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!

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

 

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

Refining the Amyloid Hypothesis

Contributed by: Dennis Fortier, President, Medical Care Corporation

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A leading theory about Alzheimer's Disease (AD) suggests that toxic plaques of beta-amyloid protein accumulate in the aging brain, destroy neurons, and cause declining cognitive function. This theory has been deeply scrutinized and modified over the past two decades of intensive research.

The notable, but poorly understood role of amyloid has driven both treatment strategies and diagnostic strategies for Alzheimer's Disease. In fact, a great majority of efforts to treat Alzheimer's disease have been based on agents that either slow production of amyloid, alter the form of amyloid, or remove amyloid from the brain. Likewise, many diagnostic approaches have been driven by measures of the amount of amyloid in the brain or spinal fluid.

New research from the Penn Medicine Department of Radiology, published in the Neurobiology of Aging, suggests that the location of amyloid plaques in the brain may be more important that the amount of amyloid in the brain. In fact, it has been widely observed (but as yet unexplained) that many older adults, who died with complete cognitive integrity, were shown at autopsy to have massive amounts of amyloid plaques in their brains.  Evidence favoring amyloid location over amyloid burden in diagnosing Alzheimer's disease offers a potential explanation for these puzzling observations.

The amyloid hypothesis has evolved considerably since it was first introduced.  This research may offer a further refinement and a better understanding of the complex pathology of Alzheimer's Disease.

Cancer Drug Not Effective in Treating Alzheimer's

Contributed by: Dennis Fortier, President, Medical Care Corporation

The media have widely reported on a recent study showing that Targretin, an FDA approved drug for treating skin cancer, was effective in clearing amyloid plaques from the brains of mice.  Given that the presence of amyloid in the brain is a pathological hallmark of Alzheimer's disease, many were optimistic about the potential for a new treatment.

Alas, the scientific process of duplicating results before accepting them as valid, is an important step in generating new knowledge.  In this case, three attempts to duplicate the original findings have all failed. That is to say, no other lab has been able to show a reduction of amyloid in the brains of mice treated with Targretin.

The original study with the positive result was conducted at Case Western University Medical Center and published in the journal Science.  In its latest edition, the same journal published a technical comment describing the negative results in three other labs.

New Generation Alzheimer's Drugs: Do They Work?

Contributed by: Dennis Fortier, President, Medical Care Corporation

We've all been hopeful that a new class of Alzheimer's drugs (monoclonal antibodies) would soon bring effective treatment to the growing number of Alzheimer's patients.

The latest approach is based on using antibodies that bind with harmful amyloid protein.  The idea is that the antibodies will be naturally flushed from the body by the immune system, and take the harmful amyloid away as well.

Major trials have now concluded on two such drugs: Bapineuzumab and Solanezumab.  The primary outcome measures of these trials were "improved cognition" and/or "improved function" versus a placebo group.  That is to say, if subjects who took these drugs had either better cognition or better physical ability to perform daily activities, compared to subjects who did not, then the drugs were probably effective enough to be approved by the FDA. On these measures, all trials have failed.

But that is not necessarily the end of the story for either drug.

A secondary analysis, performed on a combination of the data from the multiple Solanezumab trials, shows a small improvement in cognition among treated subjects.  It is a weak signal, but it provides some hope on which to build.  Especially noteworthy is that the positive effect was most evident in the earlier stage patients with healthier brains.

A stronger signal has come from a look at the targeted biomarkers (amyloid and tau proteins) that these drugs target.

Researchers have speculated (and common sense has suggested), that using such drugs to remove amyloid from the brains of subjects who have already suffered a fair amount of brain damage, may not be helpful.  The obvious experiment would be to remove the amyloid at an earlier stage, before brain damage occurs, which is before symptoms of memory loss and other cognitive decline are noted. This makes intuitive sense and is well-aligned with the possible effect detected in the Solanezumab trial on early stage subjects.

As such, a key indictor of the true potential for each drug may be actual measures of amyloid reduction in those subjects who were treated.  Researchers involved in the Bapineuzumab trial announced yesterday that the drug did in fact dramatically reduce amyloid in the brain and spinal fluid of trial subjects.  Similar biomarker data from the Solanezumab trial is expected in the coming weeks.

Overall, we wish that the drugs had produced great improvements in cognition and function.  While those goals were not met, it is encouraging to note that some, small measure of cognitive improvement may have been realized in the Solanezumab trials, and a clear reduction in amyloid protein was seen in the Bapineuzumab trials.

This leaves us with a hopeful hypothesis that, if used on subjects at an earlier stage of Alzheimer's disease, before extensive brain damage has occurred,  either or both drugs may yield more effective treatment than what is currently available.

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.

A New Approach to Treating Alzheimer's?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Promising new research, has suggested a novel approach to Alzheimer's treatment.

Regular readers of this blog are familiar with the amyloid hypothesis which suggests that the most likely approach to treating or preventing Alzheimer's disease will be to somehow limit the accumulation of beta amyloid in the brain.  Beta amyloid peptides are formed when a longer protein called amyloid precursor protein (APP) is chopped up into smaller fragments as part of the body's normal recycling process.  This hypothesis is based on the fact that beta-amyloid is notably present in the form of a sticky plaque in all cases of Alzheimer's disease.

The new research, published in the Proceedings of the National Academy of Sciences, has determined that APP travels through the brain cells along a different pathway than the beta secretase enzymes that chop it up and aid the formation of the harmful plaques.  This opens the opportunity for a "road block" strategy whereby it might be possible to limit the production beta-amyloid by preventing contact between APP and the enzymes that help to trasorm it into beta-amyloid.  Doing so could possibly prevent unwanted side effects that sometimes arise from treatments that completely block or eliminate the production of otherwise important proteins and enzymes.

While this is science is promising, the implications are still uncertain and the new knowledge is only applicable at a very basic and hypothetical level.  Nonetheless, it is another avenue through which scientists may soon be able to bring the amyloid hypothesis forward to a real world treatment against the rising threat of Alzheimer's disease.

Does Alzheimer's Begin in the Liver?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Have we been looking in the wrong place?  After all the years of studying the brain, could it actually be the liver that holds the root cause of Alzheimer's disease? 

This intriguing question has been raised by a recent publication in The Journal of Neuroscience Research.  The study, conducted by a joint team of researchers from Scripps Research Institute and Modgene, LLC, showed an interesting result in mice.  The study found a high correlation between the accumulation of liver-based, messenger RNA, expressed for genes known to correlate with early onset Alzheimer's disease, and susceptibility to the disease.  This suggests that some process outside of the brain, might be responsible for triggering the complex cascade of Alzheimer's pathology.

Importantly, a drug shown to reduce the amount of amyloid in the blood stream, also showed a reduction of amyloid in the brain.  That would not be surprising, except for the fact that the chosen drug does not pass easily through the blood/brain barrier.  Therefore, it is reasonable to conclude that amyloid load in the blood may be an important driver of higher amyloid levels in the brain.

This differs from the current understanding that amyloid plaques in the brain are formed from amyloid that was produced in the brain.  In fact, most research on Alzheimer's treatments has been focused on reducing amyloid production in the brain, or clearing amyloid from the brain.  The demonstration that amyloid may arrive in the brain from other parts of the body, may be the most important aspect of this exciting new research.

As is often the case with such novel findings, this is very early stage work that will require years of additional validation and refinement before meaningful conclusions can be drawn.  However, it is an intriguing approach, and it expands our general scientific view of potentially effective avenues to treatment.

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The Murky Role of Amyloid in the Brain

Contributed by: Dennis Fortier, President, Medical Care Corporation
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It is clear that beta-amyloid plays some role in Alzheimer's disease.  Most experts in the field believe that plaques of this protein are the key culprits, causing the death of brain cells and declining cognitive capacity.  But to be sure, there is still a lot we don't understand about how Alzheimer's disease progresses.

As testimony to this lack of clarity, data presented at the 5th annual Human Amyloid Imaging meeting, held last month in Miami, raised as many questions as were answered.  An excellent summary of the presentations is available at the Alzheimer Research Forum.

Of particular note, certain studies showed that amyloid accumulates in the brain throughout the disease course with some maximal load manifesting in the latest stages of dementia.  Other studies showed that plaque formation began several years before the first symptoms of the disease and leveled off around the time of first symptoms.  One of the largest data sets, from Avid Radiopharmaceuticals, suggested that variability of amyloid levels across individuals was so great, that group averages would continue to obscure the picture until more data is collected.

At the end of the day, amyloid will remain a target of intense scientific scrutiny until a better understanding of Alzheimer's pathology, and the role of amyloid, are both more completely understood.

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2 Steps Toward Better Alzheimer's Diagnosis

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego. ______________________________________

While we sometimes note that the press over-emphasizes the difficulty in diagnosing Alzheimer's disease, there is no doubt that new tests could make the process faster and more accurate.  Two recent news stories have converged on this theme.

First, regarding efforts to diagnose Alzheimer's using PET scans to view amyloid plaques in brain, the U.S. Food and Drug Administration’s (FDA) Advisory Committee decided that it could not recommend approval of Amyvid™ (florbetapir) at this time based on the currently available data (13-3); but, voted unanimously (16-0) to recommend approval of Amyvid conditional on specialized training being instituted for the medical professionals who would administer it.  It is expected that this training will be formalized, and FDA approval granted by the end of this year.

Second, Kristine Yaffe and colleagues at UCSF published an article in JAMA this week in which they report on a new blood test that predicts subsequent cognitive decline. In the study, they took baseline plasma samples from nearly 1,000 elderly normal volunteers and then followed the participants for nine years, regularly measuring their cognitive performance.

Unlike similar previous studies, Yaffe and colleagues looked at cognitive decline rather than conversion to Alzheimer's disease (AD). They found that a low ratio of two forms of beta-amyloid at baseline correlated with a greater drop in cognition over the duration of the study. Intriguingly, this association was strongest in participants with low levels of education, and much weaker in subjects with more education. This is in accord with the long-standing view that a person’s cognitive reserve can protect against cognitive decline. If the result proves robust in future studies, it may lead to further development of blood tests to monitor for AD.

Yaffe K, Weston A, Graff-Radford NR, Satterfield S, Simonsick EM, Younkin SG, Younkin LH, Kuller L, Ayonayon HN, Ding J, Harris TB. Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA. 2011 Jan 19;305(3):261-6.

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New Insights into the Cause of Alzheimer's

Contributed by: Dennis Fortier, President, Medical Care Corporation

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Last month, a publication in the journal Science suggested a potentially important nuance to our understanding of Alzheimer's pathology.

The most prominent theory in the field, the amyloid hypothesis, posits that excess beta-amyloid in the brain forms plaques which eventually kill brain cells and impair cognition.  However, the cause of the excess beta-amyloid is an open question.

The new study, from the University of Washington, suggests that the excess is not due to over-production but by poor clearance of amyloid.  The study, on just 24 subjects, twelve of whom had Alzheimer's and twelve of whom were cognitively normal, showed that the subjects with Alzheimer's produced beta-amyloid at about the same rate as the control group but cleared it into the blood stream about 30% slower.

If further validated, this finding could lead researchers down a more well defined path in their efforts to discover new treatments for excess amyloid in the brain.

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Top 3 AD Research Trends

Contributed by: Dennis Fortier, President, Medical Care Corporation
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One site I follow for news in this field is the Alzheimer's Research Forum. The postings there can be quite technical as they target medical researchers as an audience. Nonetheless, the content they cover is often the same content as that which gets translated into lay terms (accurately or otherwise) by journalists in the general press.

They recently summarized their opinion of the top research trends in the AD field and I found it to be an excellent summary with a rich set of links to ongoing research stories. From a public impact perspective, I have selected the three from their list that I think are most likely to make a real-world difference, or at least be worthy news stories, in the coming year.

1. Revised Diagnostic Criteria
We posted this news followed by our perspective on this change when it was first discussed last summer. I think the new criteria, which define AD based on pathological evidence as opposed to severity of symptoms, provide a great step forward and will enable earlier intervention in a clinical setting.

2. Biomarkers
The ongoing effort to better understand AD pathology brings bio-markers to the forefront of importance. This year will likely see the first FDA approval for an agent that binds to amyloid in the brain and enables visibility on a PET scan. This along with ongoing research on proteins in the blood and spinal fluid, brain volumes, cognitive measures, and a host of other bio-markers portends a year of advance for the field.

3. The Amyloid Hypothesis (or hypotheses)
As described by the editors at Alzheimer's Forum, last year saw advances in understanding of amyloid's "...production, aggregation, function, and toxicity". All of this new knowledge must be assimilated into the evolving hypotheses about the role of beta-amyloid in Alzheimer's disease.

While there is much work underway in this field and many facets to the complex problems caused by Alzheimer's disease, the three noted trends above will certainly be central themes in the news during the coming year. Follow along with our posts at this blog to stay abreast of all developments and to understand the likely effects of each.

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Could Alzheimer's be Caused by Inflammation?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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As with all unsolved scientific problems, hypotheses are constantly developed, modified, and tested with each new study shaping the ongoing debate in some way. In terms of the question "What Causes Alzheimer's?", the hypothesis that inflammation is the culprit has long been discussed and, to some degree, tested in the lab.

The LA Times ran an interesting article this week highlighting the inflammation hypothesis and describing its merits. It's a good overview of a theory that is not considered central by leading thinkers today, but may well have merit.

One quote in the article suggests that this is a "very new" way of thinking about the problem, but that is not really true. Inflammation has been fairly well scrutinized for its role in the Alzheimer's disease process. The current scientific emphasis elsewhere (primarily on the amyloid hypothesis), merely suggests that inflammation is not the most compelling avenue according to most of the experts in the field.

However, most would agree that inflammation may play some role in the complex cascade of pathology associated with this disease.
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Promising Alzheimer's Drugs on the Horizon

Contributed by: Dennis Fortier, President, Medical Care Corporation
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While we often emphasize the importance of non-pharmacologic therapies for treating Alzheimer's disease, more effective drugs could have an enormous, positive impact on our ability to combat its looming threat. A such, here is a brief summary of three of the most promising treatments in the FDA pipeline.

All three of these agents operate on the amyloid hypothesis which holds that, an accumulation of beta-amyloid, a naturally occurring protein in the brain, is the cause of Alzheimer's disease. While two recent trials on agents developed to reduce the production of beta-amyloid have failed, these three are intended to remove beta-amyloid from the brain.

Two similar drugs are Solanezumab and Bapineuzumab. Both are anti-bodies that attach to amyloid and then carry it away when they are flushed out of the body by the immune system. Solanezumab most likely operates outside of the brain which may lead to better tolerance than Bapineuzumab, which had more evidence of efficacy in its earlier stage studies. Each trial is well underway and the first published data should be forthcoming in late 2011 or early 2012.

Gammagard is Baxter's intraveneous immunoglobulin or IVIG, which also relies on removing amyloid through immune system mechanisms. IVIG is already on the market but with no approved claims for treating Alzheimer's disease.

There are certainly other approaches in the pipeline, some of which may bring better results in a shorter time frame than the three highlighted here. But these seem to have the strongest theoretical underpinnings and have bred the most optimism in the scientific community.
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Diagnosing Alzheimer's with PET Imaging

Contributed by: Dennis Fortier, President, Medical Care Corporation
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The Mayo Clinic has concluded its 2010 Medical Innovation Summit and released it's annual list of top Medical Innovations.

Coming in at number 1 on their Top 10 list is: New molecular imaging biomarker for early detection, prevention and treatment of Alzheimer's disease. Specifically, they are referring to AV-45, a radioactive agent developed by Avid Radiopharmaceuticals.

This science has been under development for quite some time and is expected to receive FDA approval in early 2011. The concept is to inject a tracer agent into the blood stream that will make it's way to the brain, bind with amyloid plaques, and light up in a PET scan. This will make the presence of amyloid in the brain more visible.

Since amyloid is a key pathological indicator (if not the cause) of Alzheimer's disease, gaining an understanding of amyloid load in the brain is useful in several regards. It can indicate the presence of AD pathology at an early stage, even before major cognitive deficits have emerged and could allow for earlier detection and timely intervention against this progressive disease process. It could be useful in measuring treatment effects which could accelerate clinical trials and bring better drugs to market more rapidly. And finally, it could potentially be used in identifying preventative agents that block or reverse the build-up of amyloid in the brain.

Similar technologies are also under development from GE and Bayer and will likely make important contributions in the global battle to thwart Alzheimer's disease in the coming decade.
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Alzheimer's Disease: Status of the Amyloid Hypothesis

Contributed by: Dennis Fortier, President, Medical Care Corporation

For some time now, the leading explanation of Alzheimer's disease has been an abnormal accumulation of beta-amyloid in the brain, which leads to cell death and impaired mental function.

While the amyloid hypothesis has been the leading explanation, it has not been universally accepted and is only one of several possible explanations of Alzheimer's pathology. Each time results are released from an FDA trial, researchers scramble to reconcile the results with what is known about treatment targets and the underlying mechanisms of disease progression.

Yesterday's announcement by Eli Lilly that they were canceling development of an agent formulate on the the amyloid hypothesis has reignited discussions about the cause of Alzheimer's disease. A very thorough summary, with cogent, expert commentary from both supporters and detractors, was published today by Bloomberg. This short article provides a balanced view of where the research community stands on the amyloid hypothesis.
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Brain Scans for Diagnosing AD

Contributed by: Dennis Fortier, President, Medical Care Corporation
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In this cleverly written, but wantonly provocative article in the Forbes blog “The Science of Business”, it takes the author only 53 words to completely mislead his audience.

In his attempt to find controversy in a straight forward advance, there are two areas where the author has blurred the truth. First, the guidelines he references, which define a very early stage of Alzheimer’s, are not intended for physicians seeing patients but for researchers doing scientific work in a laboratory. Second, adoption of a new definition by the research community has nothing to do with approval of a diagnostic process, like brain scans, that physicians would use in diagnosing patients.

Here is a more sensible summary of the situation than the one Robert Langreth has thrust upon his readership:

An expert panel, convened by the NIH and the National Alzheimer’s Association, has drafted new guidelines for defining Alzheimer’s disease. These new guidelines are intended to correct a major deficiency in the existing guidelines that were established in 1984.

Original Guidelines
The original guidelines suggest that Alzheimer’s disease is not present until the subject has dementia. Recall that the term “dementia” defines a state of impaired thinking that is so severe that subjects can no longer care for themselves without human assistance. This means that, under the old definition of Alzheimer’s disease, a subject with accumulating amyloid in their brain, and clear symptoms of memory loss, does not have Alzheimer’s disease until their impairment progresses to the point where they become dependent on others.

Obviously, this makes no sense. We wouldn’t set some late stage criteria, like blindness, before diagnosing diabetes, and we shouldn’t do so for Alzheimer’s disease. It is this old and problematic definition that has primary care physicians around the world, watching patients with memory loss, and doing nothing to treat the problem until the patient becomes demented. Only then can they consider diagnosing Alzheimer’s disease and prescribing a very late and predictably ineffective treatment regimen.

Proposed Guidelines
The new guidelines cover 3 stages of the disease:
1) AD Dementia – the definition of this progressed state is largely consistent with the original language used to describe the entire disease continuum.
2) Mild Cognitive Impairment due to AD - an earlier stage of the disease. This definition will facilitate timely intervention for patients with memory loss who are not yet demented.
3) Pre-Clinical AD - the earliest and least certain stage. It includes the period when pathological changes are underway but there are no outward symptoms of disease. These guidelines, which are the ones cited by Langreth, are clearly and expressly intended for researchers, not physicians.

Adoption into Clinical Practice
Finally, there is really no need for alarm that adoption of new definitions in the research community will unleash massive, premature change in clinical practice. Langreth makes a dangerous, conceptual leap based on the word “approved”. He states “…once a plaque brain scans gets approved the next step will be that aggressive doctors will start using it in patients with the slightest sign of fleeting memory or cognitive problems”. Lets be clear about this; adoption of new language by an expert panel has absolutely nothing to do with the FDA’s possible, eventual approval of a diagnostic test that can be used in clinical practice. The author implies a close association between these discrete events that is not justified. It is pure artistic license and sensationalism.

These are the kinds of articles that perpetrate the public’s nihilistic attitudes toward Alzheimer’s disease and prevent the kind of constructive discourse that will help us tackle the problem in a meaningful way. It is really a shame that the credibility of the Forbes imprimatur was lent to this misleading report on such a clear step forward for AD research.

Amyloid Hypothesis Evolving?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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A hallmark lesion of Alzheimer's disease, to the extent that it is currently understood, is the accumulation of amyloid plaques in the brain. Most experts agree that amyloid plays some central role in the disease pathology but there is little consensus about what that role might be.

New research out of the Mount Sinai School of Medicine and published in the Annals of Neurology suggests strongly that it is the free floating clumps, or oligomers, of amyloid protein that cause the brain damage and cognitive decline, and not necessarily the dense amyloid plaques that form when these oligomers aggregate.

While this finding helps to clarify the role of amyloid in a very complex process, there are still some key weaknesses in the amyloid hypothesis that must be explained. Primarily, we need to understand why some people with excessive plaque formation have no symptoms of Alzheimer's disease. If the free floating oligomers are present prior to plaque formation, then one would presume that symptoms of decline would manifest by the time the plaques are present.

Nonetheless, this scientific advance will most likely drive the ongoing focus of scientific inquiry to an earlier point in the amyloid cycle.

This is a perfect example of how the scientific process uncovers the answers to such complex problems: questions are identified, hypothesis are formed, conclusions are drawn, and the questions are modified. The process repeats and renews until the pieces of the puzzle are clearly exposed and fitted together.

Click this link to review prior discussions on the amyloid hypothesis.

Could Alzheimer's be Caused by Infection?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Beta amyloid is certainly a central component in Alzheimer's pathology. No one refutes that it is toxic to brain cells and that an accumulation of amyloid plaques is a hallmark indicator of Alzheimer's disease.

The amyloid hypothesis suggests heavy amyloid deposition in the brain is the underlying cause of this disease and we have discussed it here on many occasions (read past posts on the amyloid hypothesis here).

Having said that, there is no consensus and no well-validated explanation of why beta amyloid accumulates in some brains and not others. Nor is there a definitive understanding of why some people have lots of amyloid deposition but remain cognitively sharp.

Because an increased production of beta amyloid is a known reaction to head trauma and stroke, some have hypothesized that it plays a neuro-protective role and its presence is an indication of the brain attempting to repair itself from some other harm. Accordingly, beta amyloid could be viewed as part of a solution to some other problem.

Scientists at Massachusetts General’s Institute for Neurodegenerative Disease suggest that the other problem might be microbial infection. Their research, published in the journal PLos One, showed that brain tissue with lots of beta amyloid taken from Alzheimer's patients inhibited growth of several infectious organisms whereas brain tissue taken from healthy adults did not. This suggests that increased production of beta amyloid might be a natural defense mechanism when certain infections are present in the central nervous system.

If such an "infection hypothesis" is confirmed as the underlying cause of Alzheimer's, it would support the notion that amyloid toxicity is what degenerates the brain in Alzheimer's patients but would suggest a different treatment approach. That is, rather than removing the amyloid, a better approach would be to remove the infection that is stimulating amyloid production.

At that point, the challenge would be to find treatments that can cross the blood/brain barrier and fight infection in the brain.

Support for the Amyloid Hypothesis

Contributed by: Dennis Fortier, President, Medical Care Corporation
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A prevalent theory explaining the cause of Alzheimer's disease is that amyloid deposits accumulate in the brain and disrupt cell function.

While this hypothesis has driven the majority of drug development efforts over the past three years, the theory has some apparent weaknesses that must be explained. Specifically, researchers have not been able to explain why some adults with extensive amyloid deposits do not have Alzheimer's disease.

A study out of UCSF and published in Behavioral Neurology lends some support to the amyloid hypothesis. The authors reviewed over 100 published studies that involved PET scans and the PIB compound and found that there is a strong correlation between amyloid load in the brain and cognitive decline due to Alzheimer's disease. Importantly, they have documented support for the notion that there is a time lag between amyloid build-up and cognitive decline.

"Amyloid deposits appear to reach a plateau early in the disease course, when patients experience very mild symptoms or no symptoms at all," says Rabinovici, a recipient of new investigator awards from the Alzheimer's Association and the National Institute on Aging. "By the time patients have developed the symptoms of Alzheimer's disease, clinical decline and brain changes are occurring independently of further amyloid accumulation. This suggests that we have been starting treatment too late, and that amyloid-based therapies are most likely to work very early in the disease process."

Gaining a deeper understanding of the progressive pathology of Alzheimer's disease will be critical in developing effective treatment. In the meantime, the body of evidence supporting earlier intervention continues to grow.