Updates to Diagnostic Guidelines for Alzheimer’s Disease
An expert panel charged by the US National Institutes of Health National Institute on Aging and the Alzheimer’s Association has proposed revised clinical diagnostic criteria for dementia due to Alzheimer’s disease for the first time since 1984,1-3 as well as new research criteria for the predementia stages of Alzheimer’s disease. The changes reflect new scientific understanding that Alzheimer’s disease has a lengthy predementia prodrome as well as new research information about the potential significance of biomarkers.
Clinical Points
- The new guidelines for dementia and mild cognitive impairment are offered for clinical use, whereas the preclinical guidelines were developed for research purposes.
- New guidelines were intentionally made both provisional and flexible to allow for future advances coming from emerging technologies and understanding of biomarkers.
The original 1984 clinical criteria for Alzheimer’s disease required the presence of a dementia syndrome and were based exclusively on clinical symptoms: according to a literal interpretation of these criteria, people free of dementia did not have Alzheimer’s disease.4 To encompass the full continuum of the disease as we now understand it, the expert panel recently developed diagnostic guidelines for mild cognitive impairment (MCI) and “preclinical” stages of Alzheimer’s disease, as well as for dementia due to Alzheimer’s disease. The dementia and MCI guidelines are offered for clinical use, whereas the preclinical guidelines were developed for research purposes and were intentionally made both provisional and flexible to allow for future advances coming from emerging technologies and understanding of biomarkers.
Biomarkers are defined as physiological, biochemical, or anatomic parameters measured in vivo that reflect specific features of disease-related pathophysiology. Current evidence suggests that some Alzheimer’s disease biomarkers may begin to be abnormal 10 to 20 years before clinical symptoms are evident. The guidelines split biomarkers of Alzheimer’s disease into 2 categories: (1) markers of brain amyloid and (2) markers of neuronal injury. Currently, the most readily available biomarkers for amyloid predominantly include amyloid positron emission tomography (PET) imaging and cerebrospinal fluid measures of amyloid β (Aβ). The biomarkers of neuronal degeneration or injury include measures of cerebrospinal fluid tau (both total and phosphorylated tau), brain tissue metabolic activity as measured by fluorodeoxyglucose (FDG) uptake changes in PET scan, and atrophy as measured on structural magnetic resonance imaging (MRI) in patterns consistent with Alzheimer’s disease. A more comprehensive list of the major biomarkers under investigation in Alzheimer’s disease is provided in Table 1.2 Although biomarkers are increasingly employed in the research setting, their routine clinical use requires further testing and validation.
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THE PRECLINICAL STAGE OF Alzheimer’s Disease
The preclinical stage of Alzheimer’s disease describes the phase when clinical symptoms are not yet evident, but biological markers of the disease are present. Given the absence of clinical symptoms, biomarkers are necessary to establish the presence of the disease process, including amyloid buildup and other early nerve cell changes. In some individuals in the preclinical phase of Alzheimer’s disease, change in glucose utilization or presence of amyloid deposition and cerebrospinal fluid levels of amyloid or tau proteins can already be detected. Intervention at this stage may be more likely to achieve disease modification.
Because the biomarker data are not fully developed or standardized, the risk for progression to Alzheimer’s dementia is unknown for these individuals in the preclinical stage. Thus, use of these imaging and biomarker tests at this stage are recommended only for research at this time.
Mild cognitive Impairment DUE TO Alzheimer’s Disease
The guidelines for MCI due to Alzheimer’s disease, although largely intended for research purposes, expand on existing clinical guidelines. The new criteria classify MCI into 3 categories: (1) MCI core clinical criteria, (2) MCI due to Alzheimer’s disease (intermediate or high probability), and (3) MCI unlikely due to Alzheimer’s disease (Table 2).2 While the presence of core clinical symptoms defines the presence of MCI, testing of biomarkers is used to further gauge the probability that the MCI is an early manifestation of Alzheimer’s disease. The MCI core clinical criteria are defined by symptoms of cognitive impairment (typically memory problems) that are evident and measurable but do not compromise independence. Objective evidence of impairment is present, as measured by cognitive testing, in 1 or more cognitive domains. Scores 1 to 1.5 standard deviations below the mean of scores of age-and education-matched peers are typical, but these thresholds are not to be used as cutoffs to make the diagnosis. These guidelines do not specify use of any particular test and allow for clinician flexibility. Cognitive concern expressed by the patient, informant, or clinician is also incorporated in the diagnostic guidelines. To increase the likelihood that the underlying disease is a neurodegenerative disorder consistent with Alzheimer’s disease, it is necessary to rule out other systemic or brain diseases that could account for the decline in cognition such as vascular, traumatic, medical, or depressive conditions. This evaluation can be derived from further historical information and other tests including neuroimaging, laboratory studies, or formal neuropsychological testing. A summary of these criteria is outlined in Table 3.2
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Not all people with MCI will progress to Alzheimer’s dementia, and, thus, to establish an intermediate or high probability of MCI due to Alzheimer’s disease, biomarkers are used to evaluate the underlying etiology of clinical symptoms. Recommended biomarker tests include measures of elevated levels of tau or decreased levels of Aβ in the cerebrospinal fluid, reduced glucose uptake in the brain as determined by FDG-PET, and atrophy of certain areas of the brain as measured with structural MRI. Although intended primarily for the research setting, these tests may be applied in specialized clinical settings as a diagnostic adjunct to help determine possible causes of MCI symptoms.
Alzheimer’s Disease DEMENTIA
The 1984 clinical criteria for Alzheimer’s disease remain the foundation of the diagnosis in that progressive cognitive decline must be associated with impairment in functioning in daily activities. The new guidelines expand the concept of Alzheimer’s dementia beyond memory loss as its primary characteristic and incorporate the possibility that a decline in other aspects of cognition, such as anomia, visuospatial impairment, and impaired executive functioning may be the first symptoms to be noticed. Biomarkers may be used to enhance the specificity of the diagnosis. The new guidelines define all-cause dementia (Table 4) and then classify Alzheimer’s disease dementia into 3 categories: (1) probable Alzheimer’s disease dementia (Table 5), (2) possible Alzheimer’s disease dementia (Table 6), and (3) probable or possible Alzheimer’s disease dementia with evidence of supportive biomarkers. The first 2 categories are intended for clinical use, and the third is intended for research purposes at this time. Like MCI, biomarkers are used to increase or decrease the level of certainty that Alzheimer’s disease is the cause of the dementia. As the understanding and validity of these tests improve, their application in clinical practice will increase.
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PRACTICAL IMPLICATIONS
The new guidelines have limited practical implications at this time until more is known about the predictive and diagnostic values of various biomarkers. However, broadening the scope of dementia due to Alzheimer’s disease to include nonmemory cognitive decline will help clinicians appreciate the heterogeneity of the clinical presentation. Making it clear that there is a lengthy preclinical prodrome will help all of us better understand the natural history of the disease. While biomarker use is proposed only for research purposes, clinicians can consider some biomarker test results to help with the level of certainty of the clinical diagnosis. In our practice, clinically ambiguous patients may undergo FDG-PET, cerebrospinal fluid analysis, and sometimes genotyping to clarify diagnosis. Although our practice does not rely on volumetric imaging to aid in diagnosis, some specialists have incorporated this test. Amyloid PET imaging techniques are now under US Food and Drug Administration review and may become available clinically, which will further enhance the ability to render more specific dementia diagnoses.
The early, predementia stages of Alzheimer’s disease probably will provide a significant opportunity for therapeutic intervention, as intervention at this stage may be more likely to achieve disease modification. Thus, the new guidelines represent an essential step forward toward eradicating this disease.
REFERENCES
1. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292. PubMed doi:10.1016/j.jalz.2011.03.003
2. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):270-279. PubMed doi:10.1016/j.jalz.2011.03.008
3. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34(7):939-944. PubMed
4. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263-269. PubMed doi:10.1016/j.jalz.2011.03.005
Author affiliations: Dr Yaari is associate director of the Memory Disorders Clinic of Banner Alzheimer’s Institute and a clinical professor of neurology at the College of Medicine, University of Arizona, Tucson. Dr Fleisher is associate director of Brain Imaging at the Banner Alzheimer’s Institute, a neurologist at the Institute’s Memory Disorders Clinic, and an associate professor in the Department of Neurosciences at the University of California, San Diego. Dr Tariot is director of Banner Alzheimer’s Institute and a research professor of psychiatry at the College of Medicine, University of Arizona, Tucson.
Potential conflicts of interest: Dr Yaari is a consultant for Amedisys Home Health. Dr Tariot is a consultant for Acadia, AC Immune, Allergan, Eisai, Epix, Forest, Genentech, MedAvante, Memory Pharmaceuticals, Myriad, Novartis, Sanofi-Aventis, Schering-Plough, and Worldwide Clinical Trials; has received consulting fees and grant/research support from Abbott, AstraZeneca, Avid, Baxter, Bristol-Myers Squibb, GlaxoSmithKline, Elan, Eli Lilly, Medivation, Merck, Pfizer, Toyama, and Wyeth; has received educational fees from Alzheimer’s Foundation of America; has received other research support only from Janssen and GE; has received other research support from National Institute on Aging, National Institute of Mental Health, Alzheimer’s Association, Arizona Department of Health Services, and Institute for Mental Health Research; is a stock shareholder in MedAvante and Adamas; and holds a patent for “Biomarkers of Alzheimer’s Disease.” Dr Fleisher reports no conflicts of interest related to the subject of this article.
Funding/support: None reported.
