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.

New Alzheimer's Drug on Horizon? A Solid Maybe...

 

Contributed by: Dennis Fortier, President, Medical Care Corporation
________________________________________________

A new Alzheimer's drug, being co-developed by Biogen and Easai, has completed a Phase II FDA trial with seemingly positive results. The drug (BAN2401) is a monoclonal antibody that binds to certain forms of amyloid protein, which is considered by many in the field to be a key culprit in the onset and progression of Alzheimer's disease. When the antibody is flushed out of the system, it takes the harmful amyloid protein with it. Over the past five years, several similar drugs have shown glimmers of promise before ultimately failing in Phase III FDA trials.

For perspective, Phase II studies are generally smaller (fewer people enrolled) with the purpose of determining safety for various doses of a drug along with any possible side-effects at each dose of the drug. Phase III studies are generally larger, often longer, and usually a final step prior to "market approval".

Biogen recently presented a snapshot of the data from their Phase II FDA trial at the Alzheimer's Association International Conference in Chicago. While the results showed a reduction in amyloid among subjects receiving the higher doses and a possible slowing of cognitive decline at some stages, the presentation lacked details and many questions remain unanswered.

The primary questions were related to the trial design which appeared to have lower-risk patients in the high dose group and higher risk patients in the untreated (placebo) group. If this was the case, then it would be easier to show that the treatment group fared better (perhaps on both amyloid deposition and cognition) than the placebo group. In defense of this approach, it was taken as a safety measure, not as an attempt to show efficacy through some deceptive trial design. With that in mind, the results are encouraging.

Secondarily, some in the field questioned the validity of the instrument used to measure cognition. The instrument (the ADCOMS) is a composite measure that pulls certain items from various other, well-validated instruments and combines them in a new instrument specifically designed to detect subtle changes. Given the well-documented mediocrity of the instruments historically used to measure cognitive change in FDA clinical trials,  concerns about the ADCOMS should be somewhat tempered because the new instrument may not be significantly better than previous instruments, but it is probably no worse either. With this perspective, lingering angst about the ADCOMS may possibly be over-blown.

Overall, the trial results are both PROMISING and PREMATURE. While there is reason for a fair amount of optimism, one should not carry that optimism with an unrealistic amount of conviction.

Screening for Cognitive Impairment

Contributed by: Dennis Fortier, President, Medical Care Corporation
________________________________________________

Yesterday, the U.S. Preventative Services Task Force (USPSTF) ruled that there is insufficient evidence to make a recommendation, either for or against, routine screening for cognitive impairment in older adults. Today, the press is ablaze with sloppy reporting on the matter.

Many news stories (like this from US News and World Report) are conflating cognitive impairment with dementia, but readers of this blog understand that cognitive impairment may be very mild whereas dementia is, by definition  a severe loss of cognitive capacity. Many others (like this from Time), are interchanging dementia and Alzheimer's disease, which inappropriately implies that the two are one in the same, and obscures the fact that Alzheimer's is but one of the many causes of dementia.

To be clear, the USPSTF did not rule against anything. They merely concluded that the evidence is not strong enough to make a recommendation one way or the other. More importantly, their ruling was related to "screening" of "older adults" for "cognitive impairment". In other words, should the healthcare system invest in regular cognitive assessment of all older adults, whether they suspect a problem or not? Their conclusion? They're not sure.  They're not for it and not against it.

Rather, the public should monitor their cognitive health vigilantly and promptly report concerns to their physicians for a thorough evaluation. This will allow early intervention against treatable problems like thyroid dysfunction, vitamin deficiency, anxiety/depression, sleep disorders, and out of control diabetes, all known contributors to cognitive deficits. It will also facilitate early diagnosis of Alzheimer's disease.

This is important because Alzheimer's can be effectively managed for a significant percentage of patients. Effective management of Alzheimer's includes early diagnosis, physical exercise, proper diet, strict control of hypertension and diabetes, poly-therapy with a cholinesterase inhibitor and Namenda, ongoing social and intellectual stimulation, and caregiver education. All of these interventions have been shown to promote optimal disease management and, when brought together as a robust therapeutic regimen, can be surprisingly effective.

Best Evidence Yet: Using Brain Keeps it Healthy

Contributed by: Dennis Fortier, President, Medical Care Corporation

Cognition, or thinking ability, is a complex concept and is difficult to measure.  Nonetheless, many studies have shown that intellectual activity seems to be correlated with some measure of"better cognition".  This makes intuitive sense and has given rise to many "use it or lose it" type slogans aimed at our aging population.

In a study published online today in the Archives of Neurology, researchers from Berkeley's Neuroscience Institute found that, seniors who pursued intellectual hobbies throughout their lives, accumulated less amyloid plaque in their brains later in life.  This is interesting in a couple of ways.

First, while cognition can be difficult to measure, accumulated amyloid plaque in the brain has become increasingly easier to measure with new agents that bind to amyloid and "light up" during a PET scan of the brain.  We can now get a fairly accurate read of amyloid load which is, by all accounts, much more tangible than our best measures of cognition.

An important caveat to this point is that, while we can accurately measure the amount of amyloid in the brain, we are still somewhat unclear on what that means.  For sure, amyloid accumulation is neurotoxic (harmful to brain cells), but such accumulation may be a reaction to some other disease process that would be even more damaging without the presence of amyloid plaques.  This is a topic of intense, ongoing study.

The second interesting take-away from this new research is that the subjets reported a lifetime of intellectual activity.  If this work is repeated in larger studies and deemed to be conclusive, it will not mean that playing bridge and studying music in retirement will keep amyloid plaques out of the brain.  It may be that an entire lifetime of brain exercise is the minimum threshold for a meaningful benefit.

In any case, it is very encouraging to see pathological evidence supporting the theory that brain exercise can have cognitive benefits during our elder years.  We will watch ongoing research in this area with great interest.

Best Foods for a Long Life

Contributed by: Dennis Fortier, President, Medical Care Corporation

_______________________________________________________
This summary of foods you should eat for a long life, was compiled by WebMD, and is well worth clicking through and reviewing.  It is not specifically about brain health, but the overlap between overall fitness and maintaining cognition is significant.

The 5 second version is fruits, vegetables, olive oil, berries, fish, beans, nuts and dairy.  But for a short blurb on why each of those foods helps which facet of your health, I highly recommend you review the WebMD slides.

A Milkshake for Alzheimer's?

Contributed by: Dennis Fortier, President, Medical Care Corporation
_______________________________________________________

The story of a milkshake that could aid metabolism and improve cognition for Alzheimer's patients has gotten a fair amount of press, including this piece in the Wall Street Journal.  Here are a few facts to consider:

• The product is called Axona and is marketed as a "medical food", a category that does not require FDA approval.
• In the key clinical study, patients taking Axona had slightly improved cognition after 45 days, but not after 90 days.
• The group that showed the most improvement was the group with no known genetic disposition to Alzheimer's disease.
• The "experts" have fulfilled their duties as consumer advocates and pointed out all of the reasons why the limited data is not scientifically conclusive.

While I agree that there is limited data, and that patients should be cautious when interpreting the manufacturer's claims about efficacy, I think we also need to be careful not to bury novel hypotheses before they are proven incorrect.  Remember, lack of proof that something works is not the same as proof that it does not work.  In this case, the jury is still out.

The bottom line on this is that it probably has little or no beneficial effect.  However, any resourceful person with Alzheimer's disease, who is looking for every possible means of maintaining their cognitive health, might want to check it out.  There doesn't appear to be any major health-related downside and, given how little we understand about Alzheimer's disease, it might be worth the effort for some.

Worried About Your Memory? Maybe You Just Need to Sleep Better

Contributed by: Dennis Fortier, President, Medical Care Corporation
________________________________________________

We say it over and over; many common conditions cause memory loss.

Some minor forgetfulness, like inability to recall a particular word or entering a room and forgetting why, is pretty common, even in healthy people over the age of forty.  However,  more severe symptoms may indicate the presence of an underlying medical condition.  Among the many known causes of memory loss, all can be treated with some degree of success, and most can be completely cured.

While we often mention depression, medications, and thyroid disorders among the very treatable causes of memory loss, sleep disorders should also be on that list of common and treatable conditions.  A great article about this very topic was posted today on CNN's health blog, the Chart.

Sleep apnea, or interrupted sleep due to lapses in breathing, is fairly common, especially in middle-aged and older men. It can be diagnosed with high certainty in a sleep study, and generally treated with good results.  If untreated, sleep patterns can severely degrade, and chronic sleep deprivation can significantly impair alertness and cognitive function.

Given the prevalence of sleep apnea and other sleeping disorders, many worrisome signs of memory loss may be attributable to these treatable conditions.   Please keep this in mind if you are worried, or know someone who is worried about their memory, and may not be sleeping well.

What are the Chances of Losing Your Memory?

Contributed by: Dennis Fortier, President, Medical Care Corporation
________________________________________________

Severe memory loss is NOT a part of normal aging.

Yes, there are illnesses and medical conditions that can cause declines in brain health.  But no,  none of them are inevitable.  So what are the realistic chances of losing your memory as you age?

Many studies have looked at the prevalence of various problems that cause memory loss and other cognitive problems.  New figures from the Agency of Health Care Research and Quality, part of the U.S. Department of Health and Human Services, show the prevalence of "identified" problems in the health care system, as reported through their home survey.

According to this survey, the reported prevalence of cognitive disorders by age group are:

• Age 65-74: 1.1%
• Age 75-84: 6.0%
• Age 85+: 18.4%

Despite the fact that these figures include all cognitive disorders resulting in delirium, dementia, and/or memory loss, the reported prevalence is much lower than what we frequently see reported for Alzheimer's disease alone.  Here are a couple of considerations about why the figures may not match.

First, these data are based on "self-reporting" through a household survey.  Self reporting, as opposed to direct observation, is known to be somewhat inaccurate.  This is especially true among groups of people known to have memory or other cogntiive impairments.

Second, these data do not represent actual prevalence of problems.  Instead, they represent reported results from seniors on whether or not they have been clinically diagnosed with any particular problem.  Given the well documented fact that many (probably most) early stage problems go undetected for many years in primary care settings, this survey probably included people with cognitive problems who have not been diagnosed, and subsequently did not report them.

Despite the need to reconcile these data with other published findings, it is good to get a read on the prevalence of diagnosed/reported cognitive problems by age group, as a general guide toward future expectations.

Overall, the chances of facing some medical problem that will impair memory or cognition, are probably a little higher than noted in the figures above.  However, many of those problems are completely curable and all can be treated with some effectiveness.  Additionally, our ability to manage the most feared condition in this group, Alzheimer's disease, is improving each day.

You should follow Brain Today on twitter here

--------------------------------------------------------------------------------
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.

Smoking Increases Risk of Alzheimer's Disease and Vacular Dementia

Contributed by: Dennis Fortier, President, Medical Care Corporation
________________________________________________

Many of smoking's detrimental effects on long-term health have been well know for decades. Research has clearly shown that smoking can lead to lung cancer, emphysema, and heart disease. Now, based on research published this week in the Archives of Internal Medicine, we know that smoking can also dramatically increase risk for Alzheimer's disease and for vascular dementia.

In a study of more than 21 thousand subjects who were followed for an average of 23 years, Kaiser Permanente tracked smoking habits and incidence of dementia. The findings were clear:

Compared with non-smokers, those who smoked more than two packs of cigarettes a day in midlife had a "dramatic increase" in the incidence of dementia -- more than a 157 percent increased risk of developing Alzheimer's disease and a 172 percent increased risk of developing vascular dementia, Whitmer's team found.

- Lead Researcher, Rachel A. Whitmer

It should be noted that these heightened risks were demonstrated in middle-aged subjects (50-60 years old) who smoked more than 2 packs per day. Because data were not available across the full age spectrum, we cannot say with certainty if the same risks apply (or do not apply) to older or younger subjects. Those who smoke less than two packs per day did not have the same heightened risks.

While we have long known about the many risks that smoking poses to our physical health, the evidence that it could also impair our cognitive health has been historically, less substantial. This well designed study on a large sample population and a long follow-up period draws a highly valid and important conclusion.

It's another good reason to quit. More importantly, it's another good reason not to start.
--------------------------------------------------------------------------------
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 buttons below to spread this educational message as widely as possible.

How a Short Walk Helps Your Brain

Contributed by: Dennis Fortier, President, Medical Care Corporation

Regular readers of this blog have undoubtedly seen the evidence that physical exercise is good for the brain. Most of the research in this area is based on benefits associated with improved cardio-vascular health and a more consistent, oxygen-rich supply of blood to the brain.

Now, according to research from the Beckman Institute at the University of Illinois, published online in Frontiers in Aging Neuroscience, it appears that certain neurological mechanisms also play a role in translating physical exercise into better brain health.

This research recruited a group of sedentary adults aged 59 to 80 and assigned them to one of two groups. Members of the first group walked for 40 minutes at their own pace, three times per week, for one year. Members of the other group did stretching and toning exercises with similar frequency and intensity during the same period. Cognition was measured in each of the two groups at the start, mid-point, and conclusion of the study.

As expected, the walking group demonstrated significant improvements from their baseline scores. They also showed much greater improvement than those in the stretching and toning group.

The researchers were also seeking to demonstrate any neurological benefits, in addition to the expected vascular benefits provided by the exercise. To accomplish this, they used MRI to measure activity across circuits in the subject's brains. They noted an interesting finding with regard to the default mode network (DMN) which is the circuit in the brain that is most active when the brain is at rest and relatively unengaged in other activities.

In healthy brains, the DMN quickly deactivates when the person engages in a task that requires their concentration. However, in older and/or sicker brains, the DMN tends to stay active and interferes with one's attempt to focus on a more challenging task. In this study, the subjects who walked for a year showed a significantly better ability to deactivate the DMN and focus on other tasks. This was true compared to the stretching and toning group but also true compared to their own performances at the start of the study.

This is great news on two levels. We already knew that physical exercise was beneficial to both our physical and mental health. Now it seems that a light work-out, as simple as walking at one's own pace for 40 minutes per walk, three times per week, is adequate to produce a meaningful benefit. Furthermore, the benefit is derived from two distinct mechanisms, one physical and the other neurological.

--------------------------------------------------------------------------------
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 buttons below to spread this educational message as widely as possible.

The Unseen Side Effects of a Healthy Heart

Contributed by: Dennis Fortier, President, Medical Care Corporation
________________________________________________

Do you know the chances of surviving a heart attack? According to WebMD, they’re actually pretty good at about 85%.

That doesn’t mean that anyone wants to test the statistics personally nor does “survival” guarantee a high quality of life thereafter. But it may be true that as public awareness grows about heart attack victims who fully recover and live well, the prospect of heart failure becomes less of a deterrent from an unhealthy life style.

In fact, WebMD also notes that survival has become more likely despite the fact that heart attack victims are in generally worse cardio-vascular health (more high blood pressure and diabetes) than in the past. This suggests that the better survival rate is due to better medical techniques, not to a general trend toward improved vascular health.

Healthy Hearts Maintain Healthy Brains
Importantly, there are other, less obvious but perhaps more compelling reasons to care for your heart. Mainly, good vascular health is extremely important to maintaining a healthy brain. While most of us accept the fact that our tennis serve will likely slow as we age, few are so willing to accept the prospect of diminishing cognitive capacity. The good news is that cognitive decline is far from inevitable and we probably don’t need to accept it.

So how does one take good care of their heart and reap the brain related benefits? What exactly should one do? The answer is to focus on managing those risks that are known to be associated with poor heart health.

These risks include monitoring and controlling blood pressure, cholesterol, and body mass. Making the heart work extra hard to pump blood through the body is a strain that, when considered cumulatively across many years, can greatly increase the likelihood of emergent problems. The primary behaviors one should adopt are well known and should not come as a surprise; they are sensible diet and regular physical exercise.

In terms of diet, there are many helpful resources available including a very good one at the Mayo Clinic. In general, one should be sure to get the necessary proteins, vitamins, and minerals while avoiding high calorie foods containing unhealthy amounts of saturated and trans fats.

Regarding physical exercise, it needn’t be overly rigorous as much as it should be regular. Walking may be the most under-rated form of exercise but its benefits to the heart and brain are well documented. Starting each day with a 30-40 minute walk at a pace slightly faster than leisurely is easy on muscles and joints but beneficially demanding on the heart and lungs.

The Unseen Side Effects
The unseen but well established side effects of taking care of one’s heart include a healthier brain and better cognition. Evidence has been pouring in for the last year that these benefits may be much greater than many of us initially understood. In the last few months alone, our knowledge of the link between vascular health and cognitive health has increased significantly.

For example, a study at UCLA showed a strong link between obesity and brain shrinkage, a study published in the journal Neurology showed that high blood pressure is associated with memory loss, and Kaiser Permanente published that even borderline high-cholesterol increases the risk for dementia.

There is no doubt that keeping an oxygen-rich supply of blood flowing freely to the brain is key to maintaining good intellectual health and to aging with cognitive vitality. You can accomplish this through all of the well-established approaches to vascular health that we’ve all been hearing about for decades. The good news is that everything you can do to keep your heart healthy will also benefit your brain.

The purpose of this blog is to spread useful information as broadly as possible. If you found this article worthwhile, please share it with your online networks using the share button below.

_____________________________________________________________
This article was featured by Life Line Screening.

Life Line Screening, in business since 1993, is the nation's leading
provider of preventive health screenings. Screenings detect risk of
stroke, cardiovascular disease and osteoporosis and are provided in
comfortable, familiar community-based venues such as town halls and
libraries.

Physical Exercise is Great for Your Brain

Contributed by: Dennis Fortier, President, Medical Care Corporation
________________________________________________

The evidence has been accumulating for years, from a variety of sources, on multiple aspects of cognition and brain health, that physical exercise is great for your brain. While the specific mechanisms driving the health benefits are not well understood, the relationship is clear.

An excellent summary of the evidence was published today the blog BrainandSpinalCord.org. Among the facts are several indications that physical exercise may be a boon to recovery and healing of injuries. Additionally there is evidence that it can be neuro-protective and play a role in certain debilitating neurologic disorders such as Parkinson's disease and Alzheimer's disease.

It can't be said enough; staying active is a good thing.

Fatty Foods May Impair Brain Function

Contributed by: Dennis Fortier, President, Medical Care Corporation
________________________________________________

We have often written here about research that links poor vascular health to poor cognitive health and it is clear that a steady supply of oxygen rich blood is necessary to keep the brain functioning at a high level. According to research published in the FASEB Journal, it appears that eating foods with high-fat content not only contributes to poor vascular health but can directly impede brain function through a lesser understood mechanism as well.

The research, conducted at Cambridge University, used rats that had been well trained to complete a series of mazes. One group of the trained rats were then fed a high-fat diet while a control group was kept on the low-fat diet that all rats had eaten during the learning period.

Within a few days of switching to the high-fat diet, rats began making more mistakes in the maze and the number of mistakes increased consistently throughout the period of fat intake. Meanwhile, the rats that maintained a low-fat diet were able to preserve their high levels of performance in the mazes.

As we always point out, rats are not human so it is dangerous to generalize these results to us. However, when a particular diet has such a sharp and significant impact on cognitive function in other mammals, it is worth considering how that same diet might be affecting us.