An Initial Empirical Operationalization of the Earliest Stages of the Alzheimer's Continuum

Alzheimer Dis Assoc Disord. 2021 Jan-Mar;35(1):62-67. doi: 10.1097/WAD.0000000000000408.


Purpose: The Alzheimer's Continuum (AC) includes 2 preclinical stages defined by subjective cognitive complaints, transitional cognitive declines, and neurobehavioral symptoms. Operationalization of these stages is necessary for them to be applied in research.

Methods: Cognitively normal individuals with known amyloid biomarker status were selected from the National Alzheimer's Coordinating Center Uniform Data Set. Participants and their caregivers provided information on subjective cognitive complaints, neurobehavioral features, and objective cognitive functioning.

Patients: The sample included 101 amyloid positive (A+) and 447 amyloid negative (A-) individuals.

Results: Rates of subjective cognitive complaints (A+: 34.90%, A-: 29.90%) and neurobehavioral symptoms (A+: 22.40%, A-: 22.40%) did not significantly differ between A+/- individuals. However, the frequency of transitional cognitive decline was significantly higher among A+ (38.00%) than A- participants (24.90%). We explored various empirical definitions for defining the early stages of the AC among A+ participants. Rates of classification into AC stage 1 versus AC stage 2 varied depending on the number of symptoms required: 57.40% versus 42.60% (1 symptom), 28.70% versus 71.30% (2 symptoms), and 6.90% versus 93.10% (all 3 symptoms).

Conclusion: The presence of 2 of the proposed symptom classes to separate AC stage 2 from stage 1 seems to provide a good empirical balance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Alzheimer Disease / diagnosis*
  • Amyloid / metabolism
  • Amyloidosis
  • Cognition
  • Cognitive Dysfunction / psychology*
  • Disease Progression*
  • Female
  • Humans
  • Male
  • Neuropsychological Tests / statistics & numerical data
  • Prodromal Symptoms*


  • Amyloid