title: Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study.
abstract: OBJECTIVE
  Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1)E280A mutation carriers and noncarriers from the world's largest known autosomal dominant Alzheimer disease (AD) kindred.
  
  
  OBJECTIVE
  To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers.
  
  
  METHODS
  Cross-sectional measures of 18F-florbetapir positron emission tomography, 18F-fludeoxyglucose positron emission tomography, structural magnetic resonance imaging, cerebrospinal fluid (CSF), and plasma biomarkers of AD were assessed from 54 PSEN1 E280A kindred members (age range, 20-59 years).
  
  
  METHODS
  We used brain mapping algorithms to compare regional cerebral metabolic rates for glucose and gray matter volumes in cognitively unimpaired mutation carriers and noncarriers. We used regression analyses to characterize associations between age and the mean cortical to pontine 18F-florbetapir standard uptake value ratios, precuneus cerebral metabolic rates for glucose, hippocampal gray matter volume, CSF Aβ1-42, total tau and phosphorylated tau181, and plasma Aβ measurements. Age at onset of progressive biomarker changes that distinguish carriers from noncarriers was estimated using best-fitting regression models.
  
  
  RESULTS
  Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF Aβ1-42, higher CSF total tau and phosphorylated tau181, and higher plasma Aβ1-42 measurements. Sequential changes in biomarkers were seen at age 20 years (95% CI, 14-24 years) for CSF Aβ1-42, age 16 years (95% CI, 11-24 years) for the mean cortical 18F-florbetapir standard uptake value ratio, age 15 years (95% CI, 10-24 years) for precuneus cerebral metabolic rate for glucose, age 15 years (95% CI, 7-20 years) for CSF total tau, age 13 years (95% CI, 8-19 years) for phosphorylated tau181, and age 6 years (95% CI, 1-10 years) for hippocampal volume, with cognitive decline up to 6 years before the kindred's estimated median age of 44 years (95% CI, 43-45 years) at mild cognitive impairment diagnosis. No age-associated findings were seen in plasma Aβ1-42 or Aβ1-40.
  
  
  CONCLUSIONS
  This cross-sectional study provides additional information about the course of different AD biomarkers in the preclinical and clinical stages of autosomal dominant AD.
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana2Department of Neurosciences, University of California, San Diego3Arizona Alzheimer's Consortium, Phoenix4Banner Alzheimer's Institute, Phoenix, Arizona.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Fleisher
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix4Banner Alzheimer's Institute, Phoenix, Arizona5Department of Mathematics and Statistics, Arizona State University, Tempe.
authors.forename: Kewei
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston7Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Yakeel T
authors.initials: YT
authors.lastname: Quiroz
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Jakimovich
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Madelyn
authors.initials: M
authors.lastname: Gutierrez Gomez
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Langois
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix4Banner Alzheimer's Institute, Phoenix, Arizona.
authors.forename: Jessica B S
authors.initials: JB
authors.lastname: Langbaum
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix4Banner Alzheimer's Institute, Phoenix, Arizona.
authors.forename: Auttawut
authors.initials: A
authors.lastname: Roontiva
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix4Banner Alzheimer's Institute, Phoenix, Arizona.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Thiyyagura
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix4Banner Alzheimer's Institute, Phoenix, Arizona.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix4Banner Alzheimer's Institute, Phoenix, Arizona.
authors.forename: Napatkamon
authors.initials: N
authors.lastname: Ayutyanont
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Liliana
authors.initials: L
authors.lastname: Lopez
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Moreno
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Claudia
authors.initials: C
authors.lastname: Muñoz
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Victoria
authors.initials: V
authors.lastname: Tirado
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Acosta-Baena
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Margarita
authors.initials: M
authors.lastname: Giraldo
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Gloria
authors.initials: G
authors.lastname: Garcia
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix6Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix4Banner Alzheimer's Institute, Phoenix, Arizona9Department of Psychiatry, University of Arizona, Phoenix.
authors.forename: Pierre N
authors.initials: PN
authors.lastname: Tariot
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Francisco
authors.initials: F
authors.lastname: Lopera
authors.affiliation: Arizona Alzheimer's Consortium, Phoenix4Banner Alzheimer's Institute, Phoenix, Arizona9Department of Psychiatry, University of Arizona, Phoenix10Division of Neurogenomics, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
mesh_terms: D000328:Adult; D000375:Aging / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000235:genetics; D000544:Alzheimer Disease / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D003430:Cross-Sectional Studies; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid; D053764:Presenilin-1 / Q000235:genetics; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42)