title: Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease.
abstract: Clinicopathological evidence suggests that the pathology of Alzheimer's disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-β1-42 (Aβ1-42) associated with the presence of Aβ plaques, and elevated concentrations of CSF tau, ptau181 (phosphorylated tau181), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.forename: Chengjie
authors.initials: C
authors.lastname: Xiong
authors.forename: Mateusz S
authors.initials: MS
authors.lastname: Jasielec
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Bateman
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Tammie L S
authors.initials: TL
authors.lastname: Benzinger
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.forename: John M
authors.initials: JM
authors.lastname: Ringman
authors.forename: Martin N
authors.initials: MN
authors.lastname: Rossor
authors.forename: Stephen
authors.initials: S
authors.lastname: Salloway
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
authors.forename: Daniel
authors.initials: D
authors.lastname: Marcus
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Virginia D
authors.initials: VD
authors.lastname: Buckles
authors.forename: Jack H
authors.initials: JH
authors.lastname: Ladenson
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D000328:Adult; D000483:Alleles; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D003071:Cognition; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005799:Genes, Dominant; D006720:Homozygote; D006801:Humans; D007118:Immunoassay; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)