White matter microstructural abnormality precedes cortical volumetric decline in Alzheimer's disease: evidence from data-driven disease progression modelling

Sequencing the regional progression of neurodegeneration in Alzheimers disease (AD) informs disease mechanisms and facilitates identification and staging of individuals at greatest risk of imminent cognitive decline, which may aid the development of early therapeutic interventions. Previous attempts to sequence neurodegeneration have analysed measures of regional volume and identified the initial sites of atrophy. However, focal microstructural alterations in white matter have also been reported in early AD. Yet, the temporal ordering of abnormality in measures of white matter microstructure relative to grey matter volume has not been established. In this study we used event-based modelling of disease progression (EBM) to provide a data-driven evaluation of the temporal sequence of abnormality in markers of white matter microstructure relative to grey matter volume. Regional microstructural metrics derived from diffusion tensor imaging (DTI) and regional volumes from Freesurfer cortical parcellation were obtained from the Alzheimers disease Neuroimaging Initiative (ADNI) database for 441 amyloid-positive participants (81 AD-dementia, 159 mild cognitive impairment, 201 cognitively normal). The estimated sequence shows a series of abnormalities in markers of white matter microstructure, followed by sequential grey matter volumetric decline, with no overlap between the two. Analysis of positional variance and cross-validation supports the robustness of our findings. These results provide the first data-driven evidence that markers of white matter microstructural degeneration precede those of cortical volumetric decline in the AD cascade. This prompts a re-evaluation of the view that regional volumetric decline can be used to characterise the very earliest stages of AD neurodegeneration. Instead, we suggest that white matter microstructural markers provide an earlier window into AD neurodegeneration. An early staging system of AD neurodegeneration based on measures of brain microstructure may find application in selecting AD subjects with early but minimal brain damage for clinical trials that aim to prevent cognitive decline.