Background: Alzheimer’s Disease (AD) can be conceptualized as a continuum: patients progress
from normal cognition to mild cognitive impairment (MCI) due to AD, followed by increasing
severity of AD dementia. Prior research has measured transition probabilities among later stages of AD,
but not for the complete spectrum.
Objective: To estimate annual progression rates across the AD continuum and evaluate the impact of a
delay in MCI due to AD on the trajectory of AD dementia and clinical outcomes.
Methods: Patient-level longitudinal data from the National Alzheimer’s Coordinating Center for
n=18,103 patients with multiple visits over the age of 65 were used to estimate annual, age-specific transitional
probabilities between normal cognition, MCI due to AD, and AD severity states (defined by
Clinical Dementia Rating score). Multivariate models predicted the likelihood of death and institutionalization
for each health state, conditional on age and time from the previous evaluation. These probabilities
were used to populate a transition matrix describing the likelihood of progressing to a particular
disease state or death for any given current state and age. Finally, a health state model was developed to
estimate the expected effect of a reduction in the risk of transitioning from normal cognition to MCI due
to AD on disease progression rates for a cohort of 65-year-old patients over a 35-year time horizon.
Results: Annual transition probabilities to more severe states were 8%, 22%, 25%, 36%, and 16% for
normal cognition, MCI due to AD, and mild/moderate/severe AD, respectively, at age 65, and increased
as a function of age. Progression rates from normal cognition to MCI due to AD ranged from 4% to 10%
annually. Severity of cognitive impairment and age both increased the likelihood of institutionalization
and death. For a cohort of 100 patients with normal cognition at age 65, a 20% reduction in the annual
progression rate to MCI due to AD avoided 5.7 and 5.6 cases of MCI due to AD and AD, respectively.
This reduction led to less time spent in severe AD dementia health states and institutionalized, and increased
Conclusion: Transition probabilities from normal cognition through AD severity states are important for
understanding patient progression across the AD spectrum. These estimates can be used to evaluate the
clinical benefits of reducing progression from normal cognition to MCI due to AD on lifetime health