OBJECTIVES:  Development efforts for disease-modifying treatments (DMTs) in Alzheimer’s disease (AD) are increasingly focused on the predementia stages of the disease, where efficacy endpoints are less established and may include a combination of biomarker levels and more sensitive cognitive scales than are used in clinical practice. Demonstrating the economic value of DMTs indicated for the predementia stages of AD requires a modeling approach that translates these sensitive endpoints to long-term disease progression and AD dementia onset. METHODS:  A natural history microsimulation model of AD was developed to generate lifetime patient-level trajectories for cognitive, behavioral, and functional symptoms for patients who are asymptomatic, at-risk for developing Alzheimer’s dementia (ARAD), defined by elevated beta-amyloid levels but not yet meeting mild cognitive impairment due to AD criteria. A targeted literature review was conducted to estimate trajectories prior to AD dementia onset, after which published AD dementia trajectories were used. The natural history model was validated against published epidemiological studies and used to estimate the potential impact of DMTs for ARAD patients on clinical outcomes that drive costs in AD. RESULTS:  Compared with natural history, a DMT for ARAD that reduces the rate of progression by 20-50% decreases the lifetime likelihood of AD dementia (29-38% vs. 43%) and AD-related institutionalization (11-17% vs. 21%). A DMT that halts progression for 5 years reduces the lifetime likelihood of AD dementia to 27% (12% institutionalization), with a further reduction to 17-23% (6-9% institutionalization) if the halt in progression is followed by a 20-50% reduction in progression rate. CONCLUSIONS:  DMTs for ARAD have the potential to reduce progression to AD dementia and institutionalization and thus to reduce AD-related costs. Studies relating biomarker and sensitive cognitive endpoints to long-term progression patterns are essential, as the specific form of these relationships significantly influences the economic value of DMTs for ARAD.