The prevalence of AD varies among studies for a variety of reasons. A major reason is the thresholds used to define the clinical conditions. In older work, there was a sharp demarcation set between normal cognition and dementia [7
]. This was a reasonable approach and led to the boundary being set at a point on the cognitive continuum where a significant cognitive impairment was present to ensure the inclusion of only those subjects who were unquestionably impaired. As such, projects like the FHS counted moderate to severe cases as dementia, which then led to somewhat lower estimates of prevalence [7
At the other extreme, investigators like those from the EBSHP estimated the overall prevalence of dementia to be 10.3% but very age related such that, in the 85 year and older group, the estimate was 47.0% [22
]. A salient feature of that study was the heavy reliance on objective cognitive testing to determine the presence or absence of dementia. The other feature of dementia requiring an accompanying functional impairment was minimized in the EBSHP due to the difficulty in assessing that element of performance. The result of this decision was to place a heavy emphasis on cognitive testing and less on clinical judgment or the use of instruments to assess functional impairment. This decision led to a broader range of persons being counted as dementia cases.
The EBSHP prevalence figures were published in 1989, and, today, the issue of threshold used in that study could very well relate to the construct of MCI. MCI, particularly of the type that is thought to be the prodromal stages of AD, constitutes a memory impairment beyond what one would expect for age in the setting of relatively preserved daily function [31
]. Therefore, since the EBSHP investigators relied heavily on paragraph recall and discounted the role of functional impairment, their definition of dementia embraces the essence of what is being called amnestic MCI today. Hence, a difference between the FHS and the EBSHP was, in part, one of threshold of degree of cognitive impairment set for dementia.
The issue of diagnostic thresholds relates to the constructs of sensitivity and specificity. As one moves the threshold back to lesser degrees of cognitive impairment, the increased sensitivity will capture larger numbers of persons; however, specificity will be sacrificed. That is, while many persons with the amnestic form of MCI of a degenerative etiology are likely to be in the early stages of the AD process, not all will progress to AD [32
]. Therefore, from a prevalence perspective, the numbers are larger, but they may be overestimates due to over-inclusion of persons who may not have AD as the underlying pathophysiologic substrate. Alternatively, as the threshold is moved toward a greater degree of cognitive impairment, the accuracy of the diagnosis with respect to correlating with underlying AD pathophysiology is higher, and consequently, specificity is high, but it is also likely that some early cases of true AD may have been missed (sensitivity is low).
Recent efforts are underway to address the problem of thresholds of cognitive impairment by linking the clinically milder cases such as those with amnestic MCI with imaging measures and biomarkers to enhance the specificity that a given clinical condition represents the underlying pathophysiology of AD [33
]. One project directed toward this goal is the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which is a public-private partnership designed to recruit very mildly impaired subjects and predict who will progress to the dementia stage of AD through the use of neuroimaging and fluid biomarkers (in cerebrospinal fluid, plasma, or serum) [36
]. This effort has been underway for approximately 5 years, and interesting data regarding the enhancement of clinical specificity through the use of imaging and other biomarkers have been reported [33
]. The initial clinical focus of ADNI has been amnestic MCI and more recent iterations of this study have emphasized milder degrees of memory impairment. A similar effort in Europe, the DESCRIPA study, is evaluating the role of multiple predictors of progression in MCI [38
The challenge for epidemiologic studies lies in the implementation of these newer neuroimaging and biomarker techniques on a large scale. These measures tend to be quite expensive and may not be available in many epidemiologic settings and, consequently, are often deemed not practical. As will be discussed below, the MCSA, however, is an attempt to address these issues through a population-based random sample of non-demented subjects, employing state-of-the-art neuroimaging and biomarker measures to a subset of subjects to determine how these measures perform in the general community setting [39
]. Previous epidemiologic studies done at the Mayo Clinic using the medical records-linkage system of the Rochester Epidemiology Project likely had lower sensitivity at picking up the earlier stages of dementia [40
Another issue that may influence the estimation of prevalence in the community is the underlying definition of AD. Over the past several decades, AD has been defined as a clinical-pathologic entity [41
]. While that was a reasonable definition in the 1980s, this approach is a source of confusion today. More recent attempts to reformulate the constructs propose a clinical spectrum of cognitive impairment ranging from MCI through dementia and a corresponding pathophysiologic substrate believed to be responsible for the clinical symptoms. However, the 2 spectra are kept separate. Therefore, when one grafts this approach onto an epidemiologic study, one would discuss the prevalence of the clinical spectrum or the prevalence of the pathologic features of the disorder, and they may not overlap completely [43
]. Several studies have demonstrated the presence of the neuropathologic substrate for AD in the absence of clinical symptoms [45
]. Similarly, there are clinical studies of cognitive impairment consistent with a clinical diagnosis of AD in which the underlying neuropathology was variable [46
]. More recent studies employing molecular imaging techniques such as amyloid imaging will shed light on issues concerning the prevalence or at least the frequency of the amyloid substrate (abnormal amyloid deposition) in persons with and without clinical symptoms [49
]. These studies will yield an index of the prevalence of the amyloid component of the pathologic substrate of AD, and will shed light on the value of this pathologic feature in predicting the progression of AD pathology over time.
The MCSA is a population-based study of aging in Olmsted County, Minnesota. Initially, a random sample of 2,000 persons aged 70-89 years was recruited [39
]. Individuals known to be demented were enumerated and excluded from the prospective sample of non-demented subjects. The subjects each received a 3-part evaluation: clinical interview for medical history, family history, symptom onset and a corresponding interview with an informant; a cognitive assessment consisting of 9 tests in 4 cognitive domains yielding 4 domain scores and a composite z score characterizing the combination of all 4 cognitive domains, and an examination by a physician for medical history, a mental status examination and a neurological examination. The final clinical diagnosis was made by a consensus of the 3 evaluators. Based on this assessment, the prevalence figures for cognitively normal, MCI and dementia subjects were 75.0%, 14.0%, and 11.0%, respectively [52
]. With this diagnostic categorization as a baseline, the global z score representing the demarcation between MCI and dementia was −2.4. For the purpose of demonstrating the impact of moving the threshold between MCI and dementia on the prevalence of both conditions, the global z score was arbitrarily moved as shown in . When the z score was moved from −2.4 to −2.0, the prevalence of dementia increased to 13.0%. As the threshold was moved further, the prevalence numbers changed accordingly. Therefore, this exercise demonstrates the importance of threshold on the underlying prevalence of dementia. As one moves toward the inclusion of subjects with lesser degrees of cognitive impairment in the dementia spectrum, the prevalence of MCI decreases, and the prevalence of dementia increases correspondingly.
Fig. 3 The relative proportion of subjects classified as having dementia and MCI in the Mayo Clinic Study of Aging. Panel A demonstrates the current division between MCI and dementia as determined by a consensus conference. The composite cognitive z score is (more ...)
In summary, the estimate of prevalence of a condition such as dementia or AD can be complex. Since the diagnosis is made on a clinical basis, the implementation of variable sets of criteria can influence the rates. Similarly, in addition to the specific instruments and measures used, the thresholds for defining the various conditions can vary.
As is shown in , the threshold for dementia has moved over the years. The older studies characterize AD in the clearly established range [7
]. More recent studies, such as ADNI, are suggesting that, by adding imaging and fluid biomarkers to the clinical diagnosis of MCI, we will be able to characterize AD at an earlier stage. As is shown in , the criteria for MCI in the original ADNI project, now called “late MCI,” are marked by the arrow labeled “C.” In the next phase of ADNI, the “early MCI” stage will be implemented, and it will result in a movement of the threshold to the arrow labeled “D” in . The EBSHP may have anticipated these changes. The value of imaging and other biomarkers may vary depending on the level of clinical certainty [53
]. For example, biomarkers might become particularly important at the early MCI stage in making an etiological diagnosis of AD.
Fig. 4 A hypothetical threshold for differentiating mild cognitive impairment (MCI) from Alzheimer’s disease (AD). Arrow A represents the older studies of prevalence of AD. Arrow B represents more recent studies but still characterizing fully developed (more ...)
Finally, as the field moves toward an earlier identification of persons with dementia and AD, the prevalence estimates are likely to increase. The construct of MCI, particularly amnestic MCI of a presumed degenerative etiology, is very likely to represent the earliest clinical presentation of AD, and consequently, if we move the threshold back to include these cases, while maintaining the specificity of the outcomes through biomarkers, we will likely increase the prevalence of dementia and AD accordingly.