Accurate, reliable prediction of risk for Alzheimer's disease (AD) is essential for early, disease-modifying therapeutics. Multimodal MRI, such as structural and diffusion MRI, is likely to contain complementary information of neurodegenerative processes in AD. Here we tested the utility of the multimodal MRI (T1-weighted structure and diffusion MRI), combined with high-throughput brain phenotyping?morphometry and structural connectomics?and machine learning, as a diagnostic tool for AD. We used, firstly, a clinical cohort at a dementia clinic (National Health Insurance Service-Ilsan Hospital [NHIS-IH]
N = 211
110 AD, 64 mild cognitive impairment [MCI], and 37 cognitively normal with subjective memory complaints [SMC]) to test the diagnostic models
and, secondly, Alzheimer's Disease Neuroimaging Initiative (ADNI)-2 to test the generalizability. Our machine learning models trained on the morphometric and connectome estimates (number of features = 34,646) showed optimal classification accuracy (AD/SMC: 97% accuracy, MCI/SMC: 83% accuracy
AD/MCI: 97% accuracy) in NHIS-IH cohort, outperforming a benchmark model (FLAIR-based white matter hyperintensity volumes). In ADNI-2 data, the combined connectome and morphometry model showed similar or superior accuracies (AD/HC: 96%
MCI/HC: 70%
AD/MCI: 75% accuracy) compared with the CSF biomarker model (t-tau, p-tau, and Amyloid ?, and ratios). In predicting MCI to AD progression in a smaller cohort of ADNI-2 (n = 60), the morphometry model showed similar performance with 69% accuracy compared with CSF biomarker model with 70% accuracy. Our comparisons of the classifiers trained on structural MRI, diffusion MRI, FLAIR, and CSF biomarkers showed the promising utility of the white matter structural connectomes in classifying AD and MCI in addition to the widely used structural MRI-based morphometry, when combined with machine learning.