Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer's disease dementia and mild cognitive impairment. However, it is still unknown whether these alterations can be found in individuals with subjective cognitive decline, 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 Alzheimer's disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 402 participants (52 Alzheimer's disease, 66 mild cognitive impairment, 172 subjective cognitive decline and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study. We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fibre-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the Alzheimer's disease 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 used 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 Alzheimer's disease continuum, including individuals with subjective cognitive decline. The differences involved posterior cholinergic white matter in the subjective cognitive decline stage and extended to anterior frontal white matter in mild cognitive impairment and Alzheimer's disease dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e. mild cognitive impairment and Alzheimer's disease dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing subjective cognitive decline 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 subjective cognitive decline and mild cognitive impairment stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in subjective cognitive decline individuals, preceding the more widespread alterations found in mild cognitive impairment and Alzheimer's disease. The integrity of the cholinergic pathways identified the early stages of Alzheimer's disease better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert.

Ageing Epidemiology Research Unit School of Public Health Imperial College London London UK

Berlin Center for Advanced Neuroimaging Charité Universitätsmedizin Berlin Berlin Germany

Centre for Clinical Brain Sciences University of Edinburgh and UK DRI Edinburgh UK

Department for Biomedical Magnetic Resonance University of Tübingen Tübingen Germany

Department for Neurodegenerative Diseases and Geriatric Psychiatry University Hospital Bonn Bonn Germany

Department of Biomedical Engineering and Assistive Technology Czech Institute of Informatics Robotics and Cybernetics Czech Technical University Prague Prague Czech Republic

Department of Cybernetics Faculty of Electrical Engineering Czech Technical University Prague Prague Czech Republic

Department of Neuroimaging Centre for Neuroimaging Science Institute of Psychiatry Psychology and Neuroscience King's College London London UK

Department of Neurology University of Bonn Bonn Germany

Department of Psychiatry and Psychotherapy Charité Berlin Germany

Department of Psychiatry and Psychotherapy School of Medicine Technical University of Munich Munich Germany

Department of Psychiatry and Psychotherapy University Hospital LMU Munich Munich Germany

Department of Psychiatry and Psychotherapy University Medical Center Goettingen University of Goettingen Goettingen Germany

Department of Psychiatry Charité Universitätsmedizin Berlin Campus Benjamin Franklin Berlin Germany

Department of Psychiatry Medical Faculty University of Cologne Cologne Germany

Department of Psychosomatic Medicine Rostock University Medical Center Rostock Germany

Division of Clinical Geriatrics Center for Alzheimer Research Department of Neurobiology Care Sciences and Society Karolinska Institute Stockholm Sweden

Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases University of Cologne Cologne Germany

German Center for Neurodegenerative Diseases Berlin Germany

German Center for Neurodegenerative Diseases Bonn Germany

German Center for Neurodegenerative Diseases Goettingen Germany

German Center for Neurodegenerative Diseases Magdeburg Germany

German Center for Neurodegenerative Diseases Munich Germany

German Center for Neurodegenerative Diseases Rostock Germany

German Center for Neurodegenerative Diseases Tübingen Germany

Institute for Stroke and Dementia Research University Hospital LMU Munich Munich Germany

Institute of Cognitive Neurology and Dementia Research Otto von Guericke University Magdeburg Germany

Leibniz Institute for Neurobiology Magdeburg Germany

MR Research in Neurosciences Department of Cognitive Neurology Georg August University Goettingen Goettingen Germany

Munich Cluster for Systems Neurology Munich Germany

Neurosciences and Signaling Group Institute of Biomedicine Department of Medical Sciences University of Aveiro Aveiro Portugal

Section for Dementia Research Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy University of Tübingen Tübingen Germany

Sheffield Institute for Translational Neurosciences University of Sheffield Sheffield UK

Theme Inflammation and Aging Karolinska University Hospital Stockholm Sweden

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