title: Characterizing Apolipoprotein E ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques.
abstract: OBJECTIVE
  β-Amyloid peptide (Aβ) plaques are a cardinal neuropathologic feature of Alzheimer disease (AD), yet more than one-third of apolipoprotein E ε4 (APOE4) noncarriers with the clinical diagnosis of mild to moderate Alzheimer dementia may not meet positron emission tomographic criteria for significant cerebral amyloidosis.
  
  
  OBJECTIVE
  To clarify the percentage of APOE4 carriers and noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia near the end of life and minimal Aβ plaques noted at autopsy and the extent to which these cases are associated with appreciable neurofibrillary degeneration or a primary neuropathologic diagnosis other than AD.
  
  
  METHODS
  Data on participants included in this study were obtained from the National Alzheimer Coordinating Center's Uniform Data Set, which comprises longitudinal clinical assessments performed at the AD centers funded by the National Institute on Aging. Neuropathology data are available for the subset of participants who died. A total of 100 APOE4 noncarriers and 100 APOE4 carriers had the primary clinical diagnosis of mild to moderate Alzheimer dementia at their last visit, known APOE4 genotype, died within the ensuing 24 months, and underwent neuropathologic evaluation on autopsy. The study was conducted from September 1, 2005, to September 1, 2012; analysis was performed from October 9, 2012, to March 20, 2015.
  
  
  METHODS
  Standardized histopathologic assessments of AD neuropathologic changes were the primary measures of interest in this study, specifically Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque density score, diffuse plaque density score, and Braak stage for neurofibrillary degeneration. The distributions of scores for these measures were the primary outcomes.
  
  
  RESULTS
  Of the 37 APOE4 noncarriers with minimal neuritic plaques, 16 individuals (43.2%) had Braak stages III to VI ratings, and 15 of the others (75.0%) met neuropathologic criteria for other dementia-related diseases. Of the 13 APOE4 carriers with minimal neuritic plaques, 6 individuals (46.2%) had Braak stages III to VI ratings and met neuropathologic criteria for other dementia-related diseases. Similarly, of the 7 APOE4 carriers with minimal neuritic plaques and Braak stages 0 to II, 4 participants (57.1%) were thought to have pathologic changes and alterations resulting from non-AD neuropathologic features.
  
  
  CONCLUSIONS
  In this study, more than one-third of APOE4 noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia had minimal Aβ plaque accumulation in the cerebral cortex and, thus, may show limited or no benefit from otherwise effective anti-Aβ treatment. Almost half of the participants with a primary clinical diagnosis of mild to moderate Alzheimer dementia and minimal Aβ plaque accumulation had an extensive topographic distribution of neurofibrillary degeneration. Additional studies are needed to better understand and provide treatment for patients with this unexpectedly common cliniconeuropathologic condition.
authors: National Alzheimer's Coordinating Center, University of Washington, Seattle.
authors: Sarah E
authors: SE
authors: Monsell
authors: National Alzheimer's Coordinating Center, University of Washington, Seattle2Department of Epidemiology, University of Washington, Seattle.
authors: Walter A
authors: WA
authors: Kukull
authors: Banner Sun Health Research Institute, Sun City, Arizona4Arizona Alzheimer's Consortium, Phoenix, Arizona.
authors: Alex E
authors: AE
authors: Roher
authors: Banner Sun Health Research Institute, Sun City, Arizona.
authors: Chera L
authors: CL
authors: Maarouf
authors: Banner Sun Health Research Institute, Sun City, Arizona4Arizona Alzheimer's Consortium, Phoenix, Arizona.
authors: Geidy
authors: G
authors: Serrano
authors: Banner Sun Health Research Institute, Sun City, Arizona4Arizona Alzheimer's Consortium, Phoenix, Arizona.
authors: Thomas G
authors: TG
authors: Beach
authors: Department of Neurology, Mayo Clinic, Scottsdale, Arizona.
authors: Richard J
authors: RJ
authors: Caselli
authors: Department of Pathology, University of Washington, Seattle.
authors: Thomas J
authors: TJ
authors: Montine
authors: Arizona Alzheimer's Consortium, Phoenix, Arizona7Banner Alzheimer's Institute, Phoenix, Arizona8University of Arizona, Phoenix9Arizona State University, Phoenix10Translational Genomics Research Institute, Phoenix, Arizona.
authors: Eric M
authors: EM
authors: Reiman
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4