Characterizing white matter injury in Alzheimer's disease

ABSTRACT Alzheimer’s disease (AD) affects roughly 6.9 million Americans aged 65 years and older; this number is projected to grow to 13.8 million by 2060. AD is caused by build-up of neurotoxic proteins, β-amyloid and tau, as well as reactive gliosis and neurodegeneration. Other pathologies, like white matter injury, a marker of cerebrovascular disease, might also influence pathological and/or clinical AD, either by (a) directly influencing AD pathology and/or (b) modifying the relationship between AD pathology on cognition. Notably, traditional vascular risks alone cannot fully explain white matter injury; some evidence suggests that structural and social determinants of health (sSDOH) may more comprehensively capture risk of white matter injury. Previous work quantified white matter injury as composite whole brain or lobar indices, which limits comprehensive interrogation of these lesions. With the recent introduction of therapies that successfully target AD pathology, it is critical to fill this gap in knowledge and fully characterize the risk factors for and consequences of white matter injury in AD, which will guide refinement of treatments. The long-term goal of this work is to characterize white matter injury in AD, which should inform refinement of disease-modifying therapies and preventive efforts. The objective of this application is to investigate risk factors for and consequences of white matter injury in brain regions characteristically affected by AD pathology using our novel, spatially precise method for measuring white matter injury, unhealthy white matter connectivity (UWMC). We hypothesize that UWMC in AD pathology-affected brain regions will (a) be directly associated with co-localized AD pathology, (b) interact with co-localized AD pathology to influence cognition, and (c) be associated with early- and mid-life sSDOH. Our study will leverage neuroimaging and neuropsychological data collected under six completed and ongoing studies conducted at University of Pittsburgh. We will derive UWMC in brain regions characteristically affected by β-amyloid, tau, neurodegeneration, and reactive astrogliosis. We will then test (a) direct cross- sectional and longitudinal relationships of co-localized UWMC with β-amyloid, tau, neurodegeneration, and reactive astrogliosis, and (b) interactive cross-sectional and longitudinal relationships of co-localized UWMC with β-amyloid, tau, neurodegeneration, and reactive astrogliosis on cognition. In a subset of participants, we will collect additional data on early- and mid-life sSDOH and interrogate associations of these measurements with late-life regional UWMC, β-amyloid, tau, neurodegeneration, reactive astrogliosis, and cognition. The successful completion of these aims will contribute to ongoing efforts to disentangle the complex etiology of pathological and clinical AD. By leveraging state-of-the art neuroimaging techniques to investigate an emerging pathological marker, white matter injury, we are positioned to potentially identify novel disease targets, around which efforts to effectively prevent onset and progression of AD can be designed.