Recent research in Alzheimer’s disease has scientists rethinking their strategies for diagnosis and treatment.
Patients progress through increasingly severe stages of Alzheimer’s disease. The process often starts with memory problems, particularly difficulty in learning and recalling new information. As the disease progresses, other cognitive functions become impaired, such as the brain’s “executive function”—the ability to plan, make choices, and inhibit inappropriate behavior.
Pathologically, compounds associated with the disease first appear in discrete areas of the brain involved in memory processing, specifically the entorhinal cortex and hippocampus. By the time a person is symptomatic and can be diagnosed with Alzheimer’s, nerve cells in these areas are virtually gone. Thus, treating someone with established Alzheimer’s—that is, replacing lost nerve cells—is an uphill battle. Stem cell therapies may someday be used to accomplish this goal, but that day is a long way off.
In the meantime, attention has shifted from those with established Alzheimer’s disease to mildly affected patients and even cognitively normal people who are at risk. This strategy is based on the realization that Alzheimer’s disease starts many years before it is clinically diagnosed. During a long asymptomatic phase, a person appears healthy or only slightly impaired. If such a person could be identified during the early phase as someone who will go on to symptomatic disease, therapies could be directed at stopping progression and preventing further nerve cell death.
Determining who’s at risk
We have three tools available for identifying at-risk people: neuropsychological evaluation, imaging of the brain and identification of markers of Alzheimer’s disease in cerebrospinal fluid (CSF). Neuropsychological testing identifies those with early memory problems, which patients may not recognize. Brain imaging can reveal whether the entire brain or specific areas targeted in Alzheimer’s disease are shrinking due to nerve cell loss. Imaging can also identify the buildup in the brain of amyloid, a protein characteristic of Alzheimer’s disease. Thus it is possible to determine if this protein is already accumulating long before a person develops symptoms.
Alzheimer’s research groups at the University of Minnesota and Washington University School of Medicine in St. Louis are performing independent longitudinal studies in which they follow cognitively normal people and those with mild memory problems as they age. At death, a pathological diagnosis can be made via autopsy. The Washington University news release "Brain Damage Found in Cognitively Normal People with Alzheimer’s Marker" outlines the type of work that is being done to establish markers in CSF that may be associated with these presymptomatic people. The University of Minnesota study is profiled in the Star Tribune story "Nun Study Returns to Minnesota, Where Scientists Plan to Research Alzheimer’s, Dementia."
Alois Alzheimer, the first to describe the disease that now bears his name, identified two distinctive brain pathologies: one was the presence of “plaques,” which we now know contain amyloid. The other he called “tangles,” which we now know involve a protein called tau. Both of these proteins can be found in CSF in presyptomatic Alzheimer patients. As the disease progresses, beta-amyloid 42, a fragment of the amyloid protein, is reduced in CSF. In contrast, tau appears later in the disease progression and gradually increases. Thus the ratio of these two substances can be a marker of disease progression.
Where does all this leave us? Using neuropsychological testing, imaging and CSF markers, it is possible to identify those at risk for developing fullblown Alzheimer’s. The problem is that progression may take years—too long if one wants to test a drug designed to arrest this progression.
My wife, Marilyn Albert, a professor of neurology at Johns Hopkins University, is an expert on studying these presymptomatic people. She suggests that the following sequence may be more efficient. Those with mild memory impairment will be identified by neuropsychological testing and by imaging of amyloid. Subsequent progression will be monitored by changes in cognitive testing, imaging of brain volumes and markers in CSF. Thus a selected group of those at risk can be used to evaluate potential drugs to modify Alzheimer’s disease when it is still possible to change the course of the disease.