Diagnosis Without Treatment: The Perils of New Tests for Early Alzheimer’s Disease

 In April, an independent panel established by the National Institutes of Health came to the disheartening conclusion that currently, there is nothing to prevent or delay the progress of Alzheimer’s disease in those of us who are destined to join the 5 million Americans currently suffering from this dreaded ailment.

The panel  found that: “Although numerous interventions have been suggested to delay Alzheimer’s disease, the evidence is inadequate to conclude that any are effective.” Members rejected scientific evidence supporting the influence of nutritional supplements, herbal products, dietary factors, pharmaceuticals, medical conditions or even environmental exposures on the risk of contracting Alzheimer’s.

Now, just three months later, it turns out that there are big developments in the Alzheimer’s field—just not in new treatments. At a conference in Honolulu sponsored earlier this month by the National Institute on Aging and the Alzheimer’s Disease Association, researchers from three working groups announced that by using new imaging technologies, genetic testing, and tests of blood and cerebrospinal fluid, it will soon be far easier to diagnose Alzheimer’s— in some cases decades before symptoms have even appeared. These new tests are able to identify so-called biomarkers—amyloid plaques in the brain, genetic variants, proteins and other substances in body fluids—that signal a newly defined "pre-clinical" stage of Alzheimer's, when an individual has no symptoms but has positive biomarkers for the disease.  

 The chair of the working group charged with creating this pre-clinical definition was Reisa Sperling, assistant professor of neurology at Harvard Medical School. In a MedScape article about the conference, Sperling said that the group struggled with the terminology for pre-clinical Alzheimer’s disease (AD) and admitted that they knew it would provoke controversy. If these new tests for biomarkers—including a PET scan that can for the first time reveal amyloid plaques in a living brain—are used in the general public, it could double or triple the number of people diagnosed with Alzheimer's—at potentially great public and psychic expense.

But Sperling reminds critics that there are other medical conditions that are diagnosed before symptoms are apparent; including carcinoma in situ, asymptomatic coronary artery disease and kidney disease. What’s important is that “not all individuals who have these risk factors or early stages of these other diseases ever go on to manifest symptoms." Still, the MedScape article adds, “treating high cholesterol has prevented many overt cardiac and stroke events.”

Currently, doctors diagnose Alzheimer’s disease based on criteria developed 26 years ago; mainly by using neurological tests that track the progressive memory and cognitive deficits that characterize the disease trajectory. A little over a decade ago, researchers began to recognize “mild cognitive impairment;” as a condition that is strongly linked with later development of full-blown Alzheimer’s. They’ve also increasingly been using imaging techniques like MRIs and PET scans that reveal structural or functional changes in the brain associated with the disease. There is a gene variant, APOE4, which is also associated with AD: It occurs in about 40 percent of all people who develop late-onset AD and is present in about 25 to 30 percent of the general population. But AD dementia can only be definitively determined once a patient has died and an autopsy reveals the telltale amyloid plaques that are the hallmark of this disease.

It’s been an inexact diagnostic practice. According to Gina Kolata, writing in The New York Times  last month, “Even at the best medical centers, doctors often are wrong. Twenty percent of people with dementia — a loss of memory and intellectual functions — who received a diagnosis of Alzheimer’s, did not have it. There was no plaque when their brains were biopsied. Half with milder memory loss, thought to be on their way to Alzheimer’s, do not get the disease.”

The goal of the new imaging techniques and other biomarker tests is to make diagnosis far less ambiguous. They would also help better identify risk factors (gene variants, environmental factors, etc.) that can be strong predictors of who gets AD. Finally, the tests would also greatly help in clinical research by identifying a larger pool of subjects who have an earlier stage of the disease to test whether promising drugs might prevent progression of AD. The initial emphasis, according to Creighton Phelps, director of the Alzheimer's Disease Center's program at the National Institute on Aging, will be on using these new tests in clinical research and validating the predictive value of the biomarkers.

But what happens when (as it inevitably will) diagnosis of pre-clinical Alzheimer’s becomes more widely available? Dr. Ronald Pies, a professor of psychiatry at both SUNY Upstate Medical University and at Tufts University School of Medicine, writes in Psychiatric Times, “the term ‘preclinical Alzheimer’s Disease’ may be adopted—but can ‘disease’ as we ordinarily understand the term really be ‘pre-clinical’? And what will be the psychological effect of telling an asymptomatic patient, ‘You have preclinical Alzheimer’s Disease’?

“Given that, at present, we have no treatments that can halt or reverse the progression of AD neuropathology, will we not create unnecessary anxiety in thousands of otherwise ‘normal’ individuals, by carrying out widespread PET scanning for minor memory impairment? Furthermore, what if large-scale testing reveals that 20% or 40% of the general population over age 65 years have abnormal plaques on their PET scans? Will we be doing more harm than good by telling such individuals, as one expert suggested, ‘you are on the Alzheimer road’?”

Nortin Hadler, writing in The Healthcare Blog , is more direct in stating the downside of pre-clinical testing for AD: “there is a great public health danger in jumping the gun and prematurely using biomarkers in clinical practice for diagnosis or prognosis.”

“[I]t offers no advantage to our patients today. Rather it is far more likely to engulf the patient in spurious inferences at great personal expense. Biomarkers have been tested only in small and highly selected groups of patients where they have impressive rates of false positive results. That portends a great deal of over-diagnosis in less selected patients. Furthermore, all biomarker tests are expensive, some very expensive, and some have medical risks. None is near ready to be used in routine clinical practice.”

Handler and Pies, along with others who are urging caution are right. Beyond financial planning and a jump on “putting affairs in order,” there is little benefit to knowing you are going to get a degenerative and untreatable disease before you even have symptoms. Drug companies claim that they have plenty of promising AD drugs in their pipelines. But they have had scant success so far in developing effective Alzheimer’s drugs—with some 30 failures occurring as far downstream as Phase 3 trials, according to a 2009 article in the journal Current Alzheimer’s Research. “[A] formidable barrier to drug development is that we know very little about Alzheimer's disease, its pathogenesis, diagnosis, genetics and struggle with its clinical heterogeneity; we do not have full pre-clinical models on which to develop advanced therapeutic targets,” according to the authors.

Here is where the new imaging techniques and other tests for biomarkers hold promise—in aiding in a deeper understanding of what actually causes Alzheimer’s disease and as a method for identifying advanced therapeutic targets. But these tests must be used carefully only in research settings—well-designed, fully-considered and, ultimately, humane clinical trials. The technology is clearly not ready for public consumption.

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[Bob DeMarco]

The Alzheimer's Reading Room has clear, concise, usable news, research, insight and advice for the entire Alzheimer's community.

100 Million Americans have been touched by Alzheimer's Disease, 35 million are worried about Alzheimer's Disease.

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