Memory decline accompanies subthreshold amyloid accumulation

Neurology. 2018 Apr 24;90(17):e1452-e1460. doi: 10.1212/WNL.0000000000005354. Epub 2018 Mar 23.


Objective: Extensive cortical β-amyloid (Aβ positivity) has been linked to cognitive decline, but the clinical significance of elevations in Aβ within the negative range is unknown.

Methods: We examined amyloid and cognitive trajectories (memory, executive function) in 142 cognitively normal older individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative who were Aβ-negative at baseline and who had at least 2 [18F]-florbetapir PET scans over 3.9 ± 1.4 years. We determined whether Aβ accumulation was associated with longitudinal changes in memory or executive function.

Results: Among baseline-negative individuals, florbetapir slope (mean annual increase 0.002 ± 0.008 standardized uptake value ratio units/y) was not related to age, sex, education, APOE4 status, baseline memory or executive function, temporoparietal glucose metabolism, baseline hippocampal volume, or hippocampal volume change; but it was related to higher baseline cortical florbetapir, indicating that Aβ accumulation was ongoing at baseline in those who accumulated during the study. Over the course of follow-up, 13 individuals converted to florbetapir+ and 14 nearly nonoverlapping individuals converted to mild cognitive impairment or Alzheimer disease. Amyloid accumulation among baseline-negative individuals was associated with poorer longitudinal memory performance (p = 0.019), but it was not associated with changes in executive function. Reducing the sample to individuals with at least 3 timepoints to estimate the florbetapir slope strengthened the relationship further between florbetapir accumulation and memory decline (p = 0.007).

Conclusions: Memory decline accompanies Aβ accumulation in otherwise healthy, Aβ-negative older adults. Amyloid increases within the negative range may represent the earliest detectable indication of pathology with domain-specific cognitive consequences.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / diagnostic imaging*
  • Alzheimer Disease / metabolism*
  • Amyloid / metabolism*
  • Aniline Compounds / metabolism
  • Ethylene Glycols / metabolism
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Memory Disorders / diagnostic imaging*
  • Memory Disorders / metabolism*
  • Middle Aged
  • Neuropsychological Tests
  • Oxygen Radioisotopes / metabolism
  • Positron-Emission Tomography
  • Retrospective Studies
  • Time Factors


  • Amyloid
  • Aniline Compounds
  • Ethylene Glycols
  • Oxygen Radioisotopes
  • florbetapir