title: Free and cued memory in relation to biomarker-defined abnormalities in clinically normal older adults and those at risk for Alzheimer's disease.
abstract: OBJECTIVE
  Furthering our understanding of the relationship between amyloidosis (Aβ), neurodegeneration (ND), and cognition is imperative for early identification and early intervention of Alzheimer's disease (AD). However, the subtle cognitive decline differentially associated with each biomarker-defined stage of preclinical AD has yet to be fully characterized. Recent work indicates that different components of memory performance (free and cued recall) may be differentially specific to memory decline in prodromal AD. We sought to examine the relationship between free and cued recall paradigms, in addition to global composites of memory, executive functioning, and processing speed in relation to stages of preclinical AD.
  
  
  METHODS
  A total of 260 clinically normal (CN) older adults (CDR=0) from the Harvard Aging Brain study were grouped according to preclinical AD stages including Stage 0 (Aβ-/ND-), Stage 1 (Aβ+/ND-), Stage 2 (Aβ+/ND+), and suspected non-Alzheimer's associated pathology (SNAP; Aβ-/ND+). General linear models controlling for age, sex, and education were used to assess for stage-based performance differences on cognitive composites of executive functioning, processing speed, and memory in addition to free and cued delayed recall on the Selective Reminding Test (SRT) and Memory Capacity Test (MCT).
  
  
  RESULTS
  Global memory performance differed between preclinical stages with Stage 2 performing worse compared with Stage 0. When examining free and cued paradigms by memory test, only the MCT (and not the SRT) revealed group differences. More specifically, Stage 1 was associated with decrements in free recall compared with Stage 0 while Stage 2 was associated with decrements in both free and cued recall. There was a trend for the SNAP group to perform worse on free recall compared with Stage 0. Finally, there was no association between preclinical stage and global composites of executive functioning or processing speed.
  
  
  CONCLUSIONS
  Clinically normal older adults with underlying evidence of amyloidosis and neurodegeneration exhibit subtle, yet measurable differences in memory performance, but only on a challenging associative test. The sensitivity of free vs. cued memory paradigms may be dependent on preclinical stage such that reduced free recall is associated with amyloidosis alone (Stage 1) while a decline in cued recall may represent progression to amyloidosis and neurodegeneration (Stage 2). These findings may have practical applications for clinical assessment and clinical trial design.
authors.affiliation: Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: kpapp@partners.org.
authors.forename: Kathryn V
authors.initials: KV
authors.lastname: Papp
authors.affiliation: Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Amariglio
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Mormino
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Trey
authors.initials: T
authors.lastname: Hedden
authors.affiliation: Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Dekhytar
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Radiology, Massachusetts General Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Johnson
authors.affiliation: Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Massachusetts General Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Radiology, Massachusetts General Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
authors.affiliation: Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Massachusetts General Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Dorene M
authors.initials: DM
authors.lastname: Rentz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology / Q000523:psychology*; D000682:Amyloid / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D003463:Cues; D056344:Executive Function / Q000502:physiology; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D011939:Mental Recall / Q000502:physiology*; D008609:Mental Status Schedule; D009410:Nerve Degeneration / Q000000981:diagnostic imaging / Q000473:pathology; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D012306:Risk; D012720:Severity of Illness Index
chemical_list: D000682:Amyloid; D015415:Biomarkers
keywords: Biomarker stages; Free and cued memory; Preclinical Alzheimer’s disease