Alzheimer's disease diagnostic accuracy by fluid and neuroimaging ATN framework

Abstract Objectives The ATN's different modalities (fluids and neuroimaging) for each of the Aβ (A), tau (T), and neurodegeneration (N) elements are used for the biological diagnosis of Alzheimer's disease (AD). We aim to identify which ATN category achieves the highest potential for diagnosis and predictive accuracy of longitudinal cognitive decline. Methods Based on the availability of plasma ATN biomarkers (plasma‐derived Aβ42/40, p‐tau181, NFL, respectively), CSF ATN biomarkers (CSF‐derived Aβ42/Aβ40, p‐tau181, NFL), and neuroimaging ATN biomarkers (18F‐florbetapir (FBP) amyloid‐PET, 18F‐flortaucipir (FTP) tau‐PET, and fluorodeoxyglucose (FDG)‐PET), a total of 2340 participants were selected from ADNI. Results Our data analysis indicates that the area under curves (AUCs) of CSF‐A, neuroimaging‐T, and neuroimaging‐N were ranked the top three ATN candidates for accurate diagnosis of AD. Moreover, neuroimaging ATN biomarkers display the best predictive ability for longitudinal cognitive decline among the three categories. To note, neuroimaging‐T correlates well with cognitive performances in a negative correlation manner. Meanwhile, participants in the “N” element positive group, especially the CSF‐N positive group, experience the fastest cognitive decline compared with other groups defined by ATN biomarkers. In addition, the voxel‐wise analysis showed that CSF‐A related to tau accumulation and FDG–PET indexes more strongly in subjects with MCI stage. According to our analysis of the data, the best three ATN candidates for a precise diagnosis of AD are CSF‐A, neuroimaging‐T, and neuroimaging‐N. Conclusions Collectively, our findings suggest that plasma, CSF, and neuroimaging biomarkers differ considerably within the ATN framework; the most accurate target biomarkers for diagnosing AD were the CSF‐A, neuroimaging‐T, and neuroimaging‐N within each ATN modality. Moreover, neuroimaging‐T and CSF‐N both show excellent ability in the prediction of cognitive decline in two different dimensions.

The best framework biomarkers were selected through the comparison of the AUC values in different comparisons.

ATN biomarkers (ρ)
rating sum of boxes; ADNI-MEM, composite memory score; ADNI-EF, composite executive functioning score.ADAS-11 change, the average every-year decline of ADAS-11 points in 4 years; ADNI-MEM change, the average every-year decline of ADNI-MEM points in 4 years; ADNI-EF change, the average every-year decline of ADNI-EF points in 4 years.

Supplementary Table 1: Comparison of AUC values of CN/AD for biomarkers in the same dimension
The AUC results of area under ROC curve were expressed as AUC value [95% confidence interval].Delong test was used to calculate the 95% confidence interval and the AUC values of different biomarkers were compared in CN vs AD.

biomarker features based on their AUC value
The AUC result of area under ROC curve was expressed as AUC value [95% confidence interval].The 95% confidence interval was calculated by Delong test and pairwise comparison was conducted.Supplementary Table 4: Ranking the A/T/N

Supplementary Table 5: Cutoff values of AT(N) biomarkers in different comparisons
By calculating the Yoden index (sensitivity + specificity -1) of each marker to identify different cognitive groups, and sorting the results, the biomarker level corresponding to the maximum value can be obtained, which is the optimal critical point of the marker, also known as the cutoff value.

13: Influence of of ATN biomarkers on cognitive performance and decline by ATN status for 4-year follow-up
Participants can be divided into A+ and A-, T+ and T-, N+ and N-with related biomarkers in CSF, Plasma and Neuroimaging higher or lower than the threshold value;Baseline cognitive scores and cognitive annual changes were used to examine the influence of higher/lower ATN biomarkers on cognitive performances and decline over time, adjusted for age, gender, years of education; Results are mean ± SE or median [25th percent, 75th percent] according to normal distribution or not.*p < 0.05 compared to the negative status in slope.Num, number of participants; CSF, cerebro-Spinal Fluid; ADAS, Alzheimer's disease assessment scale-cognitive subscale; ADNI-MEM, composite memory score; ADNI-EF, composite executive functioning score.