Cholinergic white matter pathways along the Alzheimer's disease continuum.

Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). However, it is still unknown if these alterations can be found in individuals with subjective cognitive decline (SCD), and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the AD continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 405 participants (53 AD, 66 MCI, 174 SCD, and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Longitudinal Cognitive Impairment and Dementia Study (DELCODE). We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fiber-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the AD continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was employed to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the AD continuum, including individuals with SCD. The differences involved posterior cholinergic white matter in the SCD stage and extended to anterior frontal white matter in MCI and AD dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e., MCI and AD dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing SCD from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the SCD and MCI stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in SCD individuals, preceding the more widespread alterations found in MCI and AD. The integrity of the cholinergic pathways identified the early stages of AD better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert.