Longitudinal Study of the Transition From Healthy Aging to Alzheimer Disease

BACKGROUND: Detection of the earliest cognitive changes signifying Alzheimer disease is difficult. OBJECTIVE: To model the cognitive decline in preclinical Alzheimer disease. DESIGN: Longitudinal archival study comparing individuals who became demented during follow-up and people who remained nondemented on each of 4 cognitive factors: global, verbal memory, visuospatial, and working memory. SETTING: Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri. PARTICIPANTS: One hundred thirty-four individuals who became demented during follow-up and 310 who remained nondemented. MAIN OUTCOME MEASURES: Inflection point in longitudinal cognitive performance. RESULTS: The best-fitting model for each of the 4 factors in the stable group was linear, with a very slight downward trend on all but the Visuospatial factor. In contrast, a piecewise model with accelerated slope after a sharp inflection point provided the best fit for the group that progressed. The optimal inflection point for all 4 factors was prior to diagnosis of dementia: Global, 2 years; Verbal and Working Memory, 1 year; and Visuospatial, 3 years. These results were also obtained when data were limited to the subset (n = 44) with autopsy-confirmed Alzheimer disease. CONCLUSIONS: There is a sharp inflection point followed by accelerating decline in multiple domains of cognition, not just memory, in the preclinical period in Alzheimer disease when there is insufficient cognitive decline to warrant clinical diagnosis using conventional criteria. Early change was seen in tests of visuospatial ability, most of which were speeded. Research into early detection of cognitive disorders using only episodic memory tasks may not be sensitive to all of the early manifestations of disease