What is Alzheimer's Disease? Depends who you ask...

Contributed by: Dennis Fortier, President, Embic Corporation

The New York Times has a long-running and widely read column called "The New Old Age" that covers topics that are pertinent to our aging population. In today's article about the definition of Alzheimer's disease, I think they have manufactured an unnecessary controversy.

In this article (Apparently Healthy, but Diagnosed with Alzheimer's?), the author takes issue with proposed diagnostic guidelines for researchers studying the earliest stages of the disease when pathology begins to accumulate prior to any observable symptoms. She builds a case against the proposed guidelines and paints a picture of widespread, premature diagnoses in the nation's primary care clinics. She further intimates that the new guidelines are a plot to drive economic benefits to companies that sell therapeutics. Admittedly, such a plot is not far-fetched, but that is not what is going on here.

Within the Alzheimer's scientific ecosystem, it is well understood that a research diagnosis and a clinical diagnosis serve different purposes. In fact, the draft "guidelines document" that is the subject of the NYTimes article clearly states that it is a "research framework" and includes the following, further clarification in it's opening:

"These new criteria do not constitute clinical practice guideline recommendations."

Today's NYT article fails to distinguish the difference between researchers who are studying the earliest stages of Alzheimer's disease, and clinicians who are diagnosing and treating Alzheimer's disease in a symptomatic patient population. These two groups use justifiably different definitions of Alzheimer's disease.

The Pathological Cascade of Alzheimer's Disease

By the time you show symptoms of Alzheimer's disease, many irreversible changes have already occurred in your brain. This explains why early detection and timely intervention are so important. As described by the pathological cascade summarized in this post, treatment should ideally begin long before symptoms appear.  

The key features of the Alzheimer's disease pathological cascade include the accumulation of two types of abnormal proteins in the brain: amyloid beta (Aβ) plaques and tau tangles. The Aβ plaques are formed by the accumulation of a protein called amyloid beta, which is produced by the breakdown of a larger protein called amyloid precursor protein (APP). The tau tangles are formed by the abnormal accumulation of a protein called tau, which is essential for the normal functioning of the brain's nerve cells.

The accumulation of Aβ plaques in the brain disrupts the normal communication between brain cells and leads to inflammation and the activation of immune cells. As the disease progresses, tau proteins also start to accumulate in the brain, forming tangles that further contribute to the degeneration of brain cells. 

A simplified view of the process, which may take years, looks like this:
Protein Accumulation >> Inflammation >> Cell Death >> Symptoms

In an ideal scenario, patients would begin a regimen of disease modifying therapy (currently approved treatments can remove amyloid protein from the brain) as soon as amyloid plaques and tau tangles are present, and before inflammation, cell death, and cognitive symptoms emerge. 

Achieving such timely intervention on any meaningful scale will require a proactive mindset toward managing cognitive health along with inexpensive and non-invasive methods for detecting the early stages of the disease. Fortunately, such methods are now becoming available. One promising approach, from Embic Corporation, involves a brief cognitive test with sophisticated scoring that quantifies the unobservable cognitive processes of encoding and retrieval. These processes underly nearly all cognitive function and show clear changes in Alzheimer's patients long before symptoms of memory loss appear.

The good news is that the science of managing Alzheimer's disease, from detection to diagnosis to treatment, is moving forward quite rapidly. The bad news is that progress is happening faster than the healthcare system can embrace. Researchers need to keep racing forward and the care system needs to catch up!

Should We Screen Older Adults for Cognitive Impairment?

The US Preventative Services Task Force (USPSTF) recently addressed this question and determined that there is “insufficient evidence to assess the balance of benefits and harms” associated with such screening. In effect, they could not conclude if it was helpful, harmful, or neither.

However, the question, and the conclusion of the USPSTF, both lend themselves to widespread misinterpretation. This brief summary takes a precise look at the issue and offers some clarity.

First of all, the task force defines “screening” in a very specific way. In this case, it means assessing the cognition of  individuals with no clear signs or symptoms of a cognitive deficit. There is essentially no debate that doctors should evaluate the cognitive health of patients who do show signs of impairment; the USPSTF would agree. But “evaluating symptoms” is not the same as “screening” and is therefore, not a part of this discussion.

Assessing subjects with no symptoms is “screening” while assessing subjects who do have symptoms is “case finding”. This USTFPS opinion relates strictly to screening.

Second, the term cognitive impairment covers a wide range of disability from very mild (a subtle sense that thinking skills are becoming slower or less vital) to severe (full dementia including a loss of ability to care for oneself). The broad range of severity in this definition is problematic because, as just discussed, the term “screening” only applies to those “older adults” at the extreme mild end of this spectrum. As such, the posed question contains an inherent flaw. Either “screening” is the wrong word because it does not apply to many along the spectrum of cognitive impairment, or the term “cognitive impairment” must be precisely qualified to include only asymptomatic subjects. Otherwise, a sensible answer cannot be derived.

Finally, this discussion is further complicated by the fact that the publications, upon which the USPSTF based their conclusion, evaluated only cognitive assessment instruments designed to detect “dementia”, not the asymptomatic subjects contemplated by the notion of screening. Therefore, an evaluation of the benefits and harms of screening older adults for the full range of cognitive impairment, based on instruments that reliably detect only the most severely impaired, is neither comprehensive nor conclusive.

The bottom line, as emphasized in the accompanying editorials to the USPSTF recommendations published in JAMA, is that wide scale screening of asymptomatic populations over age 65 is not yet warranted by published evidence, but it certainly has strong theoretical appeal. 

The USPSTF’s conclusion of “insufficient evidence” should not be interpreted as a recommendation against screening, rather, it is a factual statement about the paucity of studies that have been published in this area. But it should be noted that Medicare mandates the “identification of cognitive impairment” during Welcome to Medicare exams. So when asking if we should screen older adults for cognitive impairment, at least one well-informed branch of government believes that the benefits outweigh the costs.