title: Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease.
abstract: BACKGROUND
  The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood.
  
  
  OBJECTIVE
  To examine dynamic interrelationships between Aβ42 and tau in preclinical AD.
  
  
  METHODS
  We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18).
  
  
  RESULTS
  In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p <  0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau.
  
  
  CONCLUSIONS
  The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.
authors.affiliation: The Litwin-Zucker Research Center, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA.|FIDMAG Hermanas Hospitalarias Research Foundation & CIBERSAM, Sant Boi de Llobregat, Spain.
authors.forename: Jesus J
authors.initials: JJ
authors.lastname: Gomar
authors.affiliation: The Litwin-Zucker Research Center, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA.
authors.forename: Concepcion
authors.initials: C
authors.lastname: Conejero-Goldberg
authors.affiliation: The Litwin-Zucker Research Center, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA.|Hofstra North Shore LIJ School of Medicine, Hempstead, NY, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
authors.affiliation: The Litwin-Zucker Research Center, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA.|Hofstra North Shore LIJ School of Medicine, Hempstead, NY, USA.
authors.forename: Terry E
authors.initials: TE
authors.lastname: Goldberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D001284:Atrophy; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D062706:Prodromal Symptoms; D012044:Regression Analysis; D018709:Statistics, Nonparametric; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Aβ42; brain atrophy; cerebrospinal fluid; cognition; p-tau; preclinical AD