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Roee Holtzer, PhD; Joe Verghese, MD; Cuiling Wang, PhD; Charles B. Hall, PhD; Richard B. Lipton, MD

JAMA. 2008;300(7):823-830.

Context  Neuropsychological tests are used to predict and diagnose dementia. However, to our knowledge, no studies to date have examined whether within-person across-neuropsychological test variability predicts dementia.

Objective  To examine whether within-person across-neuropsychological test variability predicts future dementia.

Design  The Einstein Aging Study (EAS) is a population-based longitudinal study of aging and dementia located in Bronx County, New York. We used Cox proportional hazards models using age as the time scale to estimate hazard ratios (HRs) for performance on individual neuropsychological tests (Free and Cued Selective Reminding Test, Digit Symbol Substitution subtest of the Wechsler Adult Intelligence Scale Revised, and the Vocabulary subtest of the Wechsler Adult Intelligence Scale Revised) and for within-person across-neuropsychological test variability as predictors of incident dementia. Analyses were stratified by sex, and controlled for education and medical illness.

Setting and Participants  A total of 1797 participants (age 70 years) enrolled in the EAS between October 1993 and December 2007. Participants seen for the baseline visit only (n = 750), prevalent dementia cases (n = 72), and those with missing follow-up information (n = 78) were excluded. A total of 897 individuals were included in this investigation. Participants had follow-up visits every 12 to 18 months.

Main Outcome Measure  Incident dementia.

Results  Sixty-one cases of incident dementia were identified during follow-up (mean [SD], 3.3 [2.4] years), of which 26 were in the highest quartile of within-person across-neuropsychological test variability. Adjusting for sex, education, and medical illness, variability was associated with incident dementia (HR for 1-point difference in variability, 3.93 [95% confidence interval {CI}, 2.04-7.56]). The association persisted even after adjusting for level of performance on individual neuropsychological tests (HR for 1-point difference in variability, 2.10 [95% CI, 1.04-4.23]). Comparing Cox models using neuropsychological tests with and without within-person across-neuropsychological test variablity showed that the former improved the prediction of dementia. Sensitivity in a model predicting dementia at 1 year also improved when neuropsychological test variability was included.

Conclusions  In this population, within-person across-neuropsychological test variability was associated with development of incident dementia independent of neuropsychological test performance. This finding needs to be confirmed in future studies.

Author Affiliations: Departments of Neurology (Drs Holtzer, Verghese, and Lipton) and Epidemiology and Population Health (Drs Wang, Hall, and Lipton), Ferkauf Graduate School of Psychology (Dr Holtzer), and Institute for Aging Research (Dr Lipton), Albert Einstein College of Medicine, Yeshiva University, Bronx, New York.

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