In fact, none of the biomarkers or imaging modalities included in the ADNI study has been validated in large numbers of patients. Without validation, none can be used as a primary outcome in drug trials, leaving researchers to fall back on imprecise cognitive measures for their main assessment of efficacy, Dr. Trojanowski said.
“If, instead, we could show that biomarkers were changing during a drug trial, in the same way that we can show changes in cholesterol or blood sugar in response to drugs, then we could have a very, very powerful new tool,” Dr. Trojanowski said.
ADNI is an important study in a worldwide effort to discover clinical markers of AD, the investigators agreed. Australia, Japan, and some European countries are undertaking similar projects. Termed “World Wide ADNI,” this informal network will facilitate the performance of international treatment trials and, ultimately, the approval of disease-modifying treatments worldwide. Researchers from these studies are working to harmonize the methodologies, increasing the statistical power of their combined results, Dr. Trojanowski said.
Dr. Weiner noted before ADNI has evaluated even a single patient, it has already changed the way scientists are attacking AD research. Most AD biomarker and imaging research now consists of small studies, each with a unique methodology. Researchers hold their information close to the vest until publication, with months and sometimes years elapsing between the study's conclusion and the sharing of its results.
Not only will all 57 ADNI study centers follow consistent protocols for all the imaging studies and biomarker collection, but also those protocols will be available to any researcher pursuing an independent study. The sharing of methodology and, eventually, of results, is another of ADNI's unique characteristics, Dr. Weiner said. All data will be sent to centralized storage hubs, which will be freely available to anyone–researcher, physician, patient, or family member–who applies for access. The information won't be subject to embargo; scans and biomarker measurements will be available online as soon as they're processed.
“We are going to share everything we get in an unprecedented way. Allowing other researchers to have immediate access to the data is going to maximize this study's effect.”
For more information, including filing a request for access to eventual data, physicians should go to www.adni-info.org
Availability of Markers Bound to Raise Thorny Questions
The first benefits of biologic or imaging markers would be felt in research, where they could hasten the development of disease-modifying drugs. But once those drugs are available, such markers also will be used to identify people most likely to benefit from them and could become part of screening to identify those at risk of developing Alzheimer's disease years before symptoms emerge.
“If and when these therapies become available, who will get them?” asked Dr. Ronald Petersen, director of the Mayo Clinical Alzheimer's Disease Research Center, Rochester, Minn. “Are we going to give them to people with memory impairment first? Or ultimately to those who are asymptomatic but who are at risk? And how will we know who these people are?”
Dr. Petersen hopes eventual findings from his own study help answer some of these questions. He is the lead investigator for the Mayo Clinic Study of Aging, a longitudinal study of 2,000 people aged 70–89 years. The National Institute on Aging provides the study's $1.5 million annual funding package.
In addition to characterizing what brain aging looks like, the study will examine the influence of genetics, family history, and medical comorbidities on the risk of developing Alzheimer's. It will combine this information with cognitive testing, biomarkers, and different imaging modalities in an effort to construct a multivariate model that could predict which apparently healthy people will develop mild cognitive impairment and who might then progress to Alzheimer's.
The Clinical Study of Aging is not related to Alzheimer's Disease Neuroimaging Initiative (ADNI), but both aim to identify the most informative biomarkers and imaging techniques for AD. Eventually, Dr. Petersen predicted, data from both studies might be used to construct a layered screening technique that could identify those who would benefit from early disease prevention or disease-modifying therapy.
Such a model probably would progress from least- to most-invasive testing depending on individual risk, he said. Patients flagged as moderate or high risk might then receive a functional brain scan and a lumbar puncture for cerebrospinal fluid marker sampling. Amyloid imaging with Pittsburgh compound B might also be part of the work-up.
In stratifying patients for treatment, “Earlier may be better than later,” said Dr. John Morris, director of the Alzheimer's Disease Research Center at Washington University, St. Louis. “We know that by the time people start experiencing memory problems, the neuropathological lesions of AD [plaques and tangles] already are present in the brain and, in brain regions vulnerable to AD, nerve cells and their synapses have been lost. Even if truly effective drugs are developed, giving them to people with symptomatic AD–even to those with mild cognitive impairment–may be too late because, by the time symptoms appear, the brain already has been damaged.”