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.

Perspective on "A Cure for Alzheimer's"

Contributed by: Dennis Fortier, President, Medical Care Corporation

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Sometimes the facts are very misleading.

For some reason, when Alzheimer's Disease is discussed in the popular press, the discussion often includes a reference to the fact that "there is no cure" for this disease. This is a true statement, but somewhat misleading.

This is misleading because it establishes "a cure" as the appropriate frame of reference for evaluating our ability to fight against this disease.

However, in medicine, we know this is not true. For example, we have no cure for hypertension, but we treat it effectively for most people. Clearly, the "no cure" frame of reference is not the most meaningful perspective on hypertension.

Also, we have no cure for diabetes, but like hypertension, we control it to a large extent for very many years.  We have no cure for the common cold, eczema  asthma, allergies, migraine, anxiety, heartburn, cancer, osteoporosis, depression, lupus  or a thousand other common, and sometimes deadly, medical ailments.  The truth is, cures are very rare in medicine.

To be clear, everyone would love to have a cure for Alzheimer's. It would greatly improve the world and eliminate much tragic suffering  But "no cure" is not the same as "no treatment", and we should not allow the "no cure" label to fill us with pessimism.

In fact, with an early Alzheimer's diagnosis (prior to the dementia stage), doctors can often delay disease progression through a robust regimen of proper diet, physical activity, tight control of chronic conditions, and poly-therapy with approved drugs.

At present, we should not despair that there is no cure. Rather, we should keep searching for a cure while embracing the reality that, like so many other medical conditions, Alzheimer's must be vigilantly diagnosed in its earliest stages and treated to the best of our current abilities.

The cure may or may not come, but initial treatments have arrived, and better treatments will follow.

Does Stress Impair Memory?

Contributed by: Dennis Fortier, President, Medical Care Corporation

The relationship between stress and memory is complex.

We all know that emotionally intense experiences tend to be effectively stored for retrieval over a lifetime.  This is an evolutionary mechanism that guides us away from dangerous situations we have previously encountered, and toward those where significant rewards were garnered.  Since stress is correlated with emotional intensity, it makes sense that there is a relationship betwen stress and memory.

In a more thorough look at the relationship, researchers from the University of Edinburgh recently published their findings in the Journal of Neuroscience.   According to their study, a moderate amount of stress can aid memory, but an intense or sustained amount of stress can be harmful.

They identified two distinct receptors in aging brains that react to cortisol, a hormone produced as a by-product of stress.  The first receptor reacted to low levels of cortisol and improved memory. The other, which reacted to higher levels of cortisol, had a negative impact on memory capacity. 

The most likely conclusion from this work is that a single stressful incindent is likely to be stored for later recall, but a lifestyle of sustained high stress, is likely to impair overall memory function.

Is Memory Loss a Sign of Future Stroke?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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The complexity of the brain is boundless.  Each day it seems, scientists uncover new findings that either raise new questions or broaden our perspective on how disease and cognition are inter-related.

According to a study from the University of Alabama, research subjects aged 45 and older, who scored poorly compared to their peers on a memory test, were about 3.5 times more likely to have a stroke in the next 5 years.

While the average age of the study participants was 67 years, the correlation between memory loss and a later stroke was especially strong at younger ages.  For example, at age 50, those who scored in the bottom 20% on the memory test were almost 10 times more likely to have a stroke in the next 5 years, compared to those who scored in the top 20%.

It is difficult to draw any concrete conclusions from this study about how, or why, poor memory performance might be a marker of pathology that increases risk for stroke.  However, each piece of evidence shapes the entire puzzle that must eventually be assembled. 

Knowing this relationship between memory performance and stroke risk will guide further thinking and move us toward a deeper understanding of brain health and function.

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The Biology of How Memories are Formed

Contributed by: Dennis Fortier, President, Medical Care Corporation
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It goes without saying, but it is worth repeating, that rats are not humans and our brains are very different. Nonetheless, a lot of what we learn about the human brain is first learned in rat brains.

With an interesting publication last week in the journal Nature, researchers at Mount Sinai School of Medicine may have embarked on key learning about how biology plays a role in preserving memories.  This work was done in rats but may have human implications.

The scientists found that a particular hormone known as IGF-II became more prevalent in a rats brains immediately after learning that entering a dark box resulted in a shock to the foot.  They also showed that by injecting the same hormone into rat brains, they could help the rats preserve a memory for a longer period of time.

This finding may prove to clarify our understanding of the biology involved in memory formation and preservation, which could lead to breakthroughs in the field of human memory enhancement.  Better insights into the hormones that play a role in the process could also lead one day to supplements that actually improve memory performance.

Again, this is early stage work performed in rats, not in humans.  Years of validation work will follow prior to any new "memory pills" that could be based on this insight.  It's interesting, but it is early.

You should follow Brain Today on twitter here

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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.