# Single-cell multi-region transcriptional and epigenomic dissection of VCID.

> **NIH NIH RF1** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $3,058,535

## Abstract

Abstract
Alzheimer’s disease (AD) and AD-related dementias (ADRDs) are major drivers of mortality, morbidity, and
health care costs for patients and their loved ones, due to the aging population, lack of predictive diagnosis,
and lack of effective treatments or prevention. Vascular contributions to cognitive impairment and dementia
(VCIDs) are key contributors to AD and ADRDs and manifest through diverse cerebrovascular lesions,
including atherosclerosis, microinfarcts, and small vessel strokes. VCIDs include cerebral small vessel disease
(CSVD), cerebral amyloid angiopathy (CAA), and a monogenic familial form of CSVD (CADASIL, Cerebral
Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). Understanding the
mechanisms and drivers of VCID will enable new biomarkers and therapeutics, similar to the success of
addressing cardiovascular disease and hypertension in heart disease. To understand the cellular mechanisms
underlying VCID across brain regions, cell types, pathology, and molecular pathways, we perform high-
resolution profiling of epigenomic and transcriptional alterations in post-mortem CNS samples from both
sporadic and genetic VCID patients. Aim 1: We profile single-nucleus RNA-sequencing (snRNA-seq) and DNA
accessibility (snATAC-seq) to create a transcriptional and epigenomic atlas of VCID across diagnoses, brain
regions, cell types, sexes, and individuals. Aim 2: We create an atlas of SVD-associated changes in genes,
modules, pathways, and cell-cell interactions. Aim 3: We predict candidate driver genes, regulators, and
pathways using causality analyses across temporal and genetic models, and we validate our results
experimentally using imaging studies. The successful execution of our studies will delineate clinically-relevant
VCID biomarkers and therapeutics across sporadic and genetic VCID, enabling us to dissect their common
and distinct molecular circuits, across four affected CNS region and all major cell types within them, and
capturing an unprecedented level of complexity and enabling rich computational comparisons. The datasets
generated and the computational analyses will provide invaluable insights for addressing the pressing medical
need of VCIDs, their temporal, region-specific, and cell-type-specific changes, which can help guide new
therapeutics.

## Key facts

- **NIH application ID:** 10532050
- **Project number:** 1RF1NS129032-01
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Myriam Heiman
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,058,535
- **Award type:** 1
- **Project period:** 2022-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10532050

## Citation

> US National Institutes of Health, RePORTER application 10532050, Single-cell multi-region transcriptional and epigenomic dissection of VCID. (1RF1NS129032-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10532050. Licensed CC0.

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