Cognitively-Related Basic Activities of Daily Living Impairment Greatly Increases the Risk of Death in Alzheimers Disease

Abstract

Introduction: Some Alzheimer's disease (AD) patients die without ever developing cognitively impaired basic activities of daily living (basic ADL), which may reflect slower disease progression or better compensatory mechanisms. Although impaired basic ADL is related to disease severity, it may exert an independent risk for death. This study examined the association between impaired basic ADL and survival of AD patients, and proposed a multistate approach for modeling the time to death for patients who demonstrate different patterns of progression of AD that do or do not include basic ADL impairment.

Methods: 1029 patients with probable AD at the Baylor College of Medicine Alzheimer's Disease and Memory Disorders Center met the criteria for this study. Two complementary definitions were used to define development of basic ADL impairment using the Physical Self-Maintenance Scale score. A weighted Cox regression model, including a time-dependent covariate (development of basic ADL impairment), and a multistate survival model were applied to examine the effect of basic ADL impairment on survival.

Results: As expected decreased ability to perform basic ADL at baseline, age at initial visit, years of education, and sex were all associated with significantly higher mortality risk. In those unimpaired at baseline, the development of basic ADL impairment was also associated with a much greater risk of death (hazard ratios 1.77-4.06) over and above the risk conferred by loss of MMSE points. A multi-state Cox model, controlling for those other variables quantified the substantive increase in hazard ratios for death conferred by the development of basic ADL impairment by two definitions and can be applied to calculate the short term risk of mortality in individual patients.

Conclusions: The current study demonstrates that the presence of basic ADL impairment or the development of such impairments are important predictors of death in AD patients, regardless of severity.

Fig 1. Three-state Markov chain used to derive predictive value of basic ADL impairment.

h_I(t) is the hazard rate for the time to basic ADL impairment. h_D1(t) is the hazard rate for the time to death among basic ADL-intact patients. h_D2(t) is the hazard rate for the time to death among basic ADL-impaired patients. The transitions between disease onset, development of basic ADL impairment, and death were modeled by quantifying the effect of baseline characteristics on basic ADL impairment and survival as well as the effect of developing basic ADL impairment on survival.

Fig 2. Predicted conditional probability of death for patients with and without cognitive based basic ADL impairment.

(A)In the left panel, impairment was defined by PSMS ≥ 7. (B)In the right panel, impairment was defined by PSMS ≥ 2 points of increase relative to baseline. The predicted conditional probability of death over the first 6 years was calculated for each sex (men in blue and women in red) assuming either intact (the solid lines) or impaired (the dashed lines) basic ADL at time of observation.