Table 1.

Key areas of research opportunity in neurodegenerative disease. There are four key areas of opportunity in neurodegenerative research, these include animal and in vitro disease models, neurovascular breakdown, in vivo imaging tools, and biomarker development. The current limitations are outlined and describe the aspects of each research opportunity that need to be overcome to make progress in the design of novel therapeutics. Finally, we highlight the key areas of research required to overcome current limitations in the design of novel therapies to treat neurodegenerative disease

Area of opportunity	Current limitation	Research required
1) Animal and in vitro disease model development.	- Modeling the multifaceted aspect of neurodegenerative disease in vitro. - Addressing the polygenic nature of disease in vitro or in animals. - Translatability of animal models of disease.	- Increased cellular complexity and modeling of cell-cell interactions over time. - Incorporation of vascular elements into multicellular in vitro models. - Generation of polygenic animal or cellular models of disease. - Patient-derived in vitro cell and organoid development. - Address protein isoform and spatiotemporal differences in disease risk and development (e.g., APOE2/3/4, and insoluble fibril versus soluble/oligomeric forms of Aβ). - Epigenetic and ’environmental’ contributions to disease. - Determine sex-based differences. - Determine if models are accurately representing manifestations in human disease.
2) Neurovascular breakdown in disease.	- Clear understanding of the temporal neurovascular events that contribute to neurodegenerative disease.	- Increased understanding of neurovascular coupling mechanisms and pathways. - Detection of the changes in the neurovasculature in vivo over time before and after disease onset.
3) In vivo imaging tools.	- Obtaining single cell resolution in vivo.	- Generation of novel imaging systems that can detect changes at the cellular level, non-invasively in humans and in animal models.
4) Biomarker development.	- Robust, early detection of disease-related biomarkers. - Most of current detection and diagnosis methods were developed using participants of Caucasian/euro-centric origin. - Many patients have comorbid diseases.	- Determination of the key prodromal changes and symptoms for each neurodegenerative disease. - Larger patient cohorts to generate more robust identification of putative biomarkers. - Improved high-throughput molecular systems to detect changes in proteins/biofluids/genes. - Address differences in disease risk stratified by sex, ethnicity, and other diverse populations. - Develop biomarkers for differential diagnosis, recruitment, and keeping in mind cross-disease, co-morbidities for improving clinical trial recruitment (better representing a diverse population). - Differential diagnosis amongst different types of glaucoma, Alzheimer’s, and related dementia, including how to address the common mixed etiology presentation of dementia. - Transcriptomic analysis of cell-type specific changes in models of development and degeneration.