# MRI Diffusion Connectomics-Based Characterization of Progression in Alzheimer's Disease
## 2 Materials and Methods
### Statistics
The Rey Auditory Verbal Learning Test (RAVLT) immediate recall scores exhibited significant differences among the diagnostic groups (CN, MCI, and AD), as evidenced by  
\begin{table}
\begin{tabular}{l c c c c c c c} \hline \hline \multicolumn{1}{c}{**Indicator**} & \multicolumn{1}{c}{**CN**} & \multicolumn{1}{c}{**MCI**} & \multicolumn{1}{c}{**AD**} & \multicolumn{1}{c}{**Mean**} & \multicolumn{1}{c}{**IQR**} & \multicolumn{1}{c}{\(\chi^{2}\)} & \multicolumn{1}{c}{\(p\)-adj**} \\ \hline \multicolumn{1}{c}{} & \multicolumn{6}{c}{Neurophysiological Indicators} \\ \hline ADAS-11 & 139 & 80 & 40 & 8.9 & 7.2 & 115.39 & 1.05 \(\times\) 10\({}^{-24}\) \\ ADAS-13 & 139 & 80 & 38 & 13.9 & 10.3 & 131.18 & 4.58 \(\times\) 10\({}^{-28}\) \\ AV45 & 92 & 42 & 25 & 1.2 & 0.4 & 24.96 & 2.29 \(\times\) 10\({}^{-5}\) \\ CDR SB & 140 & 78 & 41 & 1.4 & 1.5 & 205.51 & 3.78 \(\times\) 10\({}^{-44}\) \\ FAQ & 138 & 75 & 40 & 3.3 & 3.0 & 149.02 & 6.56 \(\times\) 10\({}^{-32}\) \\ FDG & 5 & 57 & 30 & 1.2 & 0.1 & 33.05 & 5.34 \(\times\) 10\({}^{-7}\) \\ MMSE & 138 & 82 & 40 & 27.5 & 3.0 & 108.51 & 2.74 \(\times\) 10\({}^{-23}\) \\ MOCA & 259 & 82 & 38 & 24.1 & 6.0 & 128.39 & 1.72 \(\times\) 10\({}^{-27}\) \\ RAVLT & 139 & 80 & 38 & 40.2 & 20.0 & 115.06 & 1.14 \(\times\) 10\({}^{-24}\) \\ \hline \multicolumn{1}{c}{} & \multicolumn{6}{c}{Neurobiological Indicators} \\ \hline Brain vol & 132 & 76 & 35 & 1,031,622.0 & 140,524.0 & 8.49 & 2.86 \(\times\) 10\({}^{-2}\) \\ Entorhinal vol & 130 & 77 & 34 & 3940.6 & 1031.0 & 29.08 & 3.39 \(\times\) 10\({}^{-6}\) \\ Fusiform vol & 131 & 77 & 33 & 17,953.6 & 3295.0 & 22.52 & 5.16 \(\times\) 10\({}^{-5}\) \\ Hippocamp & 133 & 76 & 32 & 7060.3 & 1531.6 & 60.00 & 8.41 \(\times\) 10\({}^{-13}\) \\ vol & 136 & 73 & 37 & 1,468,892.6 & 233,267.5 & 1.43 & 4.90 \(\times\) 10\({}^{-1}\) \\ Middle temporal & 131 & 77 & 33 & 20,163.5 & 3979.0 & 23.70 & 3.56 \(\times\) 10\({}^{-5}\) \\ vol & 135 & 75 & 35 & 40,103.4 & 27,051.5 & 21.45 & 6.60 \(\times\) 10\({}^{-5}\) \\ \hline \hlinethe Kruskal-Wallis test (\(\chi^{2}=115.06,\ p<0.001\)). Figure 3 demonstrates how the RAVLT scores progressively decrease from cognitively normal individuals to those with MCI and further to individuals with AD. In terms of neurobiological markers, volumes of key brain regions, such as the hippocampus, entorhinal cortex, fusiform gyrus, and the middle temporal gyrus, showed significant differences across the disease stages (hippocampus: \(\chi^{2}=60.00,\ p<0.001\); entorhinal: \(\chi^{2}=29.08,\ p<0.001\); fusiform: \(\chi^{2}=22.52,\ p<0.001\); middle temporal: \(\chi^{2}=23.70,\ p<0.001\)). Q2. Are WM tract features predictive of neuropsychological and neurobiological indicators? The feature reduction strategy employed by this study substantially streamlined the initial high-dimensional feature space of DWI tractography measurements to a manageable subset. From an initial 1.3 million features, we identified high variance features to reduce our dataset to 134,340 explanatory variables that were imputed and further refined by using ElasticNet regularization. The ElasticNet model's \(\alpha\) parameter, which balances L2 and L2 penalties, was optimized independently for each response variable, with values ranging from 0.5 to 0.8. This approach aimed to balance feature retention and model complexity. The final feature count for each response variable is depicted in Table 5.  
Figure 3: RAVLT density plot exhibiting differences across diagnosis classification (n = 139 for CN, n = 80 for MCI, and n = 38 for AD). Outliers appear as points beyond the whiskers.