title: Synergistic effect of β-amyloid and neurodegeneration on cognitive decline in clinically normal individuals.
abstract: OBJECTIVE
  Assessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes.
  
  
  OBJECTIVE
  To determine whether neuroimaging markers of β-amyloid (Aβ) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals.
  
  
  METHODS
  Academic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women).
  
  
  METHODS
  The Aβ status was determined with Pittsburgh Compound B-positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease-vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (Aβ-/ND-), stage 1 (Aβ(+)/ND-), stage 2 (Aβ(+)/ND(+)), and suspected non-Alzheimer disease pathology (Aβ-/ND(+)). Cognition was assessed with a composite of neuropsychological tests administered annually.
  
  
  RESULTS
  The Aβ(+) CN individuals were more likely to be classified as ND+: 59.6% of Aβ(+) CN individuals were ND(+), whereas 31.9% of Aβ- CN individuals were ND(+) (odds ratio, 3.14; 95% CI, 1.44-7.02; P = .004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both Aβ and ND, whereas diminished practice effects were observed in CN individuals positive for either Aβ or ND. Decline over time was observed only in CN individuals positive for both Aβ and ND, and decline in this group was significantly greater than that in all other groups (P < .001 for all). A significant interaction term between Aβ and ND confirmed that this decline was greater than the additive contributions of Aβ and ND (P = .04).
  
  
  CONCLUSIONS
  The co-occurrence of Aβ and ND accelerates cognitive decline in CN individuals. Therefore, both factors are important to consider in upcoming secondary prevention trials targeting CN individuals at high risk for progression to the symptomatic stages of Alzheimer disease.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Mormino
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown4Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Trey
authors.initials: T
authors.lastname: Hedden
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston3Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Schultz
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston5Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Amariglio
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston5Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Dorene M
authors.initials: DM
authors.lastname: Rentz
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston4Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston5Center for Alzheimer Research and Treatment, Department of Neurology, Brigham a.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Johnson
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston4Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston5Center for Alzheimer Research and Treatment, Department of Neurology, Brigham a.
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009483:Neuropsychological Tests
chemical_list: D016229:Amyloid beta-Peptides