Disease severity and mortality in Alzheimer's disease: an analysis using the U.S. National Alzheimer's Coordinating Center Uniform Data Set

Abstract

Background: Evidence on the relative risk of death across all stages of Alzheimer's disease (AD) is lacking but greatly needed for the evaluation of new interventions. We used data from the Uniform Data Set (UDS) of the National Alzheimer's Coordinating Center (NACC) to assess the expected survival of a person progressing to a particular stage of AD and the relative risk of death for a person in a particular stage of AD compared with cognitively normal (CN) people.

Methods: This was a retrospective observational cohort study of mortality and its determinants in participants with incident mild cognitive impairment (MCI) due to AD or AD dementia compared with CN participants. Overall survival and hazard ratios of all-cause mortality in participants ≥ 50 years of age with clinically assessed or diagnosed MCI due to AD, or mild, moderate, or severe AD dementia, confirmed by Clinical Dementia Rating scores, versus CN participants were estimated, using NACC UDS data. Participants were followed until death, censoring, or until information to determine disease stage was missing.

Results: Aged between 50 and 104 years, 12,414 participants met the eligibility criteria for the study. Participants progressing to MCI due to AD or AD dementia survived a median of 3-12 years, with higher mortality observed in more severe stages. Risk of death increased with the severity of AD dementia, with the increase significantly higher at younger ages. Participants with MCI due to AD and CN participants had a similar risk of death after controlling for confounding factors.

Conclusions: Relative all-cause mortality risk increases with AD severity, more so at younger ages. Mortality does not seem to be higher for those remaining in MCI due to AD. Findings might imply potential benefit of lower mortality if preventing or delaying the progression of AD is successful, and importantly, this potential benefit might be greater in relatively younger people. Future research should replicate our study in other samples more representative of the general US population as well as other populations around the world.

Keywords: Alzheimer; Comorbidity; Institution; Mild cognitive impairment; Mortality; Predementia; Prodromal AD.

Fig. 1

Overall survival of participants progressing to a particular stage of AD. Shaded areas show 95% confidence intervals. Some participants contribute to several stages upon progression. Please note, any comparison across stages underestimates the uncertainty because some participants contribute to several cohorts. The curve of cognitively normal lacks a relevant clinical interpretation as the starting point is their first visit at ≥ 50 years of age. Kaplan–Meier estimators were not stratified by age or other predictors; they describe the overall survival of participants with the age distribution of our sample cohorts. Numbers at risk at 0, 5, 10, and 15 years respectively: CN: 11458, 4185, 1272, 64; MCI due to AD: 937, 249, 50, 0; mild AD dementia: 522, 139, 11, 0; moderate AD dementia: 457, 77, 2, 0; severe AD dementia: 85, 8, 0, 0. AD Alzheimer’s disease, CN cognitively normal, MCI mild cognitive impairment

Fig. 2

Hazard ratios (filled lines) with 95% confidence intervals (dashed lines) of risk of death compared with cognitively normal participants by disease stage (panels) and age (x-axis). AD Alzheimer’s disease