26 National Alzheimer's Disease Centers collaborate on study of the utility of genetic testing for Alzheimer's
Scientists at 26 Alzheimer's Disease Centers have collaborated on a study that concludes that a test for a form of an Alzheimer's-related gene, called ApoE, when administered after an initial clinical evaluation, reduces the number of false positive diagnoses of Alzheimer's disease by approximately 30 percent. The researchers, who were supported by the National Institute on Aging (NIA), also reported that testing only for the E4 form of the gene, although strongly associated with Alzheimer's disease, is not sufficient to be used as a diagnostic tool by itself. In fact, nearly 40 percent of Alzheimer's patients with a confirmed diagnosis did not have the E4 form of the APOE gene.
The researchers suggest that, following a thorough evaluation by a trained physician and using recommended criteria and other diagnostic tests such as MRIs, a test for the E4 form of ApoE might be a helpful supplemental tool for physicians trying to make clinical diagnoses of different types of dementias.
According to Dr. Creighton Phelps of the NIA, "we cannot underestimate the usefulness of increasing a physician's confidence in diagnosing a disease of this magnitude. When facing a family who must bear the weight of such devastating news, most doctors would appreciate as many tools as possible to help them in their certainty of diagnosis. ApoE testing may be such a tool."
The study appears in the February 19, 1998 issue of The New England Journal of Medicine and represents the largest cooperative investigation to date among 26 Federally-funded U.S. Alzheimer's Disease Centers (ADCs). Dr. Phelps, who supervises the ADCs Program for the NIA, points out that the ADCs have been established by the NIA over the past 15 years at academic institutions nationwide to enroll patients for research studies related to Alzheimer's disease in the hope of improving diagnosis, and to create and test new therapies for the disease. For this study, data from 26 centers were pooled, and without the establishment of the ADCs, it would have been much harder and taken much longer for this study to gather data on 2,188 people.
The presence of the E4 form of the ApoE gene, discovered 5 years ago as a risk factor for Alzheimer's, is found most often in people who exhibit signs of the disease after age 65. One of three forms of ApoE, E4 has been associated with the greatest risk for Alzheimer's. Initially, researchers thought that genotyping (distinguishing among different forms of a gene) for ApoE-4 alone might be sufficient to diagnose and predict the disease. But, ApoE-4 status alone is not predictive of the disease. Other factors must contribute to the risk of developing Alzheimer's. Thus other studies are searching for additional genes or environmental factors that may also play a part in determining whether or not a person develops Alzheimer's.
The study analyzed data from 2,188 patients who had been enrolled at the Centers for diagnosis of dementia, subsequently died, and had post-mortem examinations for the presence or absence of Alzheimer's pathology in the brain. Investigators, led by Richard Mayeux, M.D., at Columbia University College of Physicians and Surgeons, were ultimately able to examine records of 1,108 women and 1,080 men submitted by the ADCs. The average age of the study participants at diagnosis was 72 and the average age at death was 77. Ninety-seven percent of those studied were Caucasian, thus limiting the extent to which these findings can be generalized to other populations.
Each of the patients received the recommended battery of clinical and behavioral tests for Alzheimer's. The patients had been followed throughout the course of their disease and their brains were examined after their death.
Ninety-three percent (1643) of those individuals found to have Alzheimer's by examining their brains after their death, i.e., their brains showed clear evidence of Alzheimer's-related changes, had been diagnosed by a physician as having the disease during their lifetime. However, 45 percent (190 persons) of those found to have other forms of dementia at the time of brain autopsy had also been diagnosed by physicians as having Alzheimer's during their lifetimes. This high rate of false positive diagnoses (45 percent) shows the limitations of using recommended clinical criteria alone.
Dr. Mayeux and colleagues examined the effect of the ApoE genotype in reducing false positive diagnoses and in adding to the assurance of clinical diagnoses. By using the ApoE genotype only in those patients who first met clinical criteria for Alzheimer's, the false positive rate of diagnosis decreased from 45 to 16 percent.
Thus, the addition of ApoE genotyping to an arsenal of other tests that are used to determine Alzheimer's status may be useful. Dr. Mayeux cautions, however, that the study was "done in a selected group of people who received treatment in specialized centers for Alzheimer's disease, and that the results do not apply to individuals of other ethnic groups or in other healthcare situations. More broad-based study is needed before these results can be assumed to be universally applicable."
The NIA, one of 18 institutes at the National Institutes of Health, leads the Federal effort in studying Alzheimer's disease and supports basic, clinical, epidemiological and social research on aging and the special needs of older people.