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Table 1 FDA-proposed stages for drug development vis-à-vis the preclinical AD, MCI due to AD, and AD dementia phases of AD proposed by NIA-AA

From: Meaningful benefits: a framework to assess disease-modifying therapies in preclinical and early Alzheimer’s disease

AD stage Clinical/biomarker presentation Cognitive and functional assessment AD clinical continuum correlate
1 No cognitive impairment, including no subjective complaints, but AD pathology is present No detectable abnormalities with sensitive neuropsychological measures Preclinical
2 Transitional cognitive change from individual baseline, with cognition remaining within normal bounds and no functional impairment
AD pathology is present
Detectable change on sensitive neuropsychological measures or subjective report of change Preclinical
3 Subtle or more apparent objective cognitive impairment
Impairment in ability to perform instrumental activities of daily living
No loss of independence
AD pathology is present
Detectable abnormalities on sensitive neuropsychological measures; mild but detectable functional impairments on sensitive measures MCI due to AD
4 From 4 to 6, gradual progression on levels of cognitive impairment; impact on ability to perform basic activities of daily living and loss of independence
AD pathology is present
Detectable abnormalities on COAs of cognition and function Mild AD dementia
5 Moderate AD dementia
6 Severe AD dementia
  1. Abbreviations: AD Alzheimer’s disease, COA clinical outcome assessment, MCI mild cognitive impairment