SAN FRANCISCO—During the past decade a number of new treatment options have become available for patients with Alzheimer’s disease, and recent studies suggest that early treatment may slow or even prevent the progression of this disorder. But do these advances warrant widespread screening for Alzheimer’s disease? At the 14th Annual Meeting of the American Association for Geriatric Psychiatry, three experts in the screening and treatment of Alzheimer’s disease examined some of the complex ethical issues that surround the development of a large-scale screening effort.

Although researchers are excited about the potential for new medications to prevent Alzheimer’s disease or slow its course, “we don’t as yet have social consensus about how you would actually get a regulatory claim that such an agent went beyond symptomatic therapies to actually modify disease,” said Peter J. Whitehouse, MD, PhD, Professor of Biomedical Ethics at Case Western Reserve University School of Medicine, Cleveland. In addition, Dr. Whitehouse noted, “we are certainly hindered in this enterprise in that we don’t have any biological markers that clearly differentiate early Alzheimer’s disease from other conditions that may cause mild cognitive impairment [MCI]”.

WHO GAINS FROM A SCREENING PROGRAM?

Dr. Whitehouse reminded the audience that the development of an Alzheimer’s disease screening program poses a significant risk for conflict of interest. For example, the manufacturer of an Alzheimer’s disease drug recently asked the Alzheimer’s Association and the American Geriatrics Society to endorse a nationwide education and screening program. Although these associations decided not to endorse the program, Dr. Whitehouse highlighted the ethical issues raised during the deliberation process. A screening program for Alzheimer’s disease is based on the desire to improve the quality of life of patients and their caregivers. However, Dr. Whitehouse said, it is “exceedingly important that the financial as well as academic ambitions associated with some of these projects be disclosed so that people can be aware that there are some biases that may enter into one’s enthusiasm for either a screening program or for a prevention trial.”

WILL EARLY RECOGNITION BENEFIT PATIENTS?

There is a tendency to assume that early recognition of any disease is valuable, Dr. Whitehouse said. For example, many would agree that early screening of men for prostate cancer is worthwhile. However, Dr. Whitehouse cautioned that “we shouldn’t necessarily jump into thinking that screening and early recognition naturally does lead automatically to benefits in patients.”

What arguments do we have that screening for Alzheimer’s disease is beneficial? Therapies such as anti-inflammatory agents or cholinesterase inhibitors could be effective if given in the early stages of the disease process, Dr. Whitehouse said, although he noted that few studies have examined the ability of these approaches to slow the rate of disease progression.

A CRITICAL LOOK AT ONGOING PREVENTION TRIALS

Sometimes considered a “gray zone” between normal brain aging and Alzheimer’s disease, MCI is generating a great deal of interest among Alzheimer’s disease researchers, said Steven H. Ferris, PhD, Professor of Psychiatry at New York University School of Medicine. Observational studies have found that MCI often evolves to dementia in a short period of time, Dr. Ferris explained, but he was quick to point out that not all patients with MCI progress to dementia. As many as 5% to 10% of these patients remain stable or even become classified as normal on subsequent evaluations. These might be individuals who have depression that remits or those who have a systemic illness that compromises brain function. Dr. Ferris added that MCI likely represents a prodromal stage of all degenerative dementias.

Nevertheless, a number of therapeutic agents are currently being tested for their ability to slow the conversion from MCI to Alzheimer’s disease. Patients with MCI are a particularly attractive population for disease progression studies because there is less need for large samples and long observation periods, explained Mary Sano, PhD, Associate Professor of Clinical Neurology at Columbia University. Primary prevention trials are costly and require large numbers of patients, she said. Furthermore, clinical trials of treatments for Alzheimer’s disease present the additional challenge of recruiting elderly patients. Some therapies currently being investigated are estrogen replacement therapy, vitamin E, ginkgo biloba, and, in MCI trials, rivastigmine, galantamine, and piracetam.

Dr. Sano noted that primary prevention trials are often susceptible to poor study design. Measuring the conversion rate to dementia over time, for instance, does not “allow us to make any statements about improvement.” Reducing symptoms without altering disease progression can seem to delay disease onset. Dr. Sano encouraged measuring outcomes such as quality of life as well as the overall cost of disease management.

IN SEARCH OF A MEANINGFUL SCREEN

“It’s remarkable how many screening programs have been implemented in medicine without randomized controlled studies of the screening programs themselves,” Dr. Whitehouse observed. “Part of evidence-based practice around screening should be to measure the outcome on the people who are participating in the screening program and to see if they find benefit in their lives.”

The specificity and sensitivity of any screening instrument need to be determined before applying it in a community setting, Dr. Whitehouse said. Many studies are based on a carefully selected clinical population. A much higher false-positive or false-negative rate may occur in a community setting due to effects of comorbid conditions, different education levels, and different cultures.

There is also debate over what the appropriate follow-up procedure should be, Dr. Whitehouse continued. Should patients who are likely to develop Alzheimer’s disease be instructed to contact their physicians? What should be done about patients who are at risk but have not seen a physician?

A STUDY ON ATTITUDES

Dr. Whitehouse and his colleagues recently began a randomized controlled trial to study attitudes about genetic counseling in patients who have an affected first-degree relative. Although “we were not quite in a state of clinical equipoise” with regards to apolipoprotein E genetic testing, a number of national panels have suggested that further research to understand people’s attitudes about these kinds of tests is appropriate.

All study participants will receive genetic counseling, although some participants will not be told their test results. The investigators will assess whether the participants are stressed by the information or whether they use the information wisely regarding life decisions.

Patient attitudes are just as important as effective treatment and screening instruments when determining the value of a widespread screening program, Dr. Whitehouse remarked. More work remains to be done to optimize a screening program for the real world. Even so, he added, individual health care providers should be trained to identify the early signs of age-related cognitive changes in their patients and evaluate them appropriately.

NR