John Morris on Preventive Therapies for Alzheimer Dementia
Fast Breaking Papers Commentary, February 2011
|
Article: APOE Predicts Amyloid-Beta but
Not Tau Alzheimer Pathology in Cognitively Normal
Aging
Authors: Morris, JC;Roe, CM;Xiong,
CJ;Fagan, AM;Goate, AM;Holtzman, DM;Mintun, MA |
John C. Morris talks with ScienceWatch.com and answers a few questions about this month's Fast Breaking Paper paper in the field of Neuroscience & Behavior.
Why do you think your paper is highly
cited?
There may be several reasons the paper has been highly cited:
a. The topic of the paper, that there exists a long preclinical stage of Alzheimer disease that is devoid of detectable cognitive deficits or decline but that ultimately may develop into Alzheimer dementia, increasingly is finding acceptance in the field and may be of critical importance to developing truly effective preventive therapies for Alzheimer dementia.
b. Identification of preclinical Alzheimer disease requires Alzheimer biomarkers, and the paper combines both imaging biomarkers (notably using the amyloid tracer, Pittsburgh Compound B, or PIB) and cerebrospinal fluid biomarkers; most prior studies have reported one or the other but not both.
c. The sample size of 241 cognitively normal individuals across a wide age range of 45 to 88 years is the largest yet reported and allows the analyses of less common factors that may reduce or increase the emergence of Alzheimer disease; for example, our sample size was sufficiently large to identify a protective effective for the APOE2 allele.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
"Preventing Alzheimer dementia will have profound public health and social implications."
It is a synthesis of knowledge about biomarkers for preclinical Alzheimer disease, antecedent to the appearance of Alzheimer dementia.
Would you summarize the significance of your paper
in layman's terms?
Changes in the brain that ultimately produce the symptoms of Alzheimer disease begin many years, perhaps decades, before Alzheimer dementia can be diagnosed. If these changes can be reliably detected in living persons, it may identify those individuals who are at great risk of developing dementia in future years and who also may be an ideal group of individuals to participate in prevention studies of Alzheimer dementia.
How did you become involved in this research, and
how would you describe the particular challenges, setbacks, and
successes that you've encountered along the way?
My research began with careful clinicopathologic correlations of persons dying with a clinical diagnosis of Alzheimer disease. My Washington University colleague, Joseph L. Price Ph.D., and I were struck with how many of our presumably healthy control participants with no evidence of dementia at time of death also demonstrated the neuropathologic lesions of Alzheimer disease. This suggested that, analogous to many chronic illnesses, there is a stage of the disorder that begins without clinical manifestations until eventually sufficient neuronal and synaptic damage occurs to produce brain failure and the cognitive symptoms of Alzheimer dementia.
Dr. Price and I noted that when the symptomatic stage of Alzheimer dementia began already in selected areas of the brain there was substantial loss of neurons. The preclinical Alzheimer cases, however, had not yet begun to have notable neuronal death. This suggested that if Alzheimer therapies are initiated once the diagnosis is made based on the presence of dementia, it may be too late to achieve a truly beneficial outcome as the brain at that stage already is damaged (i.e., has neuronal loss). The preclinical stage, however, may be a better target for therapeutic agents as neurons have not yet been lost in appreciable numbers.
Rather than depending on autopsy studies to identify preclinical Alzheimer disease, our Alzheimer Disease Research Center (ADRC) made a clear commitment to developing and evaluating biomarkers of Alzheimer disease in living persons, before there are any signs or symptoms, and to do so not just in older adulthood but also in middle age when some of the Alzheimer brain changes may first appear.
"...there exists a long preclinical stage of Alzheimer disease that is devoid of detectable cognitive deficits or decline but that ultimately may develop into Alzheimer dementia...."
Many ADRC investigators have been critically involved in this effort, including David Holtzman, Anne Fagan, Mark Mintun, Martha Storandt, James Galvin, Catherine Roe, Yvette Sheline, Alison Goate, Chengjie Xiong, Elizabeth Grant, Randy Bateman, Rick Perrin, Nigel Cairns, Dave Denise Head, David Balota, Jan Duchek, Joy Snider, Rawan Tarawneh, Mary Coats, and Virginia Buckles, just to name a few.
The major challenges in this work have been two-fold. First, to conduct longitudinal biomarker studies in cognitively normal persons from middle age to older adulthood takes enormous resources. We have been very fortunate in having our research continuously supported by the National Institute on Aging and by several foundations, and also by very generous benefactors. However, the funding climate for Alzheimer research at the National Institute on Aging recently has become severely constrained and jeopardizes the ability to support studies such as ours.
Second, there is a curious reluctance among many Alzheimer clinicians and investigators to accept that the earliest symptomatic stages of the illness represent the initial phase of Alzheimer dementia, in which there is compromise of the affected person’s ability to carry out everyday activities at their usual level because of cognitive loss. Instead, many clinicians and investigators consider the earliest stages to represent a construct commonly known as mild cognitive impairment that lacks a specific etiologic diagnosis; should symptoms worsen over time, they suggest that mild cognitive impairment "converts" to Alzheimer dementia.
The growing body of evidence provided by biomarker studies may help the field to recognize that Alzheimer disease, once it develops in the brain, is a continuous neurodegenerative process. Its clinical phase also is one of continuous cognitive decline. That is, there is no "conversion" from mild cognitive impairment to dementia but rather there is a steady progression of the Alzheimer disease process through its various stages, from no symptoms (preclinical Alzheimer disease) to early symptomatic Alzheimer dementia to more severe dementia and ultimately to death.
Where do you see your research leading in the
future?
Ultimately this research will lay the foundation for prevention trials of candidate therapeutic agents to prevent Alzheimer dementia.
Do you foresee any social or political
implications for your research?
Preventing Alzheimer dementia will have profound public health and social
implications. Indeed, if we do not develop truly effective therapeutic and
prevention strategies, the rapidly aging population in the United States
means that we will be overwhelmed by an "epidemic" of older adults with
Alzheimer dementia.
John C. Morris, M.D.
Friedman Distinguished Professor of Neurology
Washington University School of Medicine
St. Louis, MO, USA
KEYWORDS: APOLIPOPROTEIN E (APOE) GENOTYPE, AMYLOID BETA, TAU, ALZHEIMER PATHOLOGY, COGNITIVELY NORMAL AGING, PITTSBURGH COMPOUND B, CEREBROSPINAL FLUID, AMYLOID-BETA(42), PHOSPHORYLATED TAU(181), POSITRON EMISSION TOMOGRAPHY, IN-VIVO, EPSILON 4 ALLELE, BRAIN ATROPHY, A-BETA, CLINICAL EXPRESSION, TYPE 4 ALLELE, MEAN CORTICAL BINDING POTENTIAL.