Early AD Symposium: John Morris Makes the Case for "Preclinical Alzheimer's Disease"

            John Morris, MD

Dr. John Morris is a Professor at Washington University in St. Louis and Director of the Alzheimer’s Disease Research Center  there.  One of his areas of interest is detecting “preclinical Alzheimer’s disease.”  He made the case for this relatively new concept in the first day’s keynote address at the Symposium on Early Alzheimer’s Disease in Miami Beach earlier this month.

Alzheimer’s should be viewed more as a chronic disease, he said, and this concept includes a “preclinical” phase where there are changes in the brain, but no noticeable symptoms.  Despite some studies showing people with large amounts of Alzheimer’s pathology (plaques and tangles) can have normal memory and thinking, he does not believe that pathology is harmless.  He and his colleagues have shown that people with Alzheimer’s pathology who seem cognitively normal already have brain shrinkage in some areas.  Tests show that their memory and thinking has already declined over time.  They will develop dementia if they live long enough, he thinks.

Detecting Preclinical Alzheimer’s

If this still unproven chronic disease model is right, the first step is detecting preclinical Alzheimer’s by testing for biomarkers (physical or biochemical characteristics that are signs of disease), Dr. Morris says.   Specifically, he thinks a high amount of beta amyloid deposits in the brain as detected by new imaging techniques, and a low amount of beta amyloid in spinal fluid are signs of preclinical Alzheimer’s.  (Other studies, however, have suggested that these biomarkers are not necessarily associated with actual symptoms.)  An increased amount of tau (the protein that makes up Alzheimer’s tangles) in spinal fluid is also an indication of preclinical disease, he says.  He believes levels of tau in the brain rise later in the disease process.

If these biomarkers are valid, what percentage of the population has what Dr. Morris calls preclinical Alzheimer’s, with no symptoms?  As much as 4.5% of 50 to 60 year olds and approximately 25% of 70 to 80 year olds, according to unpublished results of his research.  Other studies have shown a much higher percentage of the population could be classified as having preclinical Alzheimer’s (see an Alzheimer Research Forum report on this topic).

Biomarkers for Testing Treatments for PreClinical Alzheimer’s

The next logical step is to try to treat these people diagnosed with preclinical Alzheimer’s.  By my “guesstimate” using his slide of unpublished data and census figures, that could mean over 12 million people in the U.S. alone – a huge market for any new treatment.

Taking this model further, the next step would be to use biomarkers in studies, first to screen people for Alzheimer’s clinical trials and secondly as “surrogate outcome measures” in those trials, Dr. Morris says.  “Surrogate outcome measures” means that researchers (and regulatory agencies such as the Food and Drug Administration here in the U.S.) would have to accept that if a new treatment changes these biomarkers, it is changing or preventing disease.

Many scientists see the use of these biomarkers as the next big development in Alzheimer’s research.  But some disagree with the model and the assumptions behind the use of these particular biomarkers – see Alzheimer’s Research:  Starting Over?.

If Dr. Morris and like-thinking researchers are right, the biomarkers could be a potential workaround for some of the problems in Alzheimer’s clinical trials, including:

• the difficulties of screening participants to include only those with Alzheimer’s
• the tendency of placebo groups to not decline much in shorter trials
• the long, expensive and perhaps unethical studies needed to show that a drug given to people with no symptoms actually prevents Alzheimer’s from developing.

Behind all these logical steps is the hypothesis that treating people before they have symptoms will be more successful than treating them after symptoms start, which Dr. Morris labels a “paradigm shift from cure to prevention.” 

Current Research

Paradigm shift or not, researchers have already started to include biomarkers in clinical trials.  A very small study of 28 patients showed that bapineuzumab, an anti-amyloid compound treatment did reduce amyloid in the brain.  When it comes to memory and thinking, though, Bapineuzumab has not been shown to be effective. 

As optimistic as he is about amyloid biomarkers, Dr. Morris is cautious about coming to any conclusions about treatments meant to reduce amyloid in the brains of people with no symptoms.  “Limited data shows that an anti-amyloid vaccine can reduce amyloid burden,” he says, “but there's no clinical benefit for those who are symptomatic.  Other trials have been negative.  Biomarker data suggests a model for reducing amyloid in preclinical disease.   Will it prevent Alzheimer's disease?  I don't know, but I think it's the best hope."

Prevention Trial in the Works

Given this hope, what are Dr. Morris and his colleagues planning to try to validate this model of Alzheimer’s as a chronic disease?  How will they try to prove that treating people before they have any symptoms will actually prevent dementia?  They are focusing on people whose parents have or had one of the rare Alzheimer’s genetic mutations.  People who have these mutations will almost certainly develop dementia, usually at a young age.  Researchers have been working to enroll these adult children in a study called Dominantly Inherited Alzheimer Network (DIAN).  Dr.  Morris is the principal investigator for DIAN.

Studying people from these families should eliminate or reduce the need for clinical trials where people who may never develop symptoms would have to be treated.  Because the average age of onset of dementia in this population is young, it also eliminates the need to wait twenty years or more to see which trial participants develop symptoms.  Researchers hope that even if the Alzheimer’s these families get isn’t exactly the same as late onset sporadic Alzheimer’s, it’s similar enough to move research forward.

“My colleague, Randy Bateman, MD, at Washington University, is the leader of DIAN's clinical core,” Dr. Morris wrote in an email after the Early AD Symposium. “Dr Bateman has formed a Clinical Trials Committee to investigate the initiation of a prevention trial in the DIAN cohort, where the aim is to administer an appropriate therapy to a person who is preclinical (no symptoms) but has the gene mutation, and see whether dementia onset can be delayed or prevented.  The DIAN Committee and Dr Bateman and myself met with drug company scientists and directors this past Tuesday here in Geneva and there was great enthusiasm for this approach.”

It’s too soon to say when we could see results from this early prevention trial. It will likely be several years after the trial is launched before results can be collected, analyzed and published.  “Dr Bateman would like to launch a prevention trial next year in the DIAN cohort.  It probably will not happen that quickly, but I am optimistic that in the next three years the trial will be launched.  We will see what happens from there,” Dr. Morris wrote.

Most of the presentations at the Symposium on Early Alzheimer’s Disease focused on this idea of preclinical or (very) early Alzheimer’s, and I’ll write about those presentations in future posts.

Comments

[Danny George]

Great post, Mona. I think the prevention paradigm is the right way to be moving, just don't know if the continued fixation on amyloid should take precedence over other lifestyle factors that we know can postpone aging processes and prevent associated deficits (diet, nutrition, cog stimulation, social connections, etc). Also, supposing Morris is right, what is the economic burden of treating people who are presymptomatic going to be? Can we afford to pay for drugs over 2,3,4 decades?

[Richard Taylor]

Hello

Early on-set, MCI, and now here comes the words pre-clinical Alzheimer's (PCA). This house of cards/words is built upon a foundation the existence/composition/predictability/half-life/progression has yet to be confirmed by anyone but the truest of believers (who when confronted with evidence contradicting their beliefs immediate begin to explain away the results and rush right back to their original beliefs. There is no growing consensus about anything thing(s) about Alzheimer's other than there seems to be a growing consensus (mostly by folks who are not intimately involved and committed to the idea that there is such a discrete disease that should be called Alzheimer's disease) that the very idea of something called Alzheimer's Disease and all the ideas that have grown out of that idea have not over the the past 25 years been confirmed by replicated studies.

With each wave of technology and application hopes are raised that this new tool will at long last confirm what has thus far been a "myth". Now we are imaging, now we are looking at genes, now we are searching for bio markers in any shape or form to confirm the foundation created by the hopes of the alzheimer's industry.

No one knows all the variables associated with Alzheimer's Disease, so no one is able to manipulate and control for them. Can we cure something the cause of which we don't know? Depends on how you define cure. Depends on how bad you need to keep the hope alive. Depends upon luck, prayer, hope - but certainly not science as we know it. This rushing off in all directions all at once, letting technology define what we are seeing rather than letting technology confirm what we know to be there, this seductive belief that if we name something, that something exists. If it exists we can control and manipulate it because we have named it and therefore we can at least eventually understand, manipulate, and ultimately eliminate it through chemistry...all these this and thats don't make anything true - even if a lot of well intended-well credentialed folks say it is so, it is possible, it is closer today than it was yesterday and if only we spent more money fast we would for sure answer all questions sooner and better - this is nuts! They aren't, but the loop they have created and in which they are stuck, even if the loop is getting bigger is still an artifical loop of lots of very bright people spending lots and lots of money chasing themselves, each other, their own words/labels/pet theories.

And what is even more absurd is to expect those of us who see the Emperor as naked should be challenged to prove he is naked to those who see him/her as having clothes on - they are just invisible to the naked eye, and by reductionist science we will all someday soon eventually see how fully clothed s/he is.

I do have slipping cognitive abilities, but I still know a naked emperor when I see one.

In the mean time lots of us are standing around literally freezing to our deaths waiting for science to create a new ray of sun light to cure us of our nakedness. Make us some clothes - research solutions to the the consequences of being cold. Focus on today, not tomorrow and tomorrow.
Richard

Richard

Richard