New Alzheimer's Drug on Horizon? A Solid Maybe...

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Contributed by: Dennis Fortier, President, Medical Care Corporation
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A new Alzheimer's drug, being co-developed by Biogen and Easai, has completed a Phase II FDA trial with seemingly positive results. The drug (BAN2401) is a monoclonal antibody that binds to certain forms of amyloid protein, which is considered by many in the field to be a key culprit in the onset and progression of Alzheimer's disease. When the antibody is flushed out of the system, it takes the harmful amyloid protein with it. Over the past five years, several similar drugs have shown glimmers of promise before ultimately failing in Phase III FDA trials.

For perspective, Phase II studies are generally smaller (fewer people enrolled) with the purpose of determining safety for various doses of a drug along with any possible side-effects at each dose of the drug. Phase III studies are generally larger, often longer, and usually a final step prior to "market approval".

Biogen presented a snapshot of the data from the recently concluded Phase II trial at the Alzheimer's Association International Conference in Chicago this week. While the results showed a reduction in amyloid among subjects receiving the higher doses and a possible slowing of cognitive decline at some stages, the presentation lacked details and many questions remain unanswered.

The primary questions were related to the trial design which appeared to have lower-risk patients in the high dose group and higher risk patients in the untreated (placebo) group. If this was the case, then it would be easier to show that the treatment group fared better (perhaps on both amyloid deposition and cognition) than the placebo group.

Secondarily, some in the field questioned the validity of the instrument used to measure cognition. The instrument (the ADCOMS) is a composite measure that pulls certain items from various other, well-validated instruments and combines them in a new instrument specifically designed to detect subtle changes. Given the well-documented inadequacy of the instruments historically used to measure cognitive change in FDA clinical trials, concerns about the ADCOMS are possibly over-blown.

Overall, these results are both PROMISING and PREMATURE. While there is reason for a fair amount of optimism, one should not carry that optimism with an unrealistic amount of conviction.

SAGE: A short test for detecting Alzheimer's?


Contributed by: Dennis Fortier, President, Medical Care Corporation
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The Self-Administered Gerocognitive Examination (SAGE) has received a fair amount of attention this year. Most of the attention has been driven by PR efforts and a website hosted by The Ohio State University where the test was developed.

Unfortunately, much of the press coverage has been somewhat sloppy and perhaps misleading. While the scientists who developed SAGE described it as "a test to measure thinking abilities", the press has repeatedly characterized it as an Alzheimer's test. As readers of this blog know, dozens of medical conditions can impair memory and other thinking abilities, Alzheimer's disease is merely one of them.

Press mis-characterizations aside, the data supporting the validity of the SAGE is quite minimal.  The instrument, a 15-minute self-administered questionnaire, was developed based on responses from a small sample of 63 subjects, and then validated on a sample of 1,047 subjects.

The website and support materials for the SAGE suggest that the instrument can detect dementia with fairly high accuracy of 95%. This has been the root claim for much of the ensuing press coverage. Remember though, the definition of dementia includes "impairment severe enough to interfere with social and occupational function". In this regard, a test that can detect such severe impairment may have little value, especially if it cannot detect more subtle symptoms such as those we see in the earliest stages of Alzheimer's disease.

From a clinical point of view, it is much more important to detect subtle stages of decline called Mild Cognitive Impairment (MCI). MCI is caused by a great many medical conditions and is often confused with normal, age-related changes in cognition. In fact, incorrectly assuming that subtle changes are caused by normal aging, rather than by an emerging medical condition, is the primary foe in our efforts to intervene at early stages against the various conditions that impair memory. Distinguishing the two is key to proactive management of cognitive health. According to the instrument's website, the SAGE is 62% sensitive for detecting MCI, which will provide little help for physicians trying to distinguish MCI from normal aging.

Other well-validated instruments are more useful in detecting MCI.  The most accurate test in the published literature is the MCI Screen.  It is 97% accurate in distinguishing MCI from normal aging, but it is not self-administered. Rather, it is generally administered by medical staff or a researcher. The ideal would be an instrument with the self-administering ease of the SAGE and the accuracy of the MCI Screen.

Is the Risk for Alzheimer's Disease Declining?



Contributed by: Dennis Fortier, President, Medical Care Corporation
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Stop the press! Is this good news about Alzheimer's Disease? It depends on how you look at it.

A recent perspective article*, published in the New England Journal of Medicine, cites several studies supporting the notion that the risk of having Alzheimer's disease is declining. The article notes that the probability of a person of a given age, having any form of dementia today, is lower than it was a few decades ago. That sounds positive.

Despite the tempting headline of "Declining Risk", such a trend is most likely driven by overall improvements in population health. Today's seniors are unquestionably wealthier and better educated than those of the past, they smoke less, have fewer strokes, have better managed cholesterol, and have lower blood pressure. All of those factors affect risk of Alzheimer's disease and other causes of dementia.

Also, while risk at a given age may be declining, the number of people reaching old age (and even very old age) is sharply climbing. Prevalence at a given age may be lower, but incidence at older ages is clearly rising.

There is no reason to believe that the risk of Alzheimer's disease is magically declining. There is much hope, however, that awareness about risk factors and the importance of managing them, is helping us to forestall the ravages of dementing illnesses, and buying time for the nation's R&D efforts to find better treatments.

So keep exercising, eating right, using your brains, and managing your chronic conditions.  For now, that is your best strategy for keeping your brain healthy for the longest time.

n engl j med, 369;24, nejm.org, december 122013