Identifying the optimal age to intervene in Alzheimer’s disease prevention trials: Validation of Emax modelling in sporadic Alzheimer’s disease

Abstract

AbstractBackgroundMany clinical trials of disease‐modifying therapies which seek to delay or prevent Alzheimer’s disease (AD) currently exist. However, a limitation of these trials is the absence of considering the earliest age groups at which decline in cognition can be detected to guide optimal participant recruitment.Previous work has shown that in people with Down syndrome, Emax modelling can be used to identify the trajectory of cognitive decline in the preclinical and prodromal stages of AD. We aimed to validate Emaxmodelling to identify the earliest age of change in cognition in people who developed sporadic AD and compare these individuals to healthy controls without AD.MethodOur sample consisted of participants aged 65 years old from the Enquête Sante ́ Psychologique – Risques, Incidence et Traitement (ESPRIT) study. Participants were categorised into two groups based on whether they were ever diagnosed with possible and probable AD while enrolled in the study (n = 101) or did not receive a diagnosis of any subtype of dementia (n = 1392, our healthy control group). We included measures of general cognitive functioning (Mini Mental State Examination; MMSE), verbal fluency, visual memory (Benton Visual Retention Test) and executive functioning (Trail Making Test).ResultIn people with AD, the earliest decline in general cognitive functioning could be detected in the 67‐71 age band while verbal fluency appears to decline from the 41‐45 age band and visual memory in the 82‐86 age band according to our model. In healthy controls, general cognitive functioning shows early change in the 87‐91 age band while verbal fluency starts to decline in the 43‐47 age band and executive functioning in the 85‐89 age band. Models for Trail Making Models for people with AD and visual memory for controls were not well fitted to the data.ConclusionWe have shown that sensitivity to change depend on the primary outcome so authors designing trials need to ensure the research question, population and primary outcome are consistent. This has implications particularly for trials targeting the stages of disease before dementia diagnosis.