VCID CWOW: Identifying Novel Targets to Treat Cerebral Amyloid Angiopathy - Alzheimer’s disease (AD), most common form of dementia, affects over 55 million people worldwide. Numbers are expected to double every 20 years unless improved treatments are developed. AD is characterized by amyloid plaques and neurofibrillary tangles of tau, but recently approved treatments targeting amyloid deposition show limited effectiveness. Therefore, it is critical that treatments are developed that target multiple aspects of AD and related dementias (ADRD). Small vessel cerebrovascular disease is now thought to contribute to many ADRD cases. However, no treatments that target cerebrovascular health in ADRD are available. Therefore, in response to RFA-NS-24-027 (VCID Center Without Walls [CWOW] for Understanding and Leveraging Small Vessel Cerebrovascular Disease Mechanisms in ADRD), we propose to establish The Jackson Laboratory (JAX)/Emory University/Columbia University/Rush University VCID CWOW to prioritize novel therapeutic targets for vascular contributions to cognitive impairment and dementia (VCID). We will focus on understanding factors mediating cerebral amyloid angiopathy (CAA: the deposition of amyloid in small vessels), including interactions with tau pathology and APOE genotype. APOE4 is the greatest genetic risk factor for ADRD and accelerates CAA. Despite the prevalence of CAA, the molecules that mediate its development remain to be elucidated. We hypothesize that targeting CAA, and the underlying cerebrovascular dysfunction and BBB breakdown, will prevent or slow neurodegeneration and cognitive decline in ADRD. To test our hypothesis, we will leverage expertise and resources available to the JAX/Emory/Columbia/Rush VCID CWOW. These include human samples and associated deep clinical data from the Religious Orders Study/Memory Aging Project (ROSMAP), a wealth of multi-omic data generated as part of the Accelerated Medicines Partnerships (AMP)- AD, and novel ADRD mouse models generated as part of Model Organism Development and Evaluation for Late-Onset AD (MODEL-AD). Our preliminary analyses have identified putative CAA-associated targets that are dependent on or independent of APOE4. However, small vessel-specific multi-omic datasets are lacking, hindering our sensitivity to identify cerebrovascular-specific mediators of CAA. Therefore, we will first generate and analyze vessel-enriched proteomic and single-nucleus RNA-seq datasets from ROSMAP samples showing variation in cognitive status, amyloid and tau pathology, CAA, and APOE genotype (Aim 1). We will then deeply phenotype our novel ADRD mouse model panel that shows a similar variation in CAA, APOE genotype, and tau pathology to that in the ROSMAP human samples. We will perform cognitive exams, magnetic resonance imaging, fluid biomarkers, whole-brain CAA mapping, and bulk and vessel-enriched proteomics (Aim 2). Finally, we will perform spatial transcriptomics and proteomics in human and mouse samples and integrate all data to prioritize novel vascular-specific candidates. The most promising of these will be validated in our mouse models (Aim 3). All data and resources will be made available through the AD Knowledge Portal and the JAX repository.
