Conditional Latent Diffusion for Synthetic Brain MRI in Alzheimer’s Disease: A Preprocessing-Focused Pipeline

Deep learning for Alzheimer’s disease (AD) detection from structural magnetic resonance imaging (MRI) needs large, labelled datasets, yet many cohorts hold only a few hundred participants, for which conventional augmentation adds little anatomical diversity. In a two-stage pipeline, a variational autoencoder compressed 256 × 256 coronal slices to a 32 × 32 × 8 latent space, and a class-conditional latent diffusion model under classifier-free guidance generated AD and cognitively normal (CN) images using 295 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The pipeline reached a Kernel Inception Distance (KID) of 0.030 ± 0.002 and a bias-corrected Fréchet Inception Distance (FID∞) of 43.82. A controlled ablation varying preprocessing alone improved KID by 0.0147 and precision by 0.069, both with 95% intervals excluding zero. FID did not separate the configurations. A ResNet-18 trained only on synthetic slices and tested on 44 held-out real participants (18 AD, 26 CN), each scored as the mean probability over twenty slices, reached an area under the curve of 0.779 ± 0.031 against 0.869 ± 0.027 for real data; the difference was not distinguishable at this sample size. No instance memorisation was found among 880 samples, and a size-matched control exposed a 27.7-percentage-point inflation in the standard memorisation metric. Preprocessing, therefore, measurably affects synthesis quality at the small-cohort scale, though not on every measure.