Guidelines for the Perplexed

Nortin Hadler

There has been much progress in the understanding of the biology of Alzheimer’s disease. Chemicals detected in the blood and spinal fluid of patients with Alzheimer’s and findings with new brain imaging techniques are the long sought after “biomarkers” of the disease. They are clues to its cause that are already targets for drug development. But there is a great public health danger in jumping the gun and prematurely using biomarkers in clinical practice for diagnosis or prognosis. It is for this reason that I have serious reservations about the new diagnostic guidelines proposed for the diagnosis of Alzheimer’s disease.

The current guidelines, which have served as well as possible for 26 years are based entirely on the patient’s narrative. The diagnostic label is applied when there is no better explanation for a severe and global compromise in cognition that developed insidiously. The diagnosis of Alzheimer’s when it is full blown is not a challenge. The challenge is in making the diagnosis when it is less obvious, when it is but “Possible” or “Probable.” These categories are confronted in the old criteria by considering the degree to which elements of cognition are compromised. The application of these qualified diagnostic labels provokes as much anxiety in the clinician as it does angst in the patient and foreboding in the patient’s intimate community. Maybe the fact that grandpa occasionally forgets his keys or his neighbor’s name is all there is to it; “grandpa’s losing it” or has a touch of “senility”. That would call for a supportive community, and not the specter of a slide to a dreadful fate denoted by Alzheimer’s.

The National Institute of Aging and the Alzheimer’s Association sponsored 3 panels of prominent clinical and basic scientists with relevant expertise to improve the Guidelines in light of scientific advancements. They propose dividing Alzheimer’s into three stages: preclinical (no symptoms, but positive biomarkers), mild impairment, and classic dementia. While such a categorization makes great sense and may offer an advance in the design of drug trials, it 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. The following is an object lesson:

A study was published by the Alzheimer’s Disease Cooperative Study Group in 2005. Nearly 800          septuagenarians volunteered. All had complained of insidiously progressive cognitive impairment but     none qualified even for “Possible” Alzheimer’s by the old criteria. Three years later 28% qualified for “Possible” or “Probable” but none had definite Alzheimer’s. APOE ε4 is one of the “biomarkers”; it is a genetic marker for predisposition to Alzheimer’s. It was present in about half of the volunteers. It was present in 163 (77%) of the 212 who progressed and in 260 (47%) of those who did not progress. This difference is likely real, but hardly enough to inform medical decision making. The APOE ε4 biomarker is present in too many that don’t progress and absent in too many who did progress to justify using it for diagnosis or prognosis. The APOE ε4 biomarker offers no basis for either labeling or reassuring a person without symptoms or a patient with mild symptoms.

That begs the question of what would we do differently if we could identify early Alzheimer’s patients. No drug has been shown to improve the prognosis. The study discussed above was actually a drug trial comparing the likelihood of progression if these volunteers were treated with vitamin E, donepezil (Aricept), or a placebo. There was no difference.

No one should have a screening or a diagnostic test unless the test is accurate, the result is clinically meaningful, and something important can be done as a consequence to improve the patient’s outcome. “Biomarkers” for Alzheimer’s fail, many by all 3 standards. “Biomarkers” may be ready for prime time to learn about etiology and even learn about prognosis, but not for labeling patients in the clinic.

Nortin Hadler, MD, is a professor of Medicine and Microbiology at
the University of North Carolina – Chapel Hill. Dr. Hadler is the author of
numerous articles and essays and a series of a popular books on the state of
medicine today. His most recent book is “
Stabbed in the Back: Confronting Back Pain in an Overtreated Society.”

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5 replies »

  1. Wow-fantastic article. I was unaware of the progress in research. This has been a subject of interest for many of our staff members because most have parents or grand parents who show signs of Alz. or something milder. Either way everyone seems to take that big gulp of air and hold their breath that we don’t have to face the worst case scenario. This article stirs a much needed hope on the topic. Well written and easily understood!
    Thanks for putting the time into such a sensitive subject for children and grand children alike.

  2. As someone who lost a parent to Alzheimer’s last month, I can very much appreciate this recap. Thank you.
    Our mom began developing forgetfulness at her job when she was 54 y/o. Coincidentally, this was within 1 year of contracting some illness or infection that caused her great general weakness which lasted 4-5 months. The physicians could not provide her with a diagnosis or etiology for this debilitating malaise. I was living pretty far away and didn’t keep up with all the details, but she eventually regained her strength and returned to work.
    Then, months later, she began forgetting things. There is no history of “Alz” in her family, who all lived to be in their 80-90’s and were as sharp as tacks. I’m almost sure this malaise was just a coincidental occurrence and there was probably no causal effect from one to the other.
    But I often wondered if there has been found any correlation between Alzheimer’s and some outside etiology, like a virus or chemical agent, etc. Does anyone know if that has been studied?
    Also, because Alzheimer’s is so progressive over such a long period of time, do physicians ask those with the beginning of mild impairment if they’ve had recent infections, or other recent medical history events that might be of interest? Do families even bring their loved ones to the doctor when they are showing the earliest signs?
    We never did. In fact, it wasn’t until 2 years into her mild impairment that we recognized this as being something of significance and permanence.
    So does Alzheimer’s only have a genetic component? If “yes” is the answer than are we 100% sure?
    Dr. Hadler – again, thank you for the insightful article. You make many good points.

  3. Thanks Nortin,
    As usual- right on target
    I widely circulated with attribution to you of course and The HealthCare Blog
    Dr. Rick Lippin
    (Proud To Be A “Charter Hadlerian”)

  4. Appreciated this recap that was much more coherent and lucid than some of the articles I have seen in the general media.

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