title: Apolipoprotein E epsilon4 does not modulate amyloid-β-associated neurodegeneration in preclinical Alzheimer disease.
abstract: OBJECTIVE
  Among cognitively healthy older individuals, the relationship among the 2 hallmark proteins of AD (Aβ and τ APOE ε4) and neurodegeneration is not well-understood. Here, we investigated the relationship between Aβ, p-τ, and APOE ε4 on longitudinal brain atrophy in preclinical AD.
  
  
  METHODS
  We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed-effects model, we concurrently investigated main and interactive effects between the APOE ε4 genotype and CSF Aβ(1-42), CSF p-τ and CSF Aβ(1-42), and the APOE ε4 genotype and CSF p-τ on entorhinal cortex atrophy rate. We also examined the relationship of APOE ε4, CSF p-τ, and CSF Aβ(1-42) on the atrophy rate of other AD-vulnerable neuroanatomic regions.
  
  
  RESULTS
  The full model with main and interactive effects demonstrated a significant interaction only between CSF p-τ and CSF Aβ(1-42) on entorhinal cortex atrophy rate, indicating elevated atrophy with time in individuals with increased CSF p-τ and decreased CSF Aβ(1-42). The APOE ε4 genotype was significantly and specifically associated with CSF Aβ(1-42). However, the interaction between the APOE ε4 genotype and either CSF Aβ(1-42) or CSF p-τ on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.
  
  
  CONCLUSIONS
  On the basis of our findings and building on prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD in which APOE ε4 primarily influences the pathology of Alzheimer disease via Aβ-related mechanisms, and in turn, Aβ-associated neurodegeneration occurs only in the presence of p-τ.
authors.affiliation: Department of Radiology, University of California, San Diego, La Jolla, California 92037-0841, USA. rdesikan@ucsd.edu
authors.forename: R S
authors.initials: RS
authors.lastname: Desikan
authors.forename: L K
authors.initials: LK
authors.lastname: McEvoy
authors.forename: D
authors.initials: D
authors.lastname: Holland
authors.forename: W K
authors.initials: WK
authors.lastname: Thompson
authors.forename: J B
authors.initials: JB
authors.lastname: Brewer
authors.forename: P S
authors.initials: PS
authors.lastname: Aisen
authors.forename: O A
authors.initials: OA
authors.lastname: Andreassen
authors.forename: B T
authors.initials: BT
authors.lastname: Hyman
authors.forename: R A
authors.initials: RA
authors.lastname: Sperling
authors.forename: A M
authors.initials: AM
authors.lastname: Dale
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000473:pathology; D000682:Amyloid; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D053327:Apolipoprotein E4 / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D014018:Tissue Distribution; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins