Correction to: Neurol Ther (2022) 11:413–434 https://doi.org/10.1007/s40120-022-00326-y

Following the publication of this article, the calculation of ADCOMS estimates in this publication were found to be incorrect as a result of a programming error. Resultantly, values presented in the paper text, tables and figures have been corrected in addition to estimated cut point values for the ADCOMS. This correction does not impact upon the study conclusion; the basic structure of the paper or the discussion. For completeness for this correction, the programming used to derive the ADCOMS variable has been independently checked by two analysts. The complete programming code for the whole analysis has been independently checked by one analyst. No errors or bugs were identified. Additionally, the data output file was checked against the corrected manuscript by a separate researcher.

The corrected values are given below:

ABSTRACT, Results: The following ADCOMS value ranges for the total population and Aβ + population were identified: < 0.11 indicative of normal cognition, 0.11 to < 0.31 indicative of MCI, 0.31–0.77 indicative of mild AD, and > 0.77 indicative of at least moderate AD.

Results

Sample Overview

The demographic characteristics of the study population are provided in Table 5. Scores on all the assessment measures at baseline were indicative of significantly greater impairment among the AD-related dementia group versus the MCI group, and significantly greater impairment among the MCI group versus the cognitively normal group. Among participants who were cognitively normal at both baseline and the 24-month visit, change scores on all the assessment measures were small (e.g., no change in ADCOMS values and an increase of 0.04 in CDR-SB scores). However, cognitively normal participants who progressed to MCI or AD at the 24-month visit had larger change scores (e.g., an increase of 0.12 in ADCOMS values and 1.31 in CDR-SB scores). The same was true for participants diagnosed with MCI (e.g., ADCOMS change scores of 0.04 and CDR-SB change scores of 1.50 among those who remained diagnosed with MCI versus 0.34 and 2.97, respectively, among those who progressed to AD). The same pattern of findings was observed among the subset of the population with positive amyloid β confirmation (Table 5). This suggests that the measures have reasonable known-groups validity and are sensitive to changes in disease severity, regardless of predisposition for developing AD.

Table 3 ADCOMS items and weighting.
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Table 5 Participant characteristics
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Table 6 ROC curve baseline results: optimal ADCOMS values
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Table 7 ROC curve 24-month visit results: optimal ADCOMS values
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Table 8 Biomarker values and APOE4 genotype according to ADCOMS staging score group
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Fig. 1
figure 1

Box plot of ADCOMS values at baseline by diagnosis for the total and confirmed amyloid β-positive populationsa. a Total population. b Confirmed amyloid β-positive population. AD Alzheimer’s disease, ADCOMS Alzheimer’s Disease Composite Score, MCI mild cognitive impairment. aHorizontal dashed lines represent the selected ADCOMS cut point scores (i.e., 0.11, 0.31, and 0.77). Whiskers represent the minimum and maximum values excluding outliers; the horizontal line within the box represents the median; the upper and lower portions of the box represent the upper and lower quartiles; circles represent outliers

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Fig. 2
figure 2

Box plot of ADCOMS values at 24-month visit by diagnosis for the total and confirmed amyloid β-positive populationsa. a Total population. b Confirmed amyloid β-positive population. AD Alzheimer’s disease, ADCOMS Alzheimer’s Disease Composite Score, MCI mild cognitive impairment. aHorizontal dashed lines represent the selected ADCOMS cut point scores (i.e., 0.11, 0.31, and 0.77). Whiskers represent the minimum and maximum values excluding outliers; the horizontal line within the box represents the median; the upper and lower portions of the box represent the upper and lower quartiles; circles represent outliers

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In the following subsections, the results from the ROC curves based on the published cut point scores for the reference assessment measures are presented for the baseline and the 24-month visit data. The diagnostic accuracy test results are then presented, followed by a summary and examination of the selected ADCOMS cut scores.

ROC Curves

Baseline Data

The results of the ROC curves of ADCOMS values generated using the baseline data for both the total population and the amyloid β–positive population are presented in Table 6. The ROC curves primarily suggested an optimal ADCOMS cut point score of between 0.08 to 0.11 for normal cognition versus MCI. Of note, there is no threshold on the MMSE that distinguishes between normal cognition and MCI; thus, MMSE scores could not be used for this determination. The optimal ADCOMS cut point score to distinguish between MCI and mild AD varied across the different assessment measures (Table 6). There were too few patients at baseline with a CDR or CDR-SB score indicative of moderate AD; thus, ROC curves could not be generated for differentiating mild from moderate AD using these measures. On the ADAS-Cog and MMSE, optimal scores for distinguishing between mild and moderate AD also varied (Table 6). The tests of equality between the derivation and the validation sample confirmed the results (Table 6).

Twenty-Four-Month Visit Data

The results of the ROC curves of ADCOMS values generated using the 24-month visit data for both the total population and the amyloid β-positive population are presented in Table 7. These results confirmed the finding that an optimal ADCOMS cut score of 0.08 to 0.11 distinguishes between normal cognition and MCI. For MCI and mild AD and for mild AD and moderate AD, the suggested cut score varied across the different assessment measures (Table 7). The tests of equality between the derivation and validation samples confirmed the results (Table 7).

Diagnostic Accuracy

Analyses were restricted to patients with a CDR score of 0.5 at baseline (MCI, n = 471; AD, n = 84) to determine the cut point for the ADCOMS value that differentiated between ADNI-defined clinical diagnoses of MCI or mild AD. The ROC curve demonstrated that an ADCOMS cut score of 0.31 (sensitivity = 90.5%, specificity = 86.6%) best discriminated between patients with MCI versus mild AD: 87% of patients were correctly classified. The area under the ROC curve was 0.933.

When restricting the analysis to patients with a CDR score of 1.0 at month 24 (mild AD, n = 70; moderate or severe AD, n = 24), the ROC curve demonstrated that an ADCOMS cut score of 0.77 (sensitivity = 79.2%, specificity = 68.6%) best discriminated between patients with mild AD versus moderate/severe AD: 71% of patients were correctly classified. The area under the ROC curve was 0.821.

Derived ADCOMS Staging Scores

The results from all ROC curve analyses suggested that an ADCOMS value < 0.11 is indicative of normal cognition. Correspondingly, the mean (standard deviation [SD]) ADCOMS at baseline for cognitively normal participants was 0.05 (0.03) for the total population and the population with positive amyloid β confirmation (Table 5). When the cut point scores were applied to the 24-month visit data, we found that 73% of participants from the total population (65% of patients with positive amyloid β confirmation) with an ADCOMS value less than 0.11 had a diagnosis of normal cognition rather than MCI.

For MCI, the ROC results suggested the ADCOMS value should be less than a value somewhere between 0.23 and 0.49, while the diagnostic accuracy checks suggested a score of 0.31. Therefore, an ADCOMS value of less than 0.31 was selected as the optimal score to distinguish MCI from mild AD; thus, an ADCOMS value between 0.11 and less than 0.31 is considered to be indicative of MCI. Correspondingly, the mean (SD) ADCOMS value at baseline for participants diagnosed with MCI was 0.20 (0.10) for the total population and 0.21 (0.10) for the population with positive amyloid β confirmation (Table 5). When the cut point scores were applied to the 24-month visit data, we found that 94% of participants from the total population (93% of patients from the amyloid β population) with an ADCOMS value between 0.11 and less than 0.31 had a diagnosis of MCI rather than mild AD.

The results from all ROC curve analyses suggested that the ADCOMS value should be less than somewhere between 0.62 to 1.03 for mild AD. However, the diagnostic accuracy checks suggest a score of 0.77. Therefore, an ADCOMS value less than 0.77 was selected as the optimal score to distinguish mild AD from moderate/severe AD; thus, an ADCOMS value between 0.31 and less than 0.77 is indicative of mild AD. Correspondingly, the mean (SD) ADCOMS value for participants diagnosed with mild AD at baseline in both the total population (n = 327) and population with positive amyloid β confirmation (n = 203) was 0.56 (0.18). When the cut point scores were applied to the 24-month visit data, we found that 91% of participants from the total population (93% of the population with positive amyloid β confirmation) with an ADCOMS value between 0.31 and less than 0.77 had a diagnosis of mild AD rather than moderate/severe AD.

Based on the results above, an ADCOMS value of 0.77 or greater was considered to be indicative of moderate/severe AD. Few patients were diagnosed with moderate AD at baseline; the mean (SD) ADCOMS value for participants diagnosed with moderate/severe AD at the 24-month visit was 1.07 (0.29) for the total population (n = 102) and 1.10 (0.31) for population with positive amyloid β confirmation (n = 58). When the cut point scores were applied to the 24-month visit data, we found that 62% of participants in the total population and 63% of participants with positive amyloid β confirmation with an ADCOMS value of 0.77 or greater had a diagnosis of moderate/severe AD rather than mild AD.

Figure 1a, b presents a box plot of ADCOMS values by diagnosis at baseline for the total population and amyloid β population, with horizontal lines representing the selected ADCOMS cut point scores. Figure 2a, b presents ADCOMS values at the 24-month visit, which shows that within each diagnosis, the interquartile range of ADCOMS values fell within the selected cut point range.

Table 8 presents values of the biomarkers total tau, tau phosphorylated at threonine 181 (p-tau181), and amyloid β1–42 as measured in CSF at baseline and the number of patients carrying the apolipoprotein ε4 allele (APOE4) gene according to ADCOMS staging groups. People staged as having normal cognition using the ADCOMS have significantly lower mean tau and p-tau181 levels and significantly higher mean amyloid β1–42 values than those staged as having early AD (soluble amyloid β1–42 is known to decrease as patients progress [21]). Additionally, the likelihood of being an APOE4 carrier increased across the ADCOMS staging groups, such that people staged as having moderate/severe AD had the highest likelihood of carrying this gene.

DISCUSSION

Using a large sample of participants from the North American ADNI study, we derived the following severity scoring ranges for the ADCOMS measure: a score of < 0.11 is indicative of normal cognition; a score of 0.11 to < 0.31 is indicative of MCI; a score of 0.31 to 0.77 is indicative of mild AD; and a score of > 0.77 is indicative of at least moderate AD.


ACKNOWLEDGEMENTS

We thank participants of the ADNI study. The authors would like to thank Dave Evenden, University of Southampton, for his helpful advice and comment on the calculation error of ADCOMS values.

The original article has been corrected.