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.

Did Pfizer "Hide" a Potential Treatment for Alzheimer's Disease?

Contributed by: Dennis Fortier, President, Medical Care Corporation _______________________________________________
Despite the provocative title, this post is largely a summary of a non-story. However, it is worth discussing because this "non-story" has been widely covered in the general media, often in a manner that leans strongly toward the sensational end of the news spectrum.

The facts are fairly non-controversial. Pfizer, a major pharmaceutical drug developer and marketer, performed an analysis of medical insurance data comprised of approximately 254,000 patients with rheumatoid arthritis or another inflammatory disease. The analysis revealed that, among those patients whose inflammatory disease was being treated with Enbrel, a drug marketed by Pfizer in the US, a slightly smaller percentage also had an Alzheimer's diagnosis compared to those who were not treated with Enbrel. Despite the seeming potential for Enbrel to prevent Alzheiemr's disease, Pfizer conducted further internal review and opted not to initiate a clinical trial for the purpose of measuring the efficacy of Enbrel in preventing Alzheimer's disease.

As far as I can tell, no one is disputing those facts. However, how those facts are interpreted has become a matter of creative reporting. One angle that has created a fair amount of reporting (initially in the Washington Post) suggests that, because Enbrel is nearly off patent, after which the drug will be far less profitable, Pfizer made a greedy decision and opted not to pursue a potentially promising Alzheimer's treatment. Most drug development experts disagree with that suggestion.

The noted statistical evidence of a preventative effect of Enbrel against Alzheimer's disease was far smaller than what the drug development industry would generally require before initiating a trial. Furthermore, the effects of anti-inflammatory drugs in the Alzheimer's space have been thoroughly investigated in other studies to no avail. Given that Enbrel does not cross the blood-brain barrier, it is fairly unlikely that a long and expensive trial (see previous summary here of FDA drug approval process) would yield a favorable outcome. In fact, another major marketer of pharmaceutical drugs (Amgen), who holds the rights to Enbrel outside of the US,  reviewed the same data and also concluded that further investigation was not warranted.

Overall, small statistical patterns are commonly present in large data sets like the one discussed here. However, such patterns are not necessarily indicative of an underlying treatment with a clinically meaningful effect. In the opinion of most knowledgeable scientists (as summarized here by Derek Lowe), Pfizer made a prudent decision not to further evaluate Enbrel as a potential treatment for Alzheimer's disease.

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. ____________________________________________________________