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Rationale for New Criteria
The National Institute on Aging and the Alzheimer's Association work group on diagnostic guidelines for Alzheimer's disease have updated the 1984 Alzheimer's disease criteria in four articles in the journal Alzheimer's and Dementia in 2011. In these, they describe new clinical criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to the AD pathophysiological process (MCI due to AD). Although these groups were not the first to update the 1984 criteria (see papers by Dubois and colleagues), they currently have the greatest consensus in the scientific AD community and are likely to have a lasting impact.
The new criteria were developed due to several factors that have changed since 1984:
The AD pathophysiological process likely starts years before cognitive changes and decades before onset of clinical dementia (figure 1). The concept of the 'AD pathophysiological process' is thus separated from 'AD dementia.'
Many patients whose cognition is not normal for age do not meet criteria for dementia.
Other causes of dementia are more likely mistaken for AD than are thyroid disorders and B12 deficiency.
Genetics of AD are better understood.
Biomarkers of AD are available in some centres.
New criteria are needed for research.
Specific treatments for the AD pathophysiological process are being developed; when these treatments are available it will be critical to know if patients have that process.
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Figure 1.
Postulated temporal lag between the deposition of amyloid β in amyloid plaques from an autopsy series and the development of clinical Alzheimer's disease (AD) dementia based upon three epidemiological studies (from Sperling et al).
There are three stages of AD:
Preclinical AD requires measureable changes in biomarkers and/or poor performance on challenging cognitive tests.
MCI due to AD manifests the first clinical changes. Patients and families notice mild changes in memory and other cognitive abilities; these changes can be detected through careful evaluation, but do not interfere with day-to-day activities.
Dementia due to AD is characterized by changes in two or more aspects of cognition and behaviour that interfere with function in everyday life.
One model of AD is that many factors combine to cause the accumulation of amyloid β (Aβ) in the brain, which in turn produces synaptic dysfunction, tangle formation, and neuronal death, ultimately leading to cognitive decline (Sperling et al,) (figure 2). Because events in this sequence likely take years or decades, there must be a prior 'preclinical' stage of AD (figure 3).
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Figure 2.
Hypothetical model of Alzheimer's disease (AD) pathophysiological cascade sequence (from Sperling et al).
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Figure 3.
Model of the clinical course of Alzheimer's disease (from Sperling et al). MCI, mild cognitive impairment.
Table 1 presents several currently used biomarkers of Aβ deposition or neurodegeneration. Markers of Aβ deposition include low cerebrospinal fluid (CSF) Aβ42 and positive positron emission tomography (PET) amyloid imaging. Markers of neurodegeneration include elevated CSF tau (both total and hyperphosphorylated tau), decreased metabolism in temporal and parietal cortex on flurodeoxyglucose (FDG) PET, and atrophy on MRI in temporal (medial, basal, and lateral) and medial parietal cortex. In clinical practice, one tends to divide the biomarkers by how they are obtained: structural MRI, PET, and CSF studies.
Although volumetric MRI analyses are not routinely available, we encourage all clinicians to look for qualitative patterns of atrophy in temporal (medial, basal, and lateral) and medial parietal cortex.
FDG PET scans show decreased metabolism in temporal and parietal cortex when the AD pathophysiological process has caused neurodegeneration. FDG PET scans are available to the clinician now (and are covered by Medicare in the USA). We do not, however, recommend using these scans routinely when the history, physical examination, cognitive testing, and structural imaging are all consistent with AD: it is simply not necessary. However, when one suspects an atypical neurodegenerative disease or the patient is younger than 66 years of age (when the prevalence of AD is similar to that of many other aetiologies), an FDG PET scan can help to distinguish AD from another disorder (such as dementia with Lewy bodies or frontotemporal dementia).
Several compounds that can identify Aβ deposition using PET are currently being used for research and/or are under commercial development, including Pittsburgh compound B and florbetapir. Because amyloid accumulation may occur years before clinical symptoms, PET identification of Aβ raises the possibility of identifying and treating patients with AD years before symptoms emerge—once a drug has been proven to be disease-modifying.
Standard CSF biomarkers for AD are Aβ42, total tau, and hyperphosphorylated tau. When all three markers are combined, the accuracy of the diagnosis is the highest, with sensitivity and specificity of 85–90%. Although CSF analysis is already commercially available (http://www.athenadiagnostics.com) and some clinicians use it to aid diagnosis, we view this test as promising but not yet ready for routine clinical practice.
Guided by these theoretical underpinnings, the new criteria are presented for all cause dementia, AD dementia, MCI due to AD, and—for research only—preclinical AD. (See figure 4 for an overall flow chart for the evaluation of a patient with cognitive impairment.)
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Figure 4.
Flow chart for the evaluation of a patient with cognitive impairment leading to the diagnosis of mild cognitive impairment (MCI) and dementia using the new guidelines, with references to the tables (T) and steps (S) in the text.
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