Empirically Derived Trajectories to Dementia Over 15 Years of Follow-up Identified by Using Mixed Membership Models

Alzheimer disease is the most common form of dementia in the elderly, and the complex relationships among risk factors produce highly variable natural histories from normal cognition through the prodromal stage of mild cognitive impairment (MCI) to clinical dementia. We used a novel statistical approach, mixed membership trajectory models, to capture the variety of such pathways in 652 participants in the Cardiovascular Health Study Cognition Study over 22 years of follow-up (1992-2014). We identified 3 trajectories: a healthy profile with a peak probability of MCI between 95 and 100 years of age and only a 50% probability of dementia by age 100; an intermediate profile with a peak probability of MCI between 85 and 90 years of age and progression to dementia between 90 and 95 years; and an unhealthy profile with a peak probability of progressing to MCI between ages 75 and 80 years and to dementia between the ages of 80 and 85 years. Hypertension, education, race, and the epsilon 4 allele of the apolipoprotein E gene all affected the closeness of an individual to 1 or more of the canonical trajectories. These results provide new insights into the natural history of Alzheimer disease and evidence for a potential difference in the pathophysiology of the development of dementia.