Disentangling the effects of Alzheimer's and small vessel disease on white matter fibre tracts.

Alzheimer's disease and cerebral small vessel disease are the two leading causes of cognitive decline and dementia and co-exist in most- memory clinic patients. White matter damage as assessed by diffusion MRI is a key feature in both Alzheimer's and cerebral small vessel disease. However, disease-specific biomarkers of white matter alterations are missing. Recent advances in diffusion MRI operating on the fixel level (fiber population within a voxel) promise to advance our understanding of disease-related white matter alterations. Fixel-based analysis allows to derive measures of both white matter microstructure, measured by fiber density, and macrostructure, measured by fiber-bundle cross-section. Here, we evaluated the capacity of these state-of-the-art fixel metrics to disentangle the effects of cerebral small vessel disease and Alzheimer's disease on white matter integrity. We included three independent samples (total n = 387) covering genetically defined cerebral small vessel disease and age-matched controls, the full spectrum of biomarker-confirmed Alzheimer's disease including amyloid- and tau-PET negative controls and a validation sample with presumed mixed pathology. In this cross-sectional analysis, we performed group comparisons between patients and controls and assessed associations between fixel metrics within main white matter tracts and imaging hallmarks of cerebral small vessel disease (white matter hyperintensity volume, lacune and cerebral microbleed count) and Alzheimer's disease (amyloid- and tau-PET), age and a measure of neurodegeneration (brain volume). Our results showed that i) fiber density was reduced in genetically defined cerebral small vessel disease and strongly associated with cerebral small vessel disease imaging hallmarks, ii) fiber-bundle cross-section was mainly associated with brain volume, and iii) both fiber density and fiber-bundle cross-section were reduced in the presence of amyloid, but not further exacerbated by abnormal tau deposition. Fixel metrics were only weakly associated with amyloid- and tau-PET. Taken together, our results in three independent samples suggest that fiber density captures the effect of cerebral small vessel disease, while fiber-bundle cross-section is largely determined by neurodegeneration. The ability of fixel-based imaging markers to capture distinct effects on white matter integrity can propel future applications in the context of precision medicine.