# Identification of early transcriptional and pathological changes undergone by vulnerable brain regions during prodromal Alzheimer's disease

> **NIH NIH R21** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $459,076

## Abstract

Project Summary
Alzheimer’s Disease (AD) presents a striking example of the selective cell tropism common to most
neurodegenerative diseases. Early clinical symptoms (such as memory loss) are caused by the selective
buildup of tau pathology and by the degeneration of principal neurons of the entorhinal cortex layer II (ECII).
Understanding pathological lesion formation in ECII might be key to design disease-modifying therapeutics,
since pathological tau seeds spread from ECII to other brain regions in later stages of AD. Additionally,
investigating the most AD-vulnerable neurons of the brain could reveal crucial steps in the molecular events
that lead to degeneration. In previous work, we molecularly profiled ECII neurons and compared them to
neurons more resistant to the disease using a systems-level framework. We identified novel genes and
pathways predicted to drive neuronal pathology. But we are still missing an in-depth understanding of both the
particular proteoforms of tau accumulating in the EC, and the concomitant gene expression changes occurring
in ECII neurons and surrounding glial and neuronal cells. We propose here to study postmortem TEC
(transentorhinal cortex – the subarea of the EC where the very first neurofibrillary tangles appear), EC, and
prefrontal cortex (PFC) from asymptomatic individuals with either no amyloid and tau pathology (Braak stage
0), or with amyloid and early stage neurofibrillary tangle pathology (Braak stage I/II). With these samples, we
will perform single-nucleus combinatorial indexing RNA-sequencing, in order to profile all cell types and
subtypes. Cross-referencing the single-nucleus RNA-sequencing dataset with a fully annotated mouse single-
nucleus RNA-sequencing dataset of EC will allow to identify nuclei from vulnerable ECII neurons. Performing
cell type abundance and differential expression analysis in three regions with increasing vulnerability to the
disease (TEC – EC – PFC) will yield a picture of the sequential changes occurring during early disease.
Samples will also be subjected to targeted mass spectrometry analysis to detect Aβ peptides and a number of
tau phosphorylation sites, cleavage and splice isoforms to identify potential pathological proteoforms specific to
early AD. Jointly analyzing the proteomics and transcriptomics dataset will allow us to find specific genes
correlated with the most salient proteoforms. This multimodal catalog will also be analyzed jointly with our
previously described ECII functional network, and altogether should yield exciting insight into the earliest
events occurring in vulnerable neurons as AD-type neuropathology unfolds, uncovering genes both
dysregulated and predicted to drive downstream tau pathology.

## Key facts

- **NIH application ID:** 10985320
- **Project number:** 1R21AG085464-01A1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Jean-Pierre Roussarie
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,076
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985320

## Citation

> US National Institutes of Health, RePORTER application 10985320, Identification of early transcriptional and pathological changes undergone by vulnerable brain regions during prodromal Alzheimer's disease (1R21AG085464-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10985320. Licensed CC0.

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