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Deborah Blacker, MD, ScD; Hang Lee, PhD; Alona Muzikansky, MS; Emily C. Martin, PhD; Rudolph Tanzi, PhD; John J. McArdle, PhD; Mark Moss, PhD; Marilyn Albert, PhD

Arch Neurol. 2007;64(6):862-871.

Objective  To examine neuropsychological measures among normal individuals that predict time to subsequent cognitive decline.

Design  Cognitive performance, as measured by 6 neuropsychological tests, was examined at baseline. Participants were followed up for approximately 5 years. Cox proportional hazards models were used to evaluate the neuropsychological measures at baseline that predicted time to progression from normal cognition to mild impairment. Comparable data also examined time to progression from mild impairment to a diagnosis of Alzheimer disease.

Setting  Community volunteer-based sample examined at a medical institution.

Participants  One hundred and seven individuals who were cognitively normal and 235 individuals with mild cognitive impairment at baseline.

Main Outcome Measures  Time to progression from normal cognition to mild impairment and time to progression from mild impairment to a diagnosis of Alzheimer disease.

Results  The risk of progressing from normal to mild impairment was considerably greater among those with lower scores on tests of episodic memory (eg, hazard ratio for a 1-SD decrease in the California Verbal Learning Test, 0.55; P<.001). Normal individuals who carried at least 1 copy of the apolipoprotein E 2 allele were less likely to develop cognitive impairments over time than individuals with no 2 allele (hazard ratio for presence of allele, 0.13; P = .006). Measures of both episodic memory and executive function were significant predictors of time to progression from mild impairment to a clinical diagnosis of Alzheimer disease (eg, hazard ratio for a 1-SD decrease in California Verbal Learning Test score, 0.67; P = .005; hazard ratio for a 1-SD increase in the time to complete part B of the Trail Making test, 1.40; P = .007). Among individuals with mild impairments, the apolipoprotein E 4 allele increased risk for Alzheimer disease in a dose-dependent manner; however, this effect was not significant within the context of multivariable models.

Conclusions  Episodic memory performance among normal individuals predicts time to progression to mild impairment while apolipoprotein E 2 status is associated with lower risk of cognitive decline among normal individuals. Tests of both episodic memory and executive function are predictors of time to progression from mild impairment to a clinical diagnosis of Alzheimer disease.

Author Affiliations: Departments of Psychiatry (Dr Blacker), Medicine (Dr Lee and Ms Muzikansky), and Neurology (Dr Tanzi), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Biostatistics, Harvard School of Public Health, Boston, Mass (Dr Martin); Department of Psychology, University of Southern California, Los Angeles (Dr McArdle); Department of Anatomy and Neurobiology, Boston University, Boston, Mass (Dr Moss); Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Md (Dr Albert). Dr Martin is currently with Wyeth Research, Cambridge, Mass.

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