3 Stages of Alzheimer's Disease

Contributed by: Dennis Fortier, President, Medical Care Corporation

Alzheimer's disease was clarified today.

With the announcement of new diagnostic guidelines, developed in tandem by the National Institute of Aging and the National Alzheimer's Association, we can now conceptualize the disease across a continuous spectrum with three contiguous stages of progression.  There is a pre-clinical stage, a mild cognitive impairment stage, and a dementia stage.

Pre-clinical Stage
The purpose of defining this very early stage, before the presence of any clinical symptoms, is purely to benefit research.  While there are no symptoms of disease in this stage, researchers have noted that certain biological changes, including protein levels in the brain, blood, and spinal fluid, seem to change in fairly predictable ways during the years before Alzheimer's patients manifest symptoms.  The changes are not sufficiently telling to diagnose the disease at this early stage, but identifying these individuals and enlisting them as research subjects is an important goal for the field.

Importantly, physicians will not use these criteria to diagnose such early stage Alzheimer's. The definition of this stage is purely to help researchers speak a common language about similarly characterized research subjects. 

Mild Cognitive Impairment Stage
In this stage, patients have clear underlying pathology consistent with Alzheimer's disease, and have also developed clinical symptoms of memory loss or other cognitive deficits.

The identification of this stage is the most important aspect of the new guidelines, as it will enable earlier intervention for patients who are, almost certainly, in the progressive throes of Alzheimer's, but still have relatively healthy brains.  It is hoped that existing treatments, and new treatments in the pipeline, will be optimally effective in these early stage patents.

Dementia Stage
This stage is quite consistent with our former view of the disease.  It requires the hallmark pathology of amyloid plaques in the brain, plus cognition so impaired as to meet the criteria for dementia (two or more realms of impaired cognition that interrupt daily activities of living). In the past, we did not call the problem "Alzheimer's disease" until the patient reached this end stage condition.

New Guidelines for Alzheimer's Disease are a Step in the Right Direction

Contributed by: Dennis Fortier, President, Medical Care Corporation

The announcement of new guidelines for diagnosing Alzheimer's disease is being widely covered in the press today.  The move is a solid step in the right direction, but is spawning some confusion about why the change is necessary, and how it might help.

Biggest Change: AD starts prior to Dementia
The most important change is that we will now recognize Alzheimer's disease in its early stages, prior to the patient suffering massive brain damage and becoming demented.  This is a more difficult diagnosis to make and, as such, requires a thoughtful approach.

I wrote more extensively about the benefits, and the ensuing confusion about new diagnostic guidelines for Alzheimer's disease, when the draft versions of these documents were first discussed in the summer of 2010.   I encourage you to click back and read those thoughts, but the short summary is below.

Perspective on Former Guidelines
According to the former guidelines, put in place nearly 30 years ago, Alzheimer's disease was defined in part by the presence of dementia.  As readers of this blog know, dementia requires impairment so severe that a person cannot independently care for themselves.  In this regard, the term "mild Alzheimer's" means "barely demented due to Alzheimer's pathology"'  This is a misnomer because, even in its "mild" stages, dementia is a severe condition.

To put that in perspective, imagine if we could note the high blood sugar and blurry vision caused by diabetes, but we couldn't diagnose and treat it until the patient's kidneys failed.  Any guideline, suggesting that symptoms must be severe before diagnosis, is in direct conflict with early intervention.

The former guidelines were problematic as illustrated by this example:  Suppose a 75 year old person, with a family history of Alzheimer's, noticed subtle signs of memory loss and visited a physician.  The physician then confirmed the declining memory and sought the cause of the problem.  After ruling out depression, sleep disorders, medications, thyroid malfunction, poorly controlled diabetes, vitamin deficiency, and stroke as possible causes, he noted on an MRI scan of the brain that the patient's hippocampus was shrinking.  This would be a strong indication of Alzheimer's disease.

However, since the patient in this example had only subtle memory loss, not severe cognitive impairment meeting the criteria for dementia, the physician could not diagnose Alzheimer's and initiate treatment.  According to the old guidelines, the physician would let the Alzheimer's pathology progress for months or years, until the patient suffered enough irreversible brain damage to become demented, and then they could diagnose Alzheimer's and initiate treatment.  That clearly makes no sense.

New Guidelines
Under the new guidelines, if a patient has memory loss or other cognitive deficits, and common causes of such deficits are ruled out, and pathology is consistent with Alzheimer's, then we should recognize the condition as early stage Alzheimer's disease and begin treating it.  This holds even if the patient's cognitive problem is subtle and does not meet the criteria for dementia.

Since earlier intervention bodes well for better treatment outcomes, this is a solid step in the right direction.

Alzheimer's Diagnostic Accuracy: Theory vs. Reality

Contributed by: Dennis Fortier, President, Medical Care Corporation
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The reports on diagnosing Alzheimer's disease are maddeningly conflicting.

Research in academic journals makes it clear that a primary care physician can achieve a high level of diagnostic accuracy by following published guidelines.  However, journalists report every day that Alzheimer's disease can only be definitively diagnosed with an autopsy.  So which is it?

It turns out that both statements are correct.

Definitive vs. Clinically Acceptable
It is technically true that an autopsy is required for a "definitive diagnosis".  However, in the world of practiced medicine, we rarely operate with definitive diagnoses for any disease or condition.  Instead, we rely on "clinically acceptable" diagnoses that are accurate about 85%-95% of the time.  The emphasis on "definitive", or 100% accuracy, is actually quite misleading since it establishes an unrealistic standard that is rarely met in the real world of medical practice.

As for the academic perspective, a clinically acceptable level of accuracy is indeed achievable by following published guidelines.  These guidelines involve a complete medical history including a review of medicines, neuro-psychological assessment, blood tests, and an MRI or CT image of the brain.  In some cases, a PET scan of the brain might also be required.

Diagnostic Guidelines
To paraphrase the guidelines: if a patient shows impaired short-term memory as well as impaired cued recall, is not taking any medications known to disturb memory, is not abusing alcohol or other drugs, is not depressed or suffering from anxiety, does not have any apparent or detectable infections, has no uncontrolled diabetes or hypertension, has a properly functioning thyroid and no particular vitamin deficiencies, has not suffered a recent head trauma, and has no evidence of strokes or tumors in the brain, then the physician can be quite confident that the patient has Alzheimer's disease.

Essentially, the hallmark forms of memory impairment need to be objectively confirmed by cognitive assessment, and other known causes of such impairment ruled out.  A family history of Alzheimer's disease, or a genetic test showing a particular predisposition, would add confidence to such a diagnosis.

Why the Different Perceptions?
The reason for the stark difference in the academic perception of diagnostic accuracy and the journalistic perception of diagnostic accuracy is "lag".  In this case, lag refers to the well documented time-gap between medical advance and implementation of medical advance.  In other words, medical research leaps forward much faster than physicians can learn about and implement new findings and guidelines.  Right now, there is a significant gap between best practices in the field of memory loss and the actual practices that physicians are using in their clinics.

Half of Alzheimer's Cases Misdiagnosed
Recent articles from CNN and WebMD have reported that about half of Alzheimer's cases may be misdiagnosed in clinics.  Oddly, this probably indicates progress from recent years when memory problems went largely undiagnosed and ignored, to current times when many memory problems are being improperly attributed to Alzheimer's disease.  Progressing from "doing nothing" to "doing the right thing half the time" is actually a favorable development.

With time, our over-worked physicians will gain a better command of emerging guidelines.  This will improve their collective ability to recognize problems and to accurately determine their cause before prescribing treatment.

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Top 3 AD Research Trends

Contributed by: Dennis Fortier, President, Medical Care Corporation
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One site I follow for news in this field is the Alzheimer's Research Forum. The postings there can be quite technical as they target medical researchers as an audience. Nonetheless, the content they cover is often the same content as that which gets translated into lay terms (accurately or otherwise) by journalists in the general press.

They recently summarized their opinion of the top research trends in the AD field and I found it to be an excellent summary with a rich set of links to ongoing research stories. From a public impact perspective, I have selected the three from their list that I think are most likely to make a real-world difference, or at least be worthy news stories, in the coming year.

1. Revised Diagnostic Criteria
We posted this news followed by our perspective on this change when it was first discussed last summer. I think the new criteria, which define AD based on pathological evidence as opposed to severity of symptoms, provide a great step forward and will enable earlier intervention in a clinical setting.

2. Biomarkers
The ongoing effort to better understand AD pathology brings bio-markers to the forefront of importance. This year will likely see the first FDA approval for an agent that binds to amyloid in the brain and enables visibility on a PET scan. This along with ongoing research on proteins in the blood and spinal fluid, brain volumes, cognitive measures, and a host of other bio-markers portends a year of advance for the field.

3. The Amyloid Hypothesis (or hypotheses)
As described by the editors at Alzheimer's Forum, last year saw advances in understanding of amyloid's "...production, aggregation, function, and toxicity". All of this new knowledge must be assimilated into the evolving hypotheses about the role of beta-amyloid in Alzheimer's disease.

While there is much work underway in this field and many facets to the complex problems caused by Alzheimer's disease, the three noted trends above will certainly be central themes in the news during the coming year. Follow along with our posts at this blog to stay abreast of all developments and to understand the likely effects of each.

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A better understanding and more awareness of Alzheimer's related issues can impact personal health decisions and generate significant impact across a population of aging individuals. Please use the share button below to spread this educational message as widely as possible.

Predicting Alzheimer's Disease is a Misnomer in the Press

Contributed by: Dennis Fortier, President, Medical Care Corporation
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I think there will come a day, decades from now, when a massive amount of genetic data can be combined with a massive amount of demographic data, lifestyle date, social data, and other pertinent medical data, to predict with useful accuracy, the likelihood of a particular person getting Alzheimer's disease.

The expert consensus is that we are not even remotely close to that day. Nonetheless, stories about "predicting Alzheimer's disease" abound in the general press.

The point of this post is not to discuss if, or when, we might gain such an ability to predict Alzheimer's disease. Nor is the point to debate whether or not such a prediction would be beneficial, moral, dangerous, or inconsequential. The point is to highlight how the popular press continuously confuses "predicting Alzheimer's" with "identifying Alzheimer's". This story, published online by U.S. News and World Report is a perfect example.

According to the new diagnostic guidelines from the NIH and the National Alzheimer's Association, which were penned to clarify this exact situation, Alzheimer's disease has a long period of progression that passes through a mild cognitive impairment stage prior to the later stages of dementia. Therefore, stories about new technologies for evaluating subjects with mild cognitive impairment and "predicting" if they will progress to Alzheimer's are nonsensical. Either these subjects have mild cognitive impairment because Alzheimer's is already present, or they have mild cognitive impairment due to something else.

For those with the disease, there is no need for a prediction. For those without the disease, their current state of cognitive health may or may not play a role in such a prediction. The press constantly mixes the notions of "identifying" and "predicting".

These stories perpetrate confusion and prevent a clear understanding about which scientific advances are likely to yield benefits in the real world and which are merely interesting.

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A better understanding and more awareness of Alzheimer's related issues can impact personal health decisions and generate significant impact across a population of aging individuals. Please use the share button below to spread this educational message as widely as possible.

Alzheimer's Drug Fails Phase III Trial

Contributed by: Dennis Fortier, President, Medical Care Corporation
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One of Eli Lilly's late-stage Alzheimer's drugs, the gamma-secretase inhibitor Semagacestat, has failed its Phase III FDA trial and the company has halted its development. This announcement today was somewhat expected by the research community as other gamma-secretase inhibitors, namely Flurizan (Myriad Genetics), had also been deemed ineffective in a large trial.

While this is disappointing news, the overall trend of scientific progress in the field of Alzheimer's is clearly positive. New guidelines have been proposed that will facilitate earlier intervention and better treatment results. New diagnostic tests are showing greater accuracy and bode well for more certainty in clinical practice. And perhaps most importantly, the pipeline of treatments under development is full of promising agents.

An updated summary of the current FDA pipeline for Alzheimer's treatments will be posted here later in the week.

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A better understanding and more awareness of Alzheimer's related issues can impact personal health decisions and generate significant impact across a population of aging individuals. Please use the share button below to spread this educational message as widely as possible.

Confusion about Alzheimer's Diagnostic Guidelines and Clinical Care

Contributed by: Dennis Fortier, President, Medical Care Corporation
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The press is currently overflowing with coverage of the proposed changes to the outdated guidelines for diagnosing Alzheimer's disease. Most of the articles I have read have taken a sensationalistic and misleading slant. It may be superficially interesting to emphasize that early identification of AD will benefit drug makers, but that should not overshadow the real clinical benefit of earlier intervention.

Facts in a Nutshell
Current guidelines dictate that a person who consults a physician and complains of memory loss does not have AD until they become demented. Physicians can look for other causes of memory loss, such as depression, stroke, or thyroid disorder, and treat any problems they find. However, if nothing is found, and AD is strongly suspected, the guidelines prevent an actual diagnosis and treatment until the patient's symptoms progress to the dementia stage. The new guidelines would allow physicians to identify the disease at an earlier, and perhaps more treatable, stage of progression.

This point, that our current practice of late diagnosis is partially driven by outdated diagnostic standards, is highlighted in a report today from the Medical Research Council in the UK. This report clearly shows that primary care physicians are waiting too long to diagnose dementing illnesses and therefore, not treating them optimally.

I understand the mistrust of big pharma; they've earned their reputation. But I also understand that the effort to contain the growing Alzheimer's problem will absolutely enrich those with a piece of the solution. Don't forget that it will also diminish returns for those who currently profit from caring for demented patients.

Alzheimer's disease starts with a long slow period of accumulating pathology that is still not well understood. The current practice of waiting for clear symptoms before diagnosing and treating the disease has proven disastrous because too much brain damage occurs prior to the emergence of definitive clinical signs.

Merely recognizing that the disease is underway prior to full-blown dementia is not a greedy plot underwritten by the pharmaceutical and imaging industries; it is a scientifically sound approach to improving care in this field. It will enable more timely intervention and a clearer understanding of treatment efficacy with currently approved approaches.

Yes, we need to understand the pathology better and yes, we need new treatments that stop or slow disease progression; but we will never get those if we don't look at the disease clearly. Adhering to the current guidelines that deny the presence of AD prior to the patient becoming demented is a barrier to progress.

New Treatment Guidelines for ALS

Contributed by: Dennis Fortier, President, Medical Care Corporation
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In the October 13 issue of Neurology, the American Academy of Neurology has published new treatment guidelines for amyotrophic lateral sclerosis (ALS), often called Lou Gehrig's disease.

The guidelines are designed to help physicians optimize the quality of life for their ALS patients. While many with ALS with succumb to the disease within 3 to 5 years, others live as long as ten years after diagnosis. For these patients in particular, much can be done to ensure overal health and comfort throughout the disease course.

A more complete summary and link to the full publication can be viewed here but the basic guidelines are as follows:

• prescribe Riluzole, the only FDA approved drug for ALS
• use an assisted-breathing device
• use a feeding (PEG) tube
• offer botulinum toxin B to treat drooling if oral medications do not help
• consider screening for behavioral/cognition problems because such problems might affect patients’ willingness to accept suggested treatments
• enroll early in a specialized multidisciplinary ALS clinic to optimize care

As with other neurological disorders such as Parkinson's and Alzheimer's disease, there is no cure for ALS. However, as we see across all of these diseases, we have increased our ability to manage symptoms, prolong survival, and maintain a high quality of life. One key to such success is ongoing dissemination of guidelines outlining the highest standards of care.