title: Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains.
abstract: OBJECTIVE
  Cognitive impairment and dementia, including Alzheimer disease (AD), are common within the aging population, yet the factors that render the aging brain vulnerable to these processes are unknown. Perivascular localization of aquaporin-4 (AQP4) facilitates the clearance of interstitial solutes, including amyloid-β, through the brainwide network of perivascular pathways termed the glymphatic system, which may be compromised in the aging brain.
  
  
  OBJECTIVE
  To determine whether alterations in AQP4 expression or loss of perivascular AQP4 localization are features of the aging human brain and to define their association with AD pathology.
  
  
  METHODS
  Expression of AQP4 was analyzed in postmortem frontal cortex of cognitively healthy and histopathologically confirmed individuals with AD by Western blot or immunofluorescence for AQP4, amyloid-β 1-42, and glial fibrillary acidic protein. Postmortem tissue and clinical data were provided by the Oregon Health and Science University Layton Aging and Alzheimer Disease Center and Oregon Brain Bank. Postmortem tissue from 79 individuals was evaluated, including cognitively intact "young" individuals aged younger than 60 years (range, 33-57 years), cognitively intact "aged" individuals aged older than 60 years (range, 61-96 years) with no known neurological disease, and individuals older than 60 years (range, 61-105 years) of age with a clinical history of AD confirmed by histopathological evaluation. Forty-eight patient samples (10 young, 20 aged, and 18 with AD) underwent histological analysis. Sixty patient samples underwent Western blot analysis (15 young, 24 aged, and 21 with AD).
  
  
  METHODS
  Expression of AQP4 protein, AQP4 immunoreactivity, and perivascular AQP4 localization in the frontal cortex were evaluated.
  
  
  RESULTS
  Expression of AQP4 was associated with advancing age among all individuals (R2 = 0.17; P = .003). Perivascular AQP4 localization was significantly associated with AD status independent of age (OR, 11.7 per 10% increase in localization; z = -2.89; P = .004) and was preserved among eldest individuals older than 85 years of age who remained cognitively intact. When controlling for age, loss of perivascular AQP4 localization was associated with increased amyloid-β burden (R2 = 0.15; P = .003) and increasing Braak stage (R2 = 0.14; P = .006).
  
  
  CONCLUSIONS
  In this study, altered AQP4 expression was associated with aging brains. Loss of perivascular AQP4 localization may be a factor that renders the aging brain vulnerable to the misaggregation of proteins, such as amyloid-β, in neurodegenerative conditions such as AD.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Zeppenfeld
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Simon
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland.
authors.forename: J Douglas
authors.initials: JD
authors.lastname: Haswell
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland.
authors.forename: Daryl
authors.initials: D
authors.lastname: D'Abreo
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland.
authors.forename: Charles
authors.initials: C
authors.lastname: Murchison
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland3Department of Pathology, Oregon Health and Science University, Portland.
authors.forename: Marjorie R
authors.initials: MR
authors.lastname: Grafe
authors.affiliation: Department of Pathology, Oregon Health and Science University, Portland.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.affiliation: Department of Neurology, Oregon Health and Science University, Portland.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kaye
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland4Knight Cardiovascular Research Institute, Oregon Health and Science University, Portland.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Iliff
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D051401:Aquaporin 4 / Q000378:metabolism*; D003071:Cognition / Q000502:physiology*; D003933:Diagnosis; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D051401:Aquaporin 4; D005904:Glial Fibrillary Acidic Protein; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)