March 11, 1997
Research on Alzheimer's disease is entering a new, highly productive phase and the pace of promising developments is accelerating, according to scientists at the National Institute on Aging (NIA). In an editorial examining important new findings and analyses by NIA-supported researchers and others, part of a March 12 special issue of the Journal of the American Medical Association (JAMA) dedicated to Alzheimer's disease, the scientists say that Alzheimer's disease research is coming together in such a way that "we can look forward to ever more effective weapons to combat this dreaded disease."
The wide-ranging editorial by Marcelle Morrison-Bogorad, Ph.D., Associate Director for the Neuroscience and Neuropsychology of Aging Program at the NIA, and Institute colleagues, Creighton Phelps, Ph.D., and Neil Buckholtz, Ph.D., discusses causes and risk factors, diagnosis and prognosis, the struggle of patients and families, and ethical issues in genetic testing. Morrison-Bogorad also reviewed the state of Alzheimer's disease research in remarks at a March 11 media briefing where she moderated a panel of scientists presenting selected findings from among eight papers in the JAMA special issue.
The special issue includes significant reports from researchers supported by the NIA and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health (NIH), and others. The studies further investigate the role of various forms of the apolipoprotein (apoE) gene, examine a large, extended family with a uniform genetic basis for the disease whose study might help expand understanding of genetic and environmental factors involved in determining the age of onset, and provide an overview of genetics research; assess the impact of vascular disease and stroke on the symptoms of Alzheimer's disease; demonstrate the reluctance or inability of families, especially spouses, to recognize early signs of dementia; and offer a formula for clinicians to predict the likelihood of an individual Alzheimer's patient entering a nursing home within a particular span of time.
Summaries of the research follow:
Role of ApoE-E4 and Investigation of a Number of Influential Genetic and Environmental Factors
The apoE-E4 allele, while an important genetic risk factor, may account for a fairly small fraction of the disease in the general population. Denis A. Evans, M.D., Rush Alzheimer's Disease Center and Rush Institute on Aging, Rush-Presbyterian-St. Luke's Medical Center in Chicago, and colleagues from other institutions, found an approximately two-fold increased risk of developing Alzheimer's disease associated with apoE-E4 in an East-Boston, Massachusetts, population. In this population, an estimated 13.7 percent of all Alzheimer's disease was attributable to this allele. This finding suggests that studies to identify other environmental and genetic risk factors should continue.
Variation in Early-Onset Alzheimer's Disease
Another study by F. Lopera, M.D., of Antioquia University, Medellin, Colombia, and researchers at various U.S. institutions, whose work on this project has been supported by the NIA, characterized the pathological and symptomatic variations in a large, early-onset family in Antioquia, Colombia. All affected members of the family share the same mutation in the presenilin 1 gene and show similar disease symptoms and progression. Age of onset, however, varied widely, ranging from 34 to 62 years. This, too, suggests that other genetic and environmental factors may be at work. The researchers and NIA scientists believe that further study of this particular family will yield important information about influences on the age of onset.
Genetics of Alzheimer's Disease and Genetic Testing
The notion that Alzheimer's disease can be caused by a number of different genetic factors is echoed in a review article on the genetics of Alzheimer's disease by Corinne Lendon, Ph.D., Frank Ashall, D. Phil., and Alison Goate, D.Phil., at Washington University. A great deal of progress has been made leading to the identification of three genes whose mutations can cause familial forms of early-onset disease, they note. But it is likely that additional genetic and environmental factors need to be identified, especially in late-onset disease. Much needs to be learned, for example, about how the disease develops, especially the role of beta-amyloid in neurofibrillary tangles, chronic inflammation, and neuronal cell loss.
Stephen Post, Ph.D., of Case Western Reserve University, reports on the findings of the National Study Group of leading genetics researchers, ethicists, and public policy experts, supported by the NHGRI. The panel was set up to review emerging information on genetic testing, taking into consideration the views of people in focus groups convened by the Alzheimer's Association. It concludes that apoE testing is not recommended for people without dementia. For those few people in whom early-onset disease occurs, an estimated 1-2 percent of all cases, genetic predictive testing may be possible, but must be applied with extensive counseling and with adequate safeguards for confidentiality. The panel also expressed concern about the public's incorrect impression that a predictive genetic test exists for the vast majority of people whose disease is late-onset. The potential for discrimination in life and health insurance, especially long-term care insurance, and other possible adverse consequences of testing also are pointed out.
Strokes and Dementia
In looking at the clinical course of the disease, two new findings suggest that the relationship between stroke and Alzheimer's disease may be extremely important. Arjen Slooter, M.D., and researchers at Erasmus University Medical School in Rotterdam, The Netherlands, Richard Mayeux, M.D., Columbia University, New York, and colleagues looked at apoE in dementia patients with stroke. They found apoE-E4 to be a genetic risk factor for dementia with stroke, with up to a seven-fold increase in risk. The researchers say this could mean that dementia associated with stroke and with Alzheimer's disease may share a genetic background, or it may be that people with Alzheimer's disease are just part of the population of demented patients with stroke. Either way, the scientists say, the association is strong and should be investigated further.
David Snowdon, Ph.D., and colleagues at the University of Kentucky examined the cognitive function and prevalence of dementia among a group of nuns and found that strokes may produce and exacerbate the symptoms of Alzheimer's disease. Upon their death, the nuns' brains were examined and characterized for Alzheimer's disease and other conditions. Among the nuns with abundant Alzheimer's disease lesions, those who had strokes in strategic regions of the brain had significantly poorer cognitive function and more dementia than those without strokes. While the impact of the strokes appears to depend on the location in the brain, the findings highlight the importance of cerebrovascular disease in influencing the severity of clinical symptoms in Alzheimer's disease. Perhaps, NIA scientists suggest in their editorial, "prevention or treatment of vascular disease could delay or diminish the development of symptoms in many Alzheimer's disease patients."
Diagnosis and Prognosis
There has been enormous progress in improving clinical diagnosis of dementia and Alzheimer's disease. But research from the Honolulu-Asia Aging Study by G. Webster Ross, M.D., of the Veterans Administration and colleagues from the NIA and other institutions shows that a majority of families may fail to recognize or address symptoms. In the study group of 191 Japanese-American men with dementia, for example, 52 percent of families said they did not see the symptoms at all in patients who were in the early stages of the disease. For patients whose families did recognize a memory problem, 53 percent did not receive a medical workup for memory impairment. As treatments become available, especially for the early stages of Alzheimer's disease, early detection and assessment of dementia will become more important, the researchers say. Cognitive screening and public education programs may need to be developed to help increase awareness.
Yaakov Stern, Ph.D., Columbia University, and colleagues reported on an algorithm that could provide guidance for patients, families, and clinicians on the length of time before an Alzheimer's disease patient may require nursing home care, or die. The complex formula, the first of its kind, uses cognitive test scores and other variables to predict time to nursing home and death, and was found to be on target. The researchers noted, too, that the formula, with further testing, might be used to help researchers whose clinical trial participants are Alzheimer's disease patients.
