Disorientation. Memory loss. Postmortem plaques and tangles. These clinical and pathological features define the conventional notion of Alzheimer disease. However, in recent decades, the meaning of AD has undergone a transformation. AD is moving from a disease diagnosed with tests initiated once patients complain of memory loss, to one where risk of future disability is predicted in asymptomatic people by neuroimaging, fluid biomarkers, and data modeling done on networked computers. In short, AD diagnosis is moving from the bedside to the desktop, suggested Jason Karlawish, a bioethicist at the University of Pennsylvania, Philadelphia, in a plenary talk that offered a humanistic perspective to set the stage for the detailed basic and clinical science presentations at the International Conference on Alzheimer’s Disease (ICAD) held 10-15 July in Honolulu, Hawaii.
Karlawish laid out clinical and policy implications of this changing view of AD, concluding with a plea to clinicians not to let stacks of brain images and test scores overshadow the patients and caregivers. One area where rapport with patients is particularly critical—and often lacking—is clinical testing of potential therapeutics. To help speed up trials that are becoming increasingly technology-intensive, the Alzheimer’s Association, which sponsors the annual ICAD meetings, has launched TrialMatchTM. This is a free and confidential online and phone-based system that helps match interested participants with local research studies. In this newest age of AD, this is how patients get invested and become part of a shared effort to steer the age of desktop medicine toward better treatments.
In his plenary, Karlawish cited a 1999 paper by researchers at Mayo Clinic, Rochester, Minnesota (Petersen et al., 1999) that, in his view, ushered in the most recent era of AD. Previously, AD was a model of bedside medicine—“a careful clinical history initiated with a chief complaint and concluding with anatomic examination of the brain,” Karlawish said. Nowadays, AD is no longer characterized by images of static pathology, but instead by charts depicting how a person’s risk of future disease changes with time.
Karlawish explored implications of the evolving meaning of AD by looking at other risk-factor diseases. Consider dyslipidemia. People with this condition have high levels of the so-called “bad” (aka low-density lipoprotein, or LDL) cholesterol, which puts them at elevated risk for future heart attack. Diagnosis is easy. Physicians sitting at a desktop computer can simply enter patient data (age, gender, total cholesterol, and so forth) into a Web-based risk calculator, estimate the person’s 10-year risk of having a heart attack and, importantly, prescribe medications that can reliably lower this risk. This latter criterion has not yet been met for AD. Another key feature of risk-factor conditions that AD lacks is a “discrete clinical event” that is part and parcel to how one defines the disease. The metrics that define AD are “not as clear as a bone fracture or heart attack or stroke,” Karlawish said. Given AD’s insidious onset, it can be hard to define endpoints for clinical trials that test potential AD treatments.
Nevertheless, as AD heads toward a risk model, decisions about who should and should not receive treatment may get prickly. “Why should someone who is just below the threshold of risk of persons treated in the trial, not have access to the treatment?” Karlawish said. At a more personal level, the risk factor approach presents challenges because people tend to be “very present-biased in our decision making,” Karlawish said. “We prefer to enjoy a tasty, high-fat snack and consequent weight gain and risk of diabetes, to a less pleasurable, future-oriented activity such as exercise to reduce the risk of diabetes.”
Karlawish closed by describing how economic debates over costs of risk assessments and treatment over many years could come to “replace the heart-wrenching stories of suffering patients.” He appealed to attendees not to let this happen—to be “unified in our resolve that we do not forget the patients who started us on this journey into this (most recent) age of AD.” (For more, see Karlawish plenary text).
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Indeed, patients are indispensable for advancing AD research, perhaps nowhere as poignantly as in the realm of clinical trials. This is where TrialMatchTM comes in. “If we have the treatment out there, sitting in a test tube, but we can’t get it into people to test its efficacy, then the FDA will not approve it,” said Ron Petersen of the Mayo Clinic in Rochester, Minnesota, in an ICAD press briefing. At least 50,000 volunteers (with and without AD) are needed for more than 100 trials currently underway to test some 90-100 experimental AD compounds, Petersen said. Reisa Sperling sees patients and directs AD clinical trials at Brigham and Women’s Hospital in Boston. In her experience, “we have a huge number of studies available for every stage of AD, and yet all of them are slow to enroll.” She blames lack of awareness on the part of both physicians and families for this problem. “We need get trial information to [primary care physicians] in a way they can use when they have only seven minutes with a patient in their offices,” Sperling said.
As for patients and caregivers, even those keen on participating in research often have no idea how to start looking for such opportunities. TrialMatchTM at present contains about 150 trials, including all ongoing AD trials in the U.S. government’s ClinicalTrials.gov repository, as well as a few others, said William Thies of the Alzheimer’s Association, which created the confidential website and phone system. By providing basic information including their age, gender, where they live, education level, clinical diagnosis, and medication use, patients can get connected with trials that may be a good fit for them. In addition to the online format, the service offers matching over the phone (1-800-272-3900) from 7 a.m. to 7 p.m. U.S. Central Time, Monday through Friday. Based on patient profiles and trial eligibility criteria, the association will contact potential participants about trial options and connect them with experts at those sites. Beyond the fringe benefits of research participation—i.e., access to cutting-edge research, close monitoring of health—participants gain from simply knowing they are being proactive. “Being a part of trials is really a heroic act,” Thies said. “It’s contributing your essential self.”—Esther Landhuis.
- Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999 Mar;56(3):303-8. PubMed.
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