P1-106: Longitudinal biomarker connectivity on middle-aged asymptomatic individuals and optimal design on prevention trials of Alzheimer's disease

Neurodegenerative processes associated with Alzheimer disease (AD) may begin in middle age, years before symptom onset. Ongoing secondary prevention trials all employ biomarkers in the inclusion criteria and/or as the efficacy outcomes. It remains unknown how the longitudinal rates of changes in biomarkers are associated among asymptomatic middle- to old-aged individuals, and how the biomarker connectivity can help to better design prevention trials in AD. 209 asymptomatic middle- to old-aged individuals were longitudinally assessed with the following markers: clinical and cognitive measures, magnetic resonance imaging (MRI)-based regional brain volumes, cerebrospinal fluid (CSF) biomarkers, and molecular imaging of cerebral amyloid with positron emission tomography (PET) using Pittsburgh Compound-B(PIB). Multivariate mixed models for repeated measures were used to assess the correlations of the rate of longitudinal changes across these markers. A faster intra-individual decrease of CSF Aβ42 over time was associated with a faster intra-individual increase of PIB mean cortical standardized uptake value ratio (MCSUVR), but not other markers. The rate of change in CSF Tau (Ptau181) was positively correlated with the rate of change in PIB MCSUVR and negatively correlated with hippocampal volume and global cognition. The rate of change in hippocampal volume was positively correlated with the rate of change in global cognition. Only three significant correlations were observed cross sectionally at baseline: CSF Aβ42 and PIB MCSUVR, CSF Tau and PIB MCSUVR, and CSF Aβ42 and global cognition. Sample sizes of prevention trials of AD in middle- to old-aged asymptomatic individuals can be significantly reduced if the rates of biomarker changes are used to identify at-risk subjects for such trials. Among middle- to old-aged asymptomatic individuals, longitudinal changes in CSF Tau (Ptau181), cortical PIB binding, and hippocampal volume are all associated with each other, whereas CSF Aβ42 is associated only with PIB binding. Unlike the baseline values, the longitudinal rates of change in CSF Tau (Ptau181) and hippocampal volume are all correlated with the rate of change in global cognition, validating the role of these biomarkers in tracking antecedent disease progression and in designing prevention trials in AD. Funding:. NIA P01 AG026276 (PI: JC Morris).