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Brain. 2018 Oct 1;141(10):3065-3080. doi: 10.1093/brain/awy229.

White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer's disease.

Author information

Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany.
Biomedical Center, Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
Department of Radiology, Washington University in St Louis, St Louis, MO, USA.
Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.
Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA.
Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Hertie Institute for Clinical Brain Research, Tübingen, Germany and German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia.
University of California at San Francisco, San Francisco, CA94143, USA.
Dementia Research Centre, University College London, Queen Square, London, UK.
Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
Department of Neurology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Nuclear Medicine, Technical University of Munich, Munich, Germany.
Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
Neuroscience Research Australia, Barker Street Randwick, Sydney, Australia.
School of Medical Sciences, University of New South Wales, Sydney, Australia.


White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain.

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