Amyloid negativity in patients with clinically diagnosed Alzheimer disease and MCI

Neurology. 2016 Apr 12;86(15):1377-1385. doi: 10.1212/WNL.0000000000002576. Epub 2016 Mar 11.


Objective: To examine the clinical and biomarker characteristics of patients with amyloid-negative Alzheimer disease (AD) and mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a prospective cohort study.

Methods: We first investigated the reliability of florbetapir- PET in patients with AD and patients with MCI using CSF-Aβ1-42 as a comparison amyloid measurement. We then compared florbetapir- vs florbetapir+ patients with respect to several AD-specific biomarkers, baseline and longitudinal cognitive measurements, and demographic and clinician report data.

Results: Florbetapir and CSF-Aβ1-42 +/- status agreed for 98% of ADs (89% of MCIs), indicating that most florbetapir- scans were a reliable representation of amyloid status. Florbetapir- AD (n = 27/177; 15%) and MCI (n = 74/217, 34%) were more likely to be APOE4-negative (MCI 83%, AD 96%) than their florbetapir+ counterparts (MCI 30%, AD 24%). Florbetapir- patients also had less AD-specific hypometabolism, lower CSF p-tau and t-tau, and better longitudinal cognitive performance, and were more likely to be taking medication for depression. In MCI only, florbetapir- participants had less hippocampal atrophy and hypometabolism and lower functional activity questionnaire scores compared to florbetapir+ participants.

Conclusions: Overall, image analysis problems do not appear to be a primary explanation of amyloid negativity. Florbetapir- ADNI patients have a variety of clinical and biomarker features that differ from their florbetapir+ counterparts, suggesting that one or more non-AD etiologies (which may include vascular disease and depression) account for their AD-like phenotype.

Publication types

  • Multicenter Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / diagnostic imaging*
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Biomarkers / metabolism
  • Cognitive Dysfunction / diagnostic imaging*
  • Cognitive Dysfunction / metabolism*
  • Cohort Studies
  • Female
  • Follow-Up Studies
  • Humans
  • Longitudinal Studies
  • Magnetic Resonance Imaging
  • Male
  • Peptide Fragments / metabolism*
  • Positron-Emission Tomography
  • Prospective Studies


  • Amyloid beta-Peptides
  • Biomarkers
  • Peptide Fragments
  • amyloid beta-protein (1-42)