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!

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.