult to distinguish between Alzheimer’s and other forms of dementia, especially at the early stages of the disease.
“We badly need diagnostic tests for people with mild cognitive impairment and other people at risk for Alzheimer’s disease, because there may be in the future disease-modifying therapies that could slow onset or progression of the disease,” says Sid Gilman, director of the Michigan Alzheimer’s Disease Research Center, at the University of Michigan. A method to accurately diagnose patients in the early stage of the disease could also aid in development of these therapies by allowing physicians to test experimental drugs in only those who need it.
The new test, developed by Daniel Alkon, scientific director of BRNI, targets a group of enzymes called PKCs, which are involved in long-term memory storage. Alkon and others have found that a select set of these enzymes becomes dysfunctional in Alzheimer’s disease, both in brain cells and in skin cells. (While Alzheimer’s is primarily considered a neurological disease, research over the past decade has revealed signs of the disease outside of the brain.) In addition, activating the enzymes in animal models of the disease alleviates symptoms, preventing memory loss as well as the abnormal aggregations of protein that build up in the brain.
To perform the test, physicians collect a small sample of skin cells, which are then grown in a dish. Researchers add a specific inflammatory molecule called bradykinin, which activates PKCs under normal circumstances; a dysfunctional response suggests Alzheimer’s. Preliminary results from a study of 600 patients are promising: the test correctly diagnosed 36 out of 37 patients confirmed on autopsy to have the disease, as well as 5 patients confirmed on autopsy not to have it.
Alkon’s test is just one in a number of new approaches to early detection, including measuring molecules linked to the disease in blood and cerebrospinal fluid, as well as new brain-imaging markers that can detect signs of Alzheimer’s, such as buildup of the protein beta-amyloid–a hallmark of the disease. “A number of these tests have been successful in separating Alzheimer’s patients from normal subjects, but most of them have not as yet compared those with AD to those with other neurological diseases, such as ALS,” says Gilman.
The new research is “interesting and promising, but we need to know how specific it will turn out to be,” he says. “There is a history of tests that are in the news and then disappear quietly.”
Alkon says that the skin test can distinguish between other types of neurological diseases, such as Parkinson’s, Huntington’s, and Lewy body disease–a finding that he aims to confirm in larger clinical trials. He also hopes to confirm the test’s ability to diagnose Alzheimer’s early on–within four years of when a patient first notices memory problems. Clinical diagnosis within this period can be hit or miss, with accuracy rates as low as 55 percent.
Alkon is also planning a small clinical trial of an experimental drug called bryostatin, originally tested as an anticancer drug, for Alzheimer’s. At low concentrations, the drug activates PKCs. Developing drugs that target PKCs has been somewhat difficult because some can trigger the formation of tumors. But Alkon says that he has identified structural variations in these molecules that predict which ones potentially cause tumors. His team has developed a number of novel PKC-activating compounds, which he eventually hopes to test in clinical trials.