title: Cerebrospinal fluid ratios with Aβ42 predict preclinical brain β-amyloid accumulation.
abstract: BACKGROUND
  Biomarkers are urgently needed for the critical yet understudied preclinical stage of Alzheimer's disease (AD).
  
  
  METHODS
  CSF collection, [C-11]PiB amyloid imaging, and MRI were acquired in n=104 cognitively healthy adults enriched with risk for sporadic AD. Image-derived cerebral β-amyloid (Aβ) burden, measured concurrently and longitudinally, was regressed on CSF measures of Aβ, neural injury, and inflammation, as well as ratios with Aβ42. Linear mixed effects regression was used to model the effect of the CSF measures that predicted longitudinal brain amyloid accumulation on longitudinal cognitive decline, measured by memory test scores.
  
  
  RESULTS
  At baseline, Aβ42/Aβ40and all CSF ratios to Aβ42were associated with PiB binding in AD-vulnerable regions. Longitudinally, Aβ42/Aβ40and ratios of total tau, phosphorylated-tau, neurofilament light protein, and monocyte chemoattractant protein-1 to Aβ42were associated with increased β-amyloid deposition over two years, predominantly in lateral parietal and temporal cortex. However, these CSF ratios were not significantly associated with cognitive decline, and the effect seems to be largely driven by Aβ42in the denominator.
  
  
  CONCLUSIONS
  These results corroborate previous findings that t-tau/Aβ42and p-tau/Aβ42are the strongest candidate biomarkers during the preclinical timeframe. They support a framework in which neural injury and amyloid deposition are likely occurring simultaneously. It may be that neurodegenerative processes influence progressive amyloid accumulation, even in the preclinical time frame. CSF biomarkers for non-specific axonal injury and inflammation may provide more information at more advanced stages of the preclinical time course.
authors.affiliation: Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Neuroscience Training Program, University of Wisconsin-Madison, USA, Madison, WI 53705; Neuroscience and Public Policy Program, University of Wisconsin-Madison, USA, Madison, WI 53705; Institute on Aging, University of Wisconsin-Madison, USA, Madison, WI 53706.
authors.forename: Annie M
authors.initials: AM
authors.lastname: Racine
authors.affiliation: Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Koscik
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Nicholas
authors.affiliation: Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Lindsay R
authors.initials: LR
authors.lastname: Clark
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Ozioma C
authors.initials: OC
authors.lastname: Okonkwo
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Oh
authors.affiliation: Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, USA, Madison, WI 53705.
authors.forename: Ansel T
authors.initials: AT
authors.lastname: Hillmer
authors.affiliation: Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI, 53719.
authors.forename: Dhanabalan
authors.initials: D
authors.lastname: Murali
authors.affiliation: Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Barnhart
authors.affiliation: Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Tobey J
authors.initials: TJ
authors.lastname: Betthauser
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Gallagher
authors.affiliation: Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Department of Radiology, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rowley
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: N Maritza
authors.initials: NM
authors.lastname: Dowling
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Bendlin
authors.affiliation: Institute of Neurology, University College London, London, UK.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Institute of Neurology, University College London, London, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Carlsson
authors.affiliation: Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, USA, Madison, WI 53705; Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI, 53719.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Christian
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, USA, Madison, WI 53705.
authors.forename: Sterling C
authors.initials: SC
authors.lastname: Johnson
keywords: Alzheimer’s disease; Aβ42; MCP-1; NFL; PET; PiB; YKL-40; amyloid; biological parametric mapping; biomarkers; cerebrospinal fluid; linear mixed effects; preclinical AD; tau