Understanding the mechanistic link between vascular dysfunction and Alzheimers disease-related protein accumulation in the medial temporal lobe

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Project Summary/Abstract Title: Understanding the mechanistic link between vascular dysfunction and Alzheimer’s disease-related protein accumulation in the medial temporal lobe. Cerebral small vessel disease (CSVD), which affects small vessels of the brain in the form of cerebral amyloid angiopathy (CAA) or arteriolosclerosis, is either primarily responsible or a significantly contributing factor to Alzheimer’s disease and related dementias (AD/ADRD). However, it remains unclear whether vascular pathology and AD-related pathology independently contribute to dementia or causally interact with each other. Dysfunction in perivascular clearance, one of the systems responsible for the disposal of metabolic waste products from the brain, and blood-brain barrier (BBB) leakage, both occur when CSVD pathology is present and are candidate mechanisms that could explain this interaction. The objective of the proposed research is to pinpoint the reciprocal interaction between CSVD and AD-related pathology, in order to infer its underlying mechanisms. The focus will be on the medial temporal lobe (MTL), a critical brain region for the development of AD/ADRD, because it is fundamental for cognition and it is a site where a multiplicity of AD-related pathologies coexist (e.g. Aβ-plaques, neurofibrillary tau tangles, TAR DNA binding protein 43, and neuronal loss), some of which in very early stages of the disease (e.g. tangles). Firstly, the applicant will investigate whether CSVD in the MTL worsens AD-related pathology (Hypothesis 1). Secondly, she will infer the contributing role of perivascular clearance dysfunction and BBB-leakage to these interactions (Hypothesis 2) and aims to create and validate neuroimaging markers of microvascular health in the MTL (Hypothesis 3). The innovation of this proposal lies in the use of quantitative neuroimaging and neuropathological methods, including ultra-high resolution ex vivo MRI, polarization-sensitive optical coherence tomography, and deep-learning based measures of MRI and serial histology. The proposed investigations address a significant knowledge gap, related to the complex interactions between AD and CSVD, which has been emphasized as a research priority by the NIH. Successful completion of the aims will result in histologically validated neuroimaging markers of microvascular health of the MTL, which can be applied to in vivo studies to understand the impact of disease-modifying interventions. This proposal leverages the candidate’s existing skillset and demonstrated expertise in vascular pathology and will provide an invaluable training opportunity to acquire new skills and analytic methods. This award will be instrumental for a successful transition into an independent investigator. Importantly, the support of an internationally recognized team of (co-)mentors in human CSVD and AD and the unique resources available at Massachusetts General Hospital and Harvard Medical School are key ingredients to ensure impactful results.