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 As much as 4.5% of 50 to 60 year olds and approximately 25% of 70 to 80 year olds, according to unpublished results of his research.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step is to try to treat these people diagnosed with preclinical Alzheimer’s. By my “guesstimate” using his slide of unpublished data and census figures, that could mean over 12 million people in the U.S. alone – a huge market for any new treatment.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.
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.