Advanced diffusion MRI tract signatures in Alzheimer’s disease, dementia with Lewy bodies, and the FTD/PPA spectrum

Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and primary progressive aphasia (PPA) are heterogeneous neurodegenerative syndromes with overlapping clinical features and substantial societal burden. Their phenotypic diversity, including atypical AD variants and multiple PPA subtypes, poses major challenges for early diagnosis and disease monitoring. Sensitive, non-invasive imaging biomarkers remain limited. Diffusion magnetic resonance imaging (dMRI) has evolved beyond conventional diffusion tensor imaging (DTI) to include multi-shell models such as neurite orientation dispersion and density imaging (NODDI), free-water imaging (FWI), and fixel-based analysis (FBA), which offer increased microstructural specificity by probing neurite organization, extracellular water content, and fiber-specific degeneration. In this review of 54 dMRI studies spanning AD, DLB, FTD, and PPA spectrums, we identify both convergent microstructural patterns shared across techniques and disease-specific signatures revealed by advanced models. Canonical DTI findings demonstrate consistent syndrome-related alterations, including fornix and cingulum involvement in AD, widespread diffusivity increases in DLB, uncinate fasciculus degeneration in FTD, and arcuate fasciculus disruption in PPA. Advanced dMRI methods extend these observations by revealing disease-specific neurite and free-water alterations, associations with molecular imaging markers, and improved sensitivity to clinical severity, longitudinal cognitive decline, and microstructural progression. Across syndromes and subtypes, NODDI- and FBA-based metrics consistently outperform conventional DTI. Together, this review provides a comprehensive framework for interpreting advanced dMRI markers across the AD, DLB, and the FTD-PPA spectrum, and highlights their potential for refining disease characterization and tracking neurodegenerative progression.