Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease

Nancy J. Donovan, Rebecca E. Amariglio, Amy S. Zoller, Rebecca K. Rudel, Teresa Gomez-Isla, Deborah Blacker, Bradley T. Hyman, Joseph J. Locascio, Keith A. Johnson, Reisa A. Sperling, Gad A. Marshall, Dorene M. Rentz

Research output: Contribution to journalArticlepeer-review

168 Scopus citations


Objective To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD). Methods From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms. Results Higher/better memory-semantic factor score predicted lower hazard of progression (hazard ratio [HR] = 0.4 for 1 standard deviation [SD] increase, p <0.0001), and higher/worse affective factor score predicted higher hazard (HR = 1.3 for one SD increase, p = 0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a fourfold risk of progression compared with CN (HR = 4.1, p <0.0001). Conclusion These results identify affective and memory-semantic factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI.

Original languageEnglish
Pages (from-to)1642-1651
Number of pages10
JournalAmerican Journal of Geriatric Psychiatry
Issue number12
StatePublished - 1 Dec 2014
Externally publishedYes


  • Alzheimer disease
  • NNeuropsychiatric and neuropsychological factors
  • mild cognitive impairment
  • subjective cognitive concerns


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