The week following the May 11 launch of the Memory Disorders Center was an exciting one. Continuing our recognition of the importance of Alzheimer’s disease, Dr. David Holtzman of Washington University in St. Louis joined us May 18 as the 25th Aring lecturer. The lecture is named in honor of Dr. Charles Aring, who founded the Department of Neurology at the University of Cincinnati and has attracted a long list of outstanding clinicians and researchers whose work has advanced our understanding of neurologic diseases.
Dr. Holtzman is a distinguished neurologist and neuroscientist who has published numerous papers over the last 22 years on the pathological and biochemical changes relevant to Alzheimer’s disease. Much of his work has focused on the neurobiology of apoE and its relationship to amyloid proteins. His lab has also done work related to measuring levels of amyloid and tau proteins in the cerebrospinal fluid (CSF), which may serve as an indicator for the future development of Alzheimer’s disease. While a great deal of work remains to be done to validate the use of biomarkers such as CSF protein levels, this continues to be an exciting area of research.
Dr. Holtzman’s lecture provided an overview of his work in this area. He began by introducing the widely accepted hypothesis that pathological changes relevant to Alzheimer’s disease likely begin many years before a person develops symptoms. It would naturally follow that the success of interventions directed against amyloid would require identification of persons at a minimally symptomatic or even presymptomatic state. His laboratory’s work to develop CSF markers may provide such an advance. Much of the work in this area has focused on levels of a particularly “sticky” form of amyloid in the CSF (Aβ 1-42) and levels of the protein tau (which serves as a general marker of damage to neurons). This work suggested that the combination of low Aβ 1-42 and high tau provided a marker of amyloid deposition in the brain and that these CSF measurements could be predictive even before an animal developed symptoms related to the amyloid in the brain.
His laboratory team then turned its attention to replicating these findings in humans. They studied several hundred older adults with normal cognition, mild cognitive impairment and Alzheimer’s disease. The work suggests that measurement of CSF proteins may have a similar predictive value. However, while the accuracy of the prediction is reasonably good, improvements will be required before this technique could have widespread clinical applicability. Further, the desire to provide a screening test for Alzheimer’s disease would require the availability of a treatment that would slow or stop the pathological processes important to the progression of the disease. At this time, such a treatment intervention does not exist.
There has also been significant media attention regarding the ligand-bound PET scans, which are nuclear medicine scans that would allow imaging of amyloid in the brain. These types of scans are not currently available and have not yet been proven to have clinical utility. Dr. Holtzman’s lab has utilized this type of imaging to validate the findings from CSF protein measurements.
Pathological studies suggest that by the time a person is developing early Alzheimer’s disease, amyloid pathology has already been established in many regions of the brain. It remains controversial whether this amyloid protein is pathogenic in and of itself or whether it simply represents a marker of other pathological processes in the brain, such as inflammation, microvascular changes, or changes in the levels of chemical signals necessary to ensure the continued health of neurons. Scientific evidence from pathological studies, animal models of Alzheimer’s disease and basic cellular or biochemical studies exists to support both views. Future research trials of medications directed against different proposed pathological mechanisms will clarify which of these are relevant to the manifestations of Alzheimer’s disease in humans.
Dr. Holtzman has provided important advances in the field of Alzheimer’s disease research and will continue to do so. As discussed above, the two major research efforts focus upon early detection of those at risk for the disease and the development of compounds or interventions that slow or stop the pathological changes that cause the disease. The situation is completely analogous to medicine’s approach to high blood pressure, where the goal is to identify the condition and institute treatment before a person has a heart attack or stroke.
-- Brendan Kelley, MD
The Case Western researchers reasoned that a molecule that might promote clearance of amyloid may have a beneficial effect in the disease pathogenesis. They used a mouse model of Alzheimer’s disease that
