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Original Contributions |

Evidence for Ordering of Alzheimer Disease Biomarkers

Clifford R. Jack, MD; Prashanthi Vemuri, PhD; Heather J. Wiste, BA; Stephen D. Weigand, MS; Paul S. Aisen, MD; John Q. Trojanowski, MD, PhD; Leslie M. Shaw, PhD; Matthew A. Bernstein, PhD; Ronald C. Petersen, MD, PhD; Michael W. Weiner, MD; David S. Knopman, MD; for the Alzheimer's Disease Neuroimaging Initiative
Arch Neurol. 2011;68(12):1526-1535. doi:10.1001/archneurol.2011.183.
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Published online

Objective To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.

Design Validation sample.

Setting Multisite, referral centers.

Participants A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.

Main Outcome Measures Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume).

Results Within each clinical group of the entire sample (n = 401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months.

Conclusions A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.

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Figure 1. Box plots and superimposed data points showing the distribution of Alzheimer disease (AD) biomarkers by baseline diagnosis and visit. The horizontal line in each box indicates the median, whereas the top and bottom borders of the box mark the 75th and 25th percentiles, respectively. The whiskers above and below the box mark the largest and smallest data point that is within 1.5 times the interquartile range of the top and bottom of the box. A, For participants with both baseline and 12-month data, the cerebrospinal fluid (CSF) Aβ42 level did not change from baseline to 12 months in the cognitively normal (CN) group (P = .52), the mild cognitive impairment (MCI) group (P = .13), or the AD group (P = .51). B, The CSF total tau level is shown on the log scale. It increased from baseline to 12 months in CN participants (P = .002) but not in participants with MCI (P = .12) or AD (P = .36). C, The adjusted hippocampal volume decreased from baseline to 12 months in all clinical groups (P < .001). The dotted horizontal line extending across all box plots represents the cut point denoting normal vs abnormal for each biomarker.

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Figure 2. Estimated probability of abnormality for each Alzheimer disease (AD) biomarker in all participants (n = 401) (A and B) and within the subset of participants with an abnormal cerebrospinal fluid (CSF) Aβ42 level at baseline (n = 274) (C and D). Abnormality is shown by clinical diagnosis (ie, cognitively normal [CN], mild cognitive impairment [MCI], or AD) (A and C) and Mini-Mental State Examination (MMSE) score (B and D). The cutoffs used are 192 pg/mL for the CSF Aβ42 level, 93 pg/mL for the CSF total tau level (t-tau), and 0.48 for the adjusted hippocampal volume (AHV).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Estimated proportion of participants who had abnormal Alzheimer disease (AD) biomarker values at baseline and at 12 months shown by baseline clinical diagnosis for the subset of participants with serial data (n = 298) (A) and for a subset of participants with serial data who had an abnormal cerebrospinal fluid (CSF) Aβ42 level at baseline (n = 209) (B). Values are shifted slightly along the x-axis for the middle biomarker to reduce overlap in lines. The cutoffs used are 192 pg/mL for the CSF Aβ42 level, 93 pg/mL for the CSF total tau level (t-tau), and 0.48 for the adjusted hippocampal volume (AHV). CN indicates cognitively normal; MCI, mild cognitive impairment.

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