The National Institute on Aging (NIA) and the Alzheimer's Association (AA) on Tuesday proposed a new definition for Alzheimer's disease based on biological signs, rather than symptoms, for the purpose of research—but experts say the proposal could have unintentional ramifications in clinical practice as well.
The guidelines, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, update NIA-AA's 2011 diagnostic guidelines for the disease, MedPage Today reports, and "comes on the heels of FDA policy changes to consider approving Alzheimer's drugs on biomarker changes, not clinical benefit." However, Maria Carrillo, AA's chief science officer, cautioned that the proposed guidelines, while having "undergone intense scrutiny and an extended period of public comment," are at this stage only "a research proposal … not a finished product."
Understanding Alzheimer's disease
Alzheimer's disease is a type of dementia that traditionally has been defined as a clinical syndrome involving the progressive decline of cognitive abilities—particularly memory loss—that ultimately results in the loss of independence, MedPage Today reports. There is currently no proven treatment for Alzheimer's disease.
For both research and clinical purposes, the disease's current definition is based on memory problems and other symptoms. But NIA-AA and other researchers have pointed out that the current definition presents a problem for science: Individuals enrolled in Alzheimer's studies do not always have the disease—they could have other types of dementia or medical conditions that present with similar symptoms. In fact, according to MedPage Today, as many as 30% of individuals considered to have Alzheimer's do not have amyloid plaques and tau tangle, which are considered key biological indicators of the disease.
Researchers at NIA-AA hypothesized that the inaccurate sampling could be having an effect on research into the disease and finding a cure.
Scientists propose new framework for defining Alzheimer's disease
To improve the research pool for Alzheimer's disease studies, NIA and AA proposed a new framework for defining Alzheimer's disease based on biological signs, rather than a progression of symptoms.
Under the proposed framework, individuals with biomarker evidence of beta amyloid deposition and pathologic tau would be considered to have Alzheimer's disease for research purposes. Individuals who present biomarker evidence of amyloid deposition and a normal pathologic tau biomarker would not be considered to have Alzheimer's disease, but rather "Alzheimer's pathologic change."
According to MedPage, both Alzheimer's disease and Alzheimer's pathologic change under the proposed definition would be phases on the overall Alzheimer's continuum independent of clinical symptoms, such as memory loss. Meanwhile, under the proposed definition, "neurodegenerative biomarkers and cognitive symptoms—neither of which is specific to Alzheimer's disease—would be used only to stage severity, not to define the presence of the Alzheimer's continuum," MedPage reports.
The researchers in the framework cautioned that the update is intended "for observational and interventional research only, not routine clinical care." Physicians should continue using the symptom-based assessments to diagnose the disease, as the scans and tests used to assess the biomarker evidence of the disease are not yet validated for clinical diagnosis, the Associated Press reports.
One of the framework authors, Clifford Jack of Mayo Clinic, said, "Our hope is that, by defining the disease biologically, clinical trials will be far more effective than they have been in the past and will enroll only people who actually have the disease they're being treated for."
According to Jack, if the proposed definition is approved, individuals enrolled in disease-modifying trials will receive biomarker tests to validate their diagnosis. Jack said the proposed definition would "dramatically" increase the number of people considered to have the disease. About 5.7 million U.S. residents have Alzheimer's disease under the current framework for diagnosing the disease, according to AP.
Limitations and concerns
Some experts voiced concerns about implementing the new definition—if approved—and questioned the usefulness of the change from a research-based perspective, MedPage reports.
James Hendrix, a member of the AA's Research Roundtable, and colleagues, in a perspective acknowledged that implementing the proposal would present challenges. "Obtaining biomarkers by either [cerebrospinal fluid] or by imaging adds expense and burden to any study and involves invasive procedures and/or exposure to radiation," they wrote, adding that "PET imaging technology is often not readily available outside of major medical or research centers."
Kostas Lyketsos, professor of psychiatry and behavioral sciences at Johns Hopkins Medicine, raised the question of payment for biomarker testing. "A key open question is whether payers will reimburse for the biomarker tests proposed since they are costly and not very well standardized—at present only some of these tests are covered," he said. "CMS is finishing up a study that will test the utility of biomarker testing. The results will be key."
Definition could have clinical ramifications, experts say
While experts stressed that the guidelines are not designed for clinical use, some also warned that patients might misinterpret the meaning and significance of the NIA-AA proposal, MedPage reports.
George Grossberg, director of Geriatric Psychiatry, Department of Psychiatry & Behavioral Neuroscience at St. Louis University School of Medicine, said, "At present, [the proposed definition is] primarily a research construct, to make sure that subjects in Alzheimer's clinical trials do indeed, at least, all meet biomarker criteria for Alzheimer's Disease. In the office, whether for primary care physicians or even neurologists and geriatric psychiatrists, clinical diagnosis remains most important. Clinical diagnosis can be supported by biomarkers but biomarkers are not yet ready to be used exclusively in absence of clinical symptoms."
But Sam Gandy, professor of neurology at Mount Sinai Hospital, warned of the potential "scare factor" for patients who hear about the proposed framework. He said, "Application of this definition will cause the estimates of the prevalence of [Alzheimer's disease] to skyrocket. I think that the lay public penetration of the notion that there is a 'silver tsunami' that will bankrupt and cause enormous misery to millions of families. I do not see any upside to driving up the 'scare factor.'"
Susan Besser, a family practitioner at Mercy Medical Center, said, "If the general media gets hold of [the proposal], people will be flocking to the doors of their PCP to be tested for the biomarker." She added, "We are awhile before we determine if a) the biomarkers are predictable and b) if with the positive biomarkers there actually is a treatment."
Costantino Iadecola, chair of the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, said the proposal "needs to be communicated to the general public carefully," pointing out that "this definition does not provide diagnostic insights that can be used in the doctor's office at this time" (Marchione, AP/USA Today, 4/10; George, MedPage Today, 4/10; Sergel, MedPage Today, 4/11; Jack et al., Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 4/10).
How to deliver cost-effective Alzheimer's care
Over 5.3 million Americans currently suffer from Alzheimer’s disease and related memory disorders and the Alzheimer’s Association predicts this number to triple to 13.8 million by 2050.
To learn more about how leading memory disorders programs are allocating their resources, download our brief Building a Financially Successful Alzheimer’s Disease and Memory Disorders Program.