title: Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease.
abstract: OBJECTIVE
  The accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging.
  
  
  OBJECTIVE
  To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content.
  
  
  METHODS
  Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including β-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals.
  
  
  METHODS
  Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction.
  
  
  RESULTS
  The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/β-amyloid 42, suggesting that phosphorylated tau 181/β-amyloid 42 levels modulate age-related changes in myelin water fraction.
  
  
  CONCLUSIONS
  These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease's course and lead to new markers of efficacy for prevention and treatment trials.
authors.affiliation: Waisman Center, University of Wisconsin-Madison.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Dean
authors.affiliation: Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, Oxford, England.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Hurley
authors.affiliation: Waisman Center, University of Wisconsin-Madison.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kecskemeti
authors.affiliation: Alzheimer Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison.
authors.forename: J Patrick
authors.initials: JP
authors.lastname: O'Grady
authors.affiliation: Alzheimer Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison.
authors.forename: Cristybelle
authors.initials: C
authors.lastname: Canda
authors.affiliation: Alzheimer Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison4Wisconsin Alzheimer Institute, University of Wisconsin School of Medicine and Public Health, Madison.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Davenport-Sis
authors.affiliation: Alzheimer Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison5Geriatric Research Education and Clinical Center, William S. Middleton Memorial VA Hospital, Madison, Wisconsin.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Carlsson
authors.affiliation: Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden7Department of Molecular Neuroscience, Institute of Neurology, University College London, London, England.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Alzheimer Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison4Wisconsin Alzheimer Institute, University of Wisconsin School of Medicine and Public Health, Madison5Geriatric Research Education and Clinical Center, William S. Middleton Memorial VA Hospital, Madison, Wisconsin.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Alzheimer Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison4Wisconsin Alzheimer Institute, University of Wisconsin School of Medicine and Public Health, Madison.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sager
authors.affiliation: Alzheimer Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison4Wisconsin Alzheimer Institute, University of Wisconsin School of Medicine and Public Health, Madison5Geriatric Research Education and Clinical Center, William S. Middleton Memorial VA Hospital, Madison, Wisconsin.
authors.forename: Sterling C
authors.initials: SC
authors.lastname: Johnson
authors.affiliation: Waisman Center, University of Wisconsin-Madison8Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison9Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Alexander
authors.affiliation: Alzheimer Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison5Geriatric Research Education and Clinical Center, William S. Middleton Memorial VA Hospital, Madison, Wisconsin.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Bendlin
mesh_terms: D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000473:pathology; D013223:Statistics as Topic; D014867:Water / Q000378:metabolism; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D014867:Water