John Morris on Detecting Alzheimer's at the Preclinical Stage
Special Topic of Alzheimer's Disease Interview, October 2011
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Pittsburgh compound B, or PiB, is a tracer that binds to amyloid plaques with high affinity and emits a signal that is detected by positron emission tomography. The presence of amyloid plaques as identified by PiB retention correlates very well with the CSF Alzheimer "signature." Although at present PiB remains the "gold standard" amyloid imaging tracer, other tracers have been developed and have advantages, such as a longer half-life, that may result in their increasing use.
Several groups, including ours, have shown that a sizeable percentage of cognitively healthy people have preclinical Alzheimer disease as detected by abnormal PiB scans and/or a CSF Alzheimer "signature." The frequency of preclinical Alzheimer disease increases with age, such that about one-third of cognitively normal 80-year-olds have preclinical Alzheimer's.
Our studies suggest that preclinical Alzheimer disease may begin at mid-life, probably around age 50 or 55, for some people. Because Alzheimer dementia most commonly begins after age 70, this suggests that there is a window of perhaps 20 years of the presence of Alzheimer brain changes before the symptomatic stage of the illness is manifested. Hence, this window provides an opportunity to intervene with drugs to prevent the preclinical Alzheimer process from progressing causing extensive neuronal death and the appearance of Alzheimer's disease dementia.
Will it be difficult to get people without cognitive impairment to submit to these tests? I can imagine not wanting to know what my brain looks like if I don't have symptoms that demand some diagnosis.
A very important question. At the Knight ADRC, we are studying individuals (70% are cognitively normal) who volunteer for our research assessments, including neuroimaging and lumbar puncture (spinal tap) to obtain CSF, which are repeated about every two years. What motivates them to participate? Many have had family members who have experienced Alzheimer's disease dementia and they appreciate how terrible this disease can be, so they are motivated to join the fight to conquer the illness. Also, we educate our volunteers about the promise of biomarkers to identify Alzheimer's disease at a stage where it might be prevented.
Our volunteers are a special group of individuals. Obviously, not everyone would consent to all we ask of our participants. Consider the spinal tap. It is widely believed to be not only invasive but very painful, but the reality is that properly done, it is no more discomforting than a venipuncture to obtain blood samples. (Improperly done, it can be painful). It is a misconception that the spinal tap results in paralysis.
Thousands of women during childbirth every day quite willingly have what essentially is a lumbar puncture because of the incentive to alleviate labor pain. The complication rate of these epidural procedures is very low, as it is for the spinal tap used in Alzheimer's research. The incentive, if you will, for our research volunteers to undergo the lumbar puncture is that analysis of the CSF proteins is the closest method we have to measuring brain proteins during life and so is very valuable for our research studies.
What do you consider the most promising pharmaceutical interventions?
Let me first describe one of our unique studies to illustrate why the timing of the drug intervention may be just as critical as the intervention itself. The Dominantly Inherited Alzheimer Network (DIAN) studies individuals from families in which a known gene mutation causes Alzheimer's disease. I serve as the principal investigator for DIAN and Washington University is the DIAN coordinating center, but it is an international study with sites at academic centers in the UK and Australia as well as the US; we currently are considering expansion to other countries.
DIAN is a biomarker study of a rare form of Alzheimer's disease, in which every child of a parent with a disease-causing mutation (occurring in one of three separate genes) has a 50-50 chance of inheriting that gene mutation. If they do, they are destined to develop Alzheimer's dementia, almost always at an early age (usually between age 40 and 50 years). If the offspring of the affected parent does not inherit the gene mutation, they are at no more risk than anyone else of developing Alzheimer's disease. The DIAN assessment protocols are quite comprehensive and include PiB imaging and lumbar puncture.
"The 'baby boomers' have just started turning 65 and are at the forefront of a tremendous demographic revolution that will result in the graying of America."
DIAN enrolls both mutation carriers and noncarriers from these rare families; most are cognitively normal and have not yet reached the age at which their parent developed Alzheimer dementia. The large majority of DIAN participants do not wish to know whether they have the mutation. The DIAN researchers will know but we honor the participants' wishes and keep this information confidential. Pharmaceutical companies are very interested in the DIAN cohort because the currently asymptomatic mutation carriers, who inevitably will become demented, are demonstrating biomarker changes many years before the age they are expected to develop dementia. The cohort thus is ideal to test potential therapeutic agents to see whether Alzheimer dementia might be delayed or even prevented.
The DIAN project, I believe, will be among the first, if not the first, to launch a prevention trial for Alzheimer's, likely with an anti-amyloid agent. This might be a secretase inhibitor, a vaccination, or an anti-amyloid antibody; these agents thus might reduce the production of amyloid or help to clear it more effectively from the brain. Dr. Randy Bateman of Washington University is the Clinical Core Leader for DIAN and is leading these therapeutic initiatives.
What recent research in the field excites you the most?
A recent research study conducted at the Knight ADRC by Dr. Bateman I think is very important because it enhances our understanding of Alzheimer's disease mechanisms and has direct therapeutic implications. Dr. Bateman set out to answer the question, is sporadic Alzheimer's disease (the most common form by far, occurring in older adults) associated with overproduction of amyloid-beta (as is known to happen in the dominantly inherited forms of Alzheimer's disease studied by DIAN) or with underclearance of amyloid-beta?
Participants (both cognitively normal and those with Alzheimer dementia) from the Knight ADRC were admitted to our research hospital, where an indwelling lumbar catheter was placed so that CSF can be sampled hourly for 36 or 48 hours. Dr. Bateman then administered to the participants specially labeled amino acids. He then measured the presence of the specific protein in which he is interested (such as amyloid-beta) in both CSF and blood every hour. In this way he determines how much of the labeled amino acid is present in the protein he's studying as an indication of new production of that protein. He can also determine the clearance rate of the protein.
His findings reveal that older persons with sporadic Alzheimer's disease do not clear the amyloid-beta protein as quickly as do as cognitively healthy older people. This represents the first demonstration that in living people the abnormal mechanism underlying sporadic Alzheimer's disease appears to be impaired clearance of amyloid-beta. We know for the mutation carriers it is that too much amyloid-beta is produced. But in the vastly more common sporadic form of Alzheimer's disease, it's not over-production but under-clearance of amyloid-beta. Therapeutic strategies thus should emphasize improve clearance of this protein.
This remarkable study provides a clear signal that even in late-onset sporadic Alzheimer's disease, anti-amyloid therapies still may be very important. To return to our earlier discussion, it also suggests that strategies to improve the clearance of amyloid-beta from the brain might be considered for the preclinical stage of the illness in an effort to prevent Alzheimer dementia.
If you lived in an ideal scientific world and had unlimited funding to do one experiment that you couldn't do now, what would you do?
Unlimited funding would allow anti-amyloid therapies, as well as agents that target other Alzheimer's disease mechanisms, to be tested in controlled clinical trials in individuals with preclinical Alzheimer's disease. That is, I would use the funding to try to prevent Alzheimer's disease dementia.
So you believe current anti-amyloid therapies might still work, despite the recent high-profile failure of such therapies in clinical trials?
Anti-amyloid and other therapies may yet be effective if we use them to intervene in the Alzheimer's disease process at the right time. To date, they only have been tried in the symptomatic stage of the disease when it may be too late. I'm not sure we can say that we don't already have effective therapies until we evaluate them in the preclinical stages of Alzheimer's disease.
John C. Morris, M.D.
Washington University School of Medicine
St. Louis, MO, USA
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JOHN MORRIS'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:
Petersen RC, et al., "Current concepts in mild cognitive impairment," Arch. Neurol. 58(12): 1985-92, December 2001 with 1,295 cites.. Source: Essential Science Indicators from Clarivate .
ADDITIONAL INFORMATION:
- Read a previous interview (Feb. 2011) with John Morris.
KEYWORDS: ALZHEIMER’S DISEASE, DEMOGRAPHIC REVOLUTION, BABY BOOMERS, PUBLIC HEALTH, MEDICARE, MEDICAID, RESEARCH FUNDING, SYMPTOMS, DISEASE COURSE, EARLY STAGES, ACCUMULATING PATHOLOGY, BRAIN CHANGES, HEALTHY SUBJECTS, BRAIN DAMAGE, SYMPTOM PREVENTION, MILD COGNITIVE IMPAIRMENT, BIOMARKERS, AMYLOID BETA, PITTSBURGH COMPOUND B, PET SCAN, CEREBRAL SPINAL FLUID, SPINAL TAP, DIAN STUDY, FAMILIES, GENE MUTATIONS, PROTEIN CLEARANCE, PRECLINICAL STAGES, THERAPEUTIC TIMING.
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