Alzheimer’s disease: First steps to stem the epidemic

AD guidelines updated for the first time in decades; NIH-supported revision also proposes staging of disease, potential use of biomarkers

Lloyd Dunlap
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CHICAGO—For the first time in 27 years, clinical diagnostic criteria forAlzheimer's disease (AD) dementia have been revised, and research guidelinesfor earlier stages of the disease have been characterized to reflect a deeperunderstanding of the disorder. The National Institute on Aging/Alzheimer'sAssociation Diagnostic Guidelines for Alzheimer's Disease outline some newapproaches for clinicians and provide scientists with more advanced guidelinesfor moving forward with research on diagnosis and treatments.
Dr. Maria Carrillo, senior director, medical and scientificrelations at the Alzheimer's Association, refers to the current situation as an"epidemic" and a "crisis." Association figures show that while breast cancer,prostate cancer, heart disease, stroke and HIV have declined between 2000 and2008 from 3 percent to 29 percent, AD has increased by 66 percent. In terms ofresearch dollars, federal funding for cancer research is about $6 billionannually, cardiovascular disease research is about $4 billion and HIV/AIDS isabout $3 billion each year, the association observes, while AD research fundingin fiscal 2011 will be just $480 million.
Prospectively, Carrillo notes that the number of peopleafflicted with AD will likely triple from 3 million today to 9 million by 2050.And with AD, it is not just those with the disease who suffer, it's also theircaregivers. In 2010, 14.9 millionfamily and friends provided 17 billion hours of unpaid care to those with ADand other dementias. The economic value of this unpaid care totaled $202.6billion. AD is the only cause of death among the top 10 in America without away to prevent, cure or even slow its progression.
The new guidelines (see sidebar) represent the first updatessince 1984, when the fear was that an Orwellian future lay in wait. They weredeveloped by expert panels convened last year by the National Institute onAging, part of the National Institutes of Health (NIH), and the Alzheimer'sAssociation. Preliminary recommendations were announced at the association'sInternational Conference on Alzheimer's Disease in July 2010, followed by acomment period. The panels purposefully left the guidelines flexible to allowfor changes that could come from emerging technologies and advances inunderstanding of biomarkers and the disease process itself.
The original criteria were the first to address the diseaseand described only later stages, when symptoms of dementia are already evident.The assumption was that people free of dementia symptoms were disease-free.Diagnosis was confirmed only at autopsy, when the hallmarks of the disease,abnormal amounts of amyloid proteins forming plaques and tau proteins formingtangles, were found in the brain. The updated guidelines cover the fullspectrum of the disease as it gradually changes over many years. They describethe earliest preclinical stages of the disease, mild cognitive impairment anddementia due to AD pathology. Importantly, the guidelines now address the useof imaging and biomarkers in blood and spinal fluid that may help determinewhether changes in the brain and those in body fluids are due to AD. Biomarkersare increasingly employed in the research setting to detect onset of thedisease and to track progression, but cannot yet be used routinely in clinicaldiagnosis without further testing and validation. 
According to Carrillo, the Alzheimer's Association'sResearch Roundtable provided the original impetus to relook at the ADdiagnostic criteria. The roundtable is a consortium of scientists from thepharmaceutical, biotechnology, diagnostics, imaging and cognitive testingindustries and senior staff and advisors from the association. Begun in 2003with four sponsors, the roundtable now includes more than 20 corporatesponsors, each of whom sends several senior scientists to the roundtable tobenefit from the state-of-the-field scientific presentations, collegialinteractions and networking opportunities. Additional attendees includeinvestigators from academia and such government organizations as the U.S. Foodand Drug Administration, the European Medicines Agency and the NIH.
Roundtable members explored a broadrange of AD science topics, including: new data and technologies that mayimprove the diagnosis of AD, especially in its earliest and mildest stages; neuropsychologicaltesting, genetic factors and biochemical and neuroimaging biomarkers that couldcontribute to an earlier and more accurate AD diagnosis; and lessons learnedabout clinical trial design that may help shape future clinical trials of drugsaimed at slowing or stopping the progression of AD. The outputs of roundtablemeetings are published as articles in the Alzheimer's Association's journal, Alzheimer's & Dementia.
To facilitate clinical trials, the association's TrialMatchprovides a free service by Internet and telephone that makes it easy for peoplewith AD, caregivers, families and physicians to locate and connect to ADclinical trials based on personal criteria (diagnosis, stage of disease) andlocation. It is the first service of its kind in AD, Carrillo notes. More than40,000 people have visited the website. Nearly 2,500 people have been referredto matched clinical study sites. As a result, there have been at least 101 newenrollments into AD clinical trials.
"We believe that the publication of these (guidelines) is amajor milestone for the field," says Dr. William Thies, chief medical andscientific officer at the Alzheimer's Association. "Our vision is that thisprocess will result in improved diagnosis and treatment of Alzheimer's, andwill drive research that ultimately will enable us to detect and treat thedisease earlier and more effectively. This would allow more people to livefull, rich lives without—or with a minimum of—Alzheimer's symptoms."

Alzheimer's Disease: The new diagnostic criteria
To reflect what has been learned, the National Institute onAging/Alzheimer's Association Diagnostic Guidelines for Alzheimer's Diseasecover three distinct stages of the disease:

Preclinical: The stage for which theguidelines only apply in a research setting describes a phase in which brainchanges, including amyloid buildup and other early nerve cell changes, mayalready be in process without evidence of clinical symptoms. In some people,amyloid buildup can be detected with positron emission tomography (PET) scansand cerebrospinal fluid (CSF) analysis, but it is unknown what the risk forprogression to AD dementia is for these individuals. Use of these imaging andbiomarker tests at this stage is recommended only for research. Thesebiomarkers are still being developed and standardized and are not ready for useby clinicians in general practice.
Mild Cognitive Impairment (MCI): Primarily for research, the guidelines for the MCIstage also clarify existing guidelines for use in a clinical setting. The MCIstage is marked by symptoms of memory problems, enough to be noticed andmeasured, but not compromising a person's independence. People with MCI may ormay not progress to AD dementia. Researchers will particularly focus onstandardizing biomarkers for amyloid and for other possible signs of injury tothe brain. Currently, biomarkers include elevated levels of tau or decreasedlevels of beta-amyloid in the CSF, reduced glucose uptake in the brain asdetermined by PET and atrophy of certain areas of the brain as seen withstructural magnetic resonance imaging (MRI).
Alzheimer's Dementia:These criteria apply to the final stage of the disease, and are most relevantfor doctors and patients. They outline ways clinicians should approachevaluating causes and progression of cognitive decline. The guidelines alsoexpand the concept of AD dementia beyond memory loss as its most centralcharacteristic. A decline in other aspects of cognition, such as word finding,vision/spatial issues and impaired reasoning or judgment may be the firstsymptom to be noticed. At this stage, biomarker test results may be used insome cases to increase or decrease the level of certainty about a diagnosis ofAD dementia and to distinguish it from other dementias, even as the validity ofsuch tests is still under study for application in everyday clinical practice.

Lloyd Dunlap

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