F2-03-04: assessing clinical meaningfulness of outcomes in the alzheimer's prevention initiative generation program

The Alzheimer's Prevention Initiative Generation Program consists of two trials: Generation Studies 1 and 2. Generation Study 1 is recruiting cognitively unimpaired APOE4 homozygotes ages 60-75; Generation Study 2 is recruiting cognitively unimpaired APOE4 carriers (homozygotes and heterozygotes, heterozygotes must also have elevated brain amyloid). Both are evaluating whether amyloid-based treatments can delay or prevent the onset of clinical symptoms associated with AD. Primary endpoints in both trials are time-to-event (diagnosis of MCI or dementia due to AD) and change in the APCC (Alzheimer's Prevention Initiative Preclinical Cognitive Composite) Test Score. The APCC is an empirically derived composite cognitive endpoint that also incorporates a theoretical understanding of clinical progression of AD. Partial least squares (PLS) regression analyses were used to examine longitudinal data from three observational cohort studies, identifying the combination of cognitive assessments optimally sensitive to tracking preclinical cognitive decline in individuals who subsequently progressed to the clinical stages of MCI or dementia due to AD while controlling for normal aging and practice effects using data from those who remained cognitively unimpaired. The Insights to Model Alzheimer's Progression in real life (iMAP) study is a 5-year, multinational, prospective, longitudinal, non-interventional cohort study being launched to assess the ability of the APCC and other cognitive batteries to predict clinically meaningful outcomes. The APCC consists of Word List Delayed, Logical Memory Delayed, Symbol Digit Modalities, Judgment of Line Orientation, Ravens Progressive Matrices Subset, MMSE Orientation to Place and Time. iMAP will recruit 1270 participants, of whom 620 will be cognitively unimpaired, 300 with MCI, and 350 with mild AD. A high proportion of APOE4 carriers will be enrolled to increase likelihood of progression in cognitively unimpaired participants. In other cohorts, no enrichment is planned. iMAP is the first large scale, prospective effort, to establish clinical meaningfulness of composite cognitive endpoints. The study is being conducted in parallel to the Generation Program to capture later disease stages and comply with the regulatory requirements.