There is an urgent need for reliable monitoring markers in Alzheimer’s disease (AD) clinical trials, especially for neuroinflammation. Specific and sensitive follow-up markers for AD patients in clinical care are also critically needed. Most currently available biomarkers in AD are used for diagnostic, such as blood-based biomarkers (e.g. amyloid-beta). White matter microstructure deterioration, which can be assessed in vivo using diffusion MRI (dMRI), is now known to be an early event in the development of AD, happening in preclinical stages. Several studies have shown that dMRI measures within the white matter can detect disease earlier than hippocampal volume and are better predictors of future cognitive decline in MCI. Most importantly, our dMRI measures of neuroinflammation, demyelination and axonal disruption showed great promise as:

i) disease progression biomarkers in the longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, with greater relative sensitivity to change along the disease continuum compared to blood-based AD pathology markers.

ii) monitoring endpoints in a phase 1 clinical trial, with important improvements of these measures in AD-vulnerable white matter tracts throughout the study.

In this project, we will first validate and compare our 3 novel dMRI biomarkers of neuroinflammation, demyelination and axonal disruption with other recognized, gold standard, and validated imaging and fluid-based markers in the TRIAD cohort. TRIAD is the largest longitudinal study across the AD spectrum with microglial activation PET imaging and cutting-edge MRI. Secondly, we will evaluate longitudinal trajectories of our biomarkers along the disease continuum, with respect to gold standard cognitive and memory tests, and confirm their potential for a “monitoring” context of use in AD clinical trials. The outcome of this proposal will be the submission of a Biomarker Qualification Program to the FDA, for the approbation of our biomarkers as monitoring endpoints for future AD clinical trials.