Evaluation of the neurovascular unit in the setting of pathogenesis and treatment of autosomal dominant Alzheimer disease

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PROJECT SUMMARY The overall objective of this proposal is to support the candidate’s career development and transition to that of an independent researcher. The outlined training plan will equip the applicant with the necessary skills to conduct innovative research in a rich, interdisciplinary, and collaborative environment, facilitating the investigation of new avenues of clinical research and trials. By utilizing multimodal imaging techniques and molecular and cellular proteomic approaches, the candidate will reinforce an already strong background in neuroimaging, learn and integrate new approaches to gain a greater holistic understanding of Alzheimer disease (AD) etiology and pathophysiology, and contribute to the success of potential new therapies for AD. β- amyloid (Aβ), one of the earliest biomarkers to accumulate during AD progression, is the most targeted factor for therapeutic intervention. However, other components, such as vascular and inflammatory/immune changes, also occur during AD progression, adding to the complexity of fully characterizing AD pathogenesis. The neurovascular unit (NVU) is relevant to the study of vascular, immune, and Aβ changes in AD, as it comprises neuronal-astrocyte signaling and the blood-brain barrier, which play a role in Aβ clearance. Age-related comorbidities in late-onset AD (LOAD) are challenging to distinguish from AD-related changes involved in the progression of the disease. This proposal aims to disconnect age- from disease-related changes to vascular and immune components and to understand the impact of these disease-related changes on anti-Aβ treatment outcomes. This will be accomplished by studying these factors in autosomal dominant AD (ADAD), a rare form of AD with a known genetic etiology and with early age of symptom onset. Previous studies utilizing proteomic approaches and imaging to assess NVU disruption have focused on LOAD populations. The goal of Aim 1 of this proposal is to assess changes in the NVU in known carriers of ADAD-related mutations and with markers of vascular changes and generate a proteomic profile of NVU changes. The goal of Aim 2 is to define the temporality and association of NVU disruption relative to other established markers of disease progression. The goal of Aim 3 is to define the influence of NVU disruption on outcomes of Aβ clearance therapies, as well as on the incidence of treatment side effects and the association with primary clinical and cognitive outcomes. Successful completion of this proposed research project will improve our understanding of the vascular- and immune-related processes involved in AD and their relationship with Aβ, the pathophysiology of AD, and their influence on treatment-related Aβ changes.