title: Longitudinal Cerebrospinal Fluid Biomarker Changes in Preclinical Alzheimer Disease During Middle Age.
abstract: OBJECTIVE
  Individuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted for AD secondary prevention trials. How early during the normal life span underlying AD pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined.
  
  
  OBJECTIVE
  To characterize the within-person trajectories of cerebrospinal fluid (CSF) biomarkers of AD over time and their association with changes in brain amyloid deposition and cognitive decline in cognitively normal middle-aged individuals.
  
  
  METHODS
  As part of a cohort study, cognitively normal (Clinical Dementia Rating [CDR] of 0) middle-aged research volunteers (n = 169) enrolled in the Adult Children Study at Washington University, St Louis, Missouri, had undergone serial CSF collection and longitudinal clinical assessment (mean, 6 years; range, 0.91-11.3 years) at 3-year intervals at the time of analysis, between January 2003 and November 2013. A subset (n = 74) had also undergone longitudinal amyloid positron emission tomographic imaging with Pittsburgh compound B (PiB) in the same period. Serial CSF samples were analyzed for β-amyloid 40 (Aβ40), Aβ42, total tau, tau phosphorylated at threonine 181 (P-tau181), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Within-person measures were plotted according to age and AD risk defined by APOE genotype (ε4 carriers vs noncarriers). Linear mixed models were used to compare estimated biomarker slopes among middle-age bins at baseline (early, 45-54 years; mid, 55-64 years; late, 65-74 years) and between risk groups. Within-person changes in CSF biomarkers were also compared with changes in cortical PiB binding and progression to a CDR higher than 0 at follow-up.
  
  
  METHODS
  Changes in Aβ40, Aβ42, total tau, P-tau181, VILIP-1, and YKL-40 and, in a subset of participants, changes in cortical PiB binding.
  
  
  RESULTS
  While there were no consistent longitudinal patterns in Aβ40 (P = .001-.97), longitudinal reductions in Aβ42 were observed in some individuals as early as early middle age (P ≤ .05) and low Aβ42 levels were associated with the development of cortical PiB-positive amyloid plaques (area under receiver operating characteristic curve = 0.9352; 95% CI, 0.8895-0.9808), especially in mid middle age (P < .001). Markers of neuronal injury (total tau, P-tau181, and VILIP-1) dramatically increased in some individuals in mid and late middle age (P ≤ .02), whereas the neuroinflammation marker YKL-40 increased consistently throughout middle age (P ≤ .003). These patterns were more apparent in at-risk ε4 carriers (Aβ42 in an allele dose-dependent manner) and appeared to be associated with future cognitive deficits as determined by CDR.
  
  
  CONCLUSIONS
  Longitudinal CSF biomarker patterns consistent with AD are first detectable during early middle age and are associated with later amyloid positivity and cognitive decline. Such measures may be useful for targeting middle-aged, asymptomatic individuals for therapeutic trials designed to prevent cognitive decline.
authors.affiliation: Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri2Department of Neurology, Washington University, St Louis, Missouri3Hope Center for Neurodegenerative Disorders, Washington University, St Louis, Missouri.
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Sutphen
authors.affiliation: Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri4Division of Biostatistics, Washington University, St Louis, Missouri.
authors.forename: Mateusz S
authors.initials: MS
authors.lastname: Jasielec
authors.affiliation: Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri2Department of Neurology, Washington University, St Louis, Missouri3Hope Center for Neurodegenerative Disorders, Washington University, St Louis, Missouri.
authors.forename: Aarti R
authors.initials: AR
authors.lastname: Shah
authors.affiliation: Department of Pathology and Immunology, Washington University, St Louis, Missouri.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Macy
authors.affiliation: Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri4Division of Biostatistics, Washington University, St Louis, Missouri.
authors.forename: Chengjie
authors.initials: C
authors.lastname: Xiong
authors.affiliation: Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri6Department of Radiology, Washington University, St Louis, Missouri.
authors.forename: Andrei G
authors.initials: AG
authors.lastname: Vlassenko
authors.affiliation: Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri6Department of Radiology, Washington University, St Louis, Missouri.
authors.forename: Tammie L S
authors.initials: TL
authors.lastname: Benzinger
authors.affiliation: ADx NeuroSciences, Ghent, Belgium.
authors.forename: Erik E J
authors.initials: EE
authors.lastname: Stoops
authors.affiliation: ADx NeuroSciences, Ghent, Belgium.
authors.forename: Hugo M J
authors.initials: HM
authors.lastname: Vanderstichele
authors.affiliation: EUROIMMUN, Lübeck, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Brix
authors.affiliation: Fujirebio US, Malvern, Pennsylvania.
authors.forename: Heather D
authors.initials: HD
authors.lastname: Darby
authors.affiliation: Fujirebio Europe, Ghent, Belgium.
authors.forename: Manu L J
authors.initials: ML
authors.lastname: Vandijck
authors.affiliation: Department of Pathology and Immunology, Washington University, St Louis, Missouri.
authors.forename: Jack H
authors.initials: JH
authors.lastname: Ladenson
authors.affiliation: Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri2Department of Neurology, Washington University, St Louis, Missouri3Hope Center for Neurodegenerative Disorders, Washington University, St Louis, Missouri.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri2Department of Neurology, Washington University, St Louis, Missouri3Hope Center for Neurodegenerative Disorders, Washington University, St Louis, Missouri.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri2Department of Neurology, Washington University, St Louis, Missouri3Hope Center for Neurodegenerative Disorders, Washington University, St Louis, Missouri.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
mesh_terms: D054392:Adipokines / Q000134:cerebrospinal fluid; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D000814:Aniline Compounds / Q000378:metabolism; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D000071451:Chitinase-3-Like Protein 1; D015331:Cohort Studies; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D037102:Lectins / Q000134:cerebrospinal fluid; D008297:Male; D008875:Middle Aged; D051596:Neurocalcin / Q000134:cerebrospinal fluid; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D049268:Positron-Emission Tomography; D013844:Thiazoles / Q000378:metabolism; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D054392:Adipokines; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D015415:Biomarkers; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins; D051596:Neurocalcin; D010446:Peptide Fragments; D013844:Thiazoles; C496688:VSNL1 protein, human; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins