"What is N?" Towards operationalizing neurodegeneration in Alzheimer's and related dementias

PROJECT SUMMARY / ABSTRACT Neurodegeneration markers (N markers) are associated with cognitive impairment in Alzheimer's disease (AD) and related dementias. Since they are more proximally related to cognitive decline than AD-specific biomarkers (amyloid and tau measures), they have been proposed as surrogate endpoints in clinical trials and even for prognosis in the clinical setting. Despite the promise of N markers, several barriers to their implementation exist. The major limitations include i) only validation in convenience samples that exclude those with significant cerebrovascular disease rather than the general population, ii) lack of systematic comparison of the frequently used N markers across modalities (i.e., imaging, CSF, blood) to predict cognitive outcomes at varying levels of AD and cerebrovascular disease pathology, and iii) lack of understanding of the pathological profile associated with each N marker. In the current application, our overall goal is to understand the unique information each N marker (imaging, CSF, blood) provides with regards to cognitive decline and underlying pathology to optimize their use in clinical practice and clinical trials. We will utilize the Mayo Clinic Study of Aging (MCSA) a longitudinal population-based study where participants undergo psychometric, neurologic, and neuroimaging investigations (MRI, amyloid and tau PET, FDG PET), and blood draws; a subset also have CSF and/or post- mortem data as the primary dataset for this grant. In Aim 1, we will compare N markers from neuroimaging, CSF, and blood in MCSA in relation to demographics (including socioeconomic status), in vivo AD (amyloid and tau PET) and cerebrovascular disease biomarkers, and cognition. We will validate some of these relationships in a biracial Mayo Clinic Jacksonville sample and in ADNI. In Aim 2, we will conduct an ante- mortem N marker – post-mortem validation study to determine the pathological profiles associated with (each and combination of) N markers. The findings of the grant will lead to better understanding of N markers associated with longitudinal cognitive decline and the pathologies associated these N markers. This knowledge will inform clinical trial design and guidance of which N marker(s) to choose for future clinical use for AD and ADRD.