We found a strong relationship between the AD8, a brief, informant-based, dementia screening tool, and biomarkers of Alzheimer’s disease. Individuals with AD8 scores of ≥2 had a biomarker phenotype (positive PiB binding, low CSF Aβ42, high tau, high tau phosphorylated at threonine 181) consistent with Alzheimer’s disease. A positive AD8 screening test corresponded to lower performance on tests of episodic memory, supporting a clinical phenotype of Alzheimer’s disease. A brief informant-based dementia screening assessment such as the AD8 performs as well as the ‘gold standard’ for informant-based assessments, the CDR, in its relationship to biomarkers of Alzheimer’s disease, and it correlates more strongly than the MMSE and Short Blessed Test to CSF biomarkers of Alzheimer’s disease. Lastly, informant-based assessments provide superior sensitivity to the MMSE in detecting dementia and changes in biomarkers of Alzheimer’s disease, particularly at the early symptomatic stages.
Alzheimer’s disease is under-recognized and under-diagnosed in the community (Boise et al., 1999
; Meuser et al., 2004
). This may be due, in part, to the lack of brief measures that can discriminate normal ageing from very mild dementia. A number of brief screening measures (i.e. the MMSE) are already in use, but most are based on patient performance and are therefore unable to detect or quantify change from previous levels of function. Some performance-based measures are also insensitive to subtle changes in high functioning individuals (i.e. ceiling effects) who may score well within the normal range throughout the early stages of dementia. These same measures also may prevent detection of dementia in individuals with poorer lifelong abilities. Furthermore, many cognitive tests are culturally insensitive and may underestimate the abilities of African Americans and other minority groups (Lorentz et al., 2002
; Espino et al., 2004
; Parker and Philp, 2004
). The AD8 is without ceiling effects and is valid in assessing individuals regardless of age, gender, language, race or educational level (Galvin et al., 2006
Dementia screening has not been a routine medical practice, partly due to the lack of sensitive, specific and culturally sensitive means of detection. Published criteria for the diagnosis of Alzheimer’s disease (McKhann et al., 1984
) require standard assessments of patients, and more recent recommendations also include querying a knowledgeable informant (Dubois et al., 2007
). In a community study comparing individuals with mild cognitive impairment to determine who would progress to clinical dementia, only baseline functional impairment as measured by the CDR, without contribution from demographic, cognitive or neuroimaging variables, or mild cognitive impairment subtype, accounted for the differences in conversion rates across the two cohorts (Farias et al., 2009
). The investigators concluded that the degree of functional impairment at baseline, rather than test performance, is the most important predictor of conversion to dementia. Not only is the CDR sensitive to early symptomatic Alzheimer’s disease, but unlike the AD8 it provides sufficient information to stage dementia severity and monitor dementia progression. Due to the length of time required to complete the interview, however, the CDR is unlikely to be suitable for general clinical practice. The AD8 has been validated against the CDR and neuropsychological testing to detect dementia (Galvin et al., 2005a
, 2006, 2007a
). The value of the AD8 is that it not only is brief but corresponds to more detailed evaluations, neuropsychological testing and biomarkers of Alzheimer’s disease. However, it is designed primarily as a screening tool to identify those individuals at risk for a more extensive work-up for staging and differential diagnosis such as the CDR and/or neuropsychological testing. It is important to note that both informant-based methods, the AD8 and the CDR, are at least as good as any objective measures. Thus if simple screening is the aim, because the AD8 is comparable to the CDR both in direct comparison and in its relationship to biomarkers, it could be recommended for this simple goal on the basis of utility and brevity.
In parallel, there has been much effort to improve the detection of the underlying pathological basis of Alzheimer’s disease by developing biomarkers of disease that may represent manifestations of disease during the earliest preclinical stages (Perrin et al., 2009
). However, many biomarkers are invasive (lumbar puncture), expose individuals to radioactive tracers (PET), may be uncomfortable (MRI) and may not be readily available in all clinical settings.
Our finding that the AD8 is correlated with biomarkers of Alzheimer’s disease helps to address the gap in our understanding of how best to detect Alzheimer’s disease at the earliest possible stage in primary care settings. Expert centres have little difficulty in diagnosing Alzheimer’s disease, but in the community, diagnoses may be delayed because of an inability to effectively detect cognitive impairment in the setting of a busy office practice. The use of a brief test such as the AD8 may improve strategies for detecting dementia in the community and in developing countries where biomarkers may not be readily available, and may enhance and enrich clinical trial recruitment by increasing the likelihood that participants have underlying biomarker abnormalities that are increasingly becoming required for inclusion.
Our study has limitations. Our sample is not population based. The AD8 uses informant information; the absence of an observant informant may limit use in certain clinical situations. However, informant interviews can be successfully applied in populations with lower educational attainment (Galvin et al., 2007a
; Espinosa et al., 2008
; Malmstrom et al., 2009
). Additionally, the AD8 can be used as a patient interview in the absence of an informant (Galvin et al., 2007a
) and can be administered in person or by phone (Galvin et al., 2006
). Dementia screening requires a consideration of the population at risk and the sensitivity and specificity of the instruments used (Holsinger et al., 2007
). A large number of false positive individuals might expend limited health care funds. Conversely, a large number of false negative individuals would be denied treatment and might miss opportunities to participate in clinical research studies. A staged dementia screening approach would then make the most sense. The AD8 given to the informant would detect intra-individual change and interference with daily function and, if positive, a brief performance test—such as word-list or paragraph recall—would confirm the presence of episodic memory deficits (Galvin et al., 2007b
). We have previously demonstrated that the MMSE did not add to the discriminative ability of the AD8 (Galvin et al., 2007b
), and from the data presented here, the MMSE would fail to detect 85% of the individuals who were clinically rated as demented, performed poorly on tests of episodic memory and had biomarker changes supporting a diagnosis of Alzheimer’s disease. More detailed assessments, such as the CDR and neuropsychological testing, would then be used to stage dementia severity and assist in differential diagnosis. There are non-demented individuals in our sample who have biomarker abnormalities suggestive of preclinical Alzheimer’s disease that neither the AD8 nor the CDR can detect. At the present time, it is impossible to identify these individuals during a cross-sectional evaluation; however, clues from longitudinal analyses suggest that individuals with preclinical disease have absence of practice effects (Galvin, et al., 2005b
) and greater rates of annual change on neuropsychological testing (Storandt, et al., 2009
) with inflection points in performance occurring 1–3 years prior to clinical diagnosis (Johnson et al., 2009
). Further work is needed to determine whether the AD8 is sensitive to longitudinal change.