Trajectories of cognitive decline in Alzheimer's disease

Abstract

Background: Late-onset Alzheimer disease (LOAD) is a clinically heterogeneous complex disease defined by progressively disabling cognitive impairment. Psychotic symptoms which affect approximately one-half of LOAD subjects have been associated with more rapid cognitive decline. However, the variety of cognitive trajectories in LOAD, and their correlates, have not been well defined. We therefore used latent class modeling to characterize trajectories of cognitive and behavioral decline in a cohort of AD subjects.

Methods: 201 Caucasian subjects with possible or probable Alzheimer's disease (AD) were evaluated for cognitive and psychotic symptoms at regular intervals for up to 13.5 years. Cognitive symptoms were evaluated serially with the Mini-mental State Examination (MMSE), and psychotic symptoms were rated using the CERAD behavioral rating scale (CBRS). Analyses undertaken were latent class mixture models of quadratic trajectories including a random intercept with initial MMSE score, age, gender, education, and APOE 4 count modeled as concomitant variables. In a secondary analysis, psychosis status was also included.

Results: AD subjects showed six trajectories with significantly different courses and rates of cognitive decline. The concomitant variables included in the best latent class trajectory model were initial MMSE and age. Greater burden of psychotic symptoms increased the probability of following a trajectory of more rapid cognitive decline in all age and initial MMSE groups. APOE 4 was not associated with any trajectory.

Conclusion: Trajectory modeling of longitudinal cognitive and behavioral data may provide enhanced resolution of phenotypic variation in AD.

Figure 1

Cognitive Trajectories of AD subjects and representative concomitant distributions of the trajectories for ages 68 and 78 and initial MMSE scores of 16, 21, and 26. In the top panel, the vertical axis represents MMSE scores; the horizontal axis represents years of follow-up. In the bottom panel the lengths of the bars represent the probabilities of a subject with a particular combination of concomitant variable values falling along the correspondingly colored trajectory. The horizontal extent of each bar represents 100%.

Figure 2

Cognitive and behavioral trajectories of AD subjects. In the top panel, the vertical axis represents MMSE scores; the horizontal axis represents years of follow-up. The bottom panel is a graphical representation of the probabilities of belonging to a particular trajectory for subjects with particular combinations of initial MMSE, sex and psychosis status. P=Psychotic; N= not Psychotic; 26/21/16=initial MMSE, 68/78=age.