# Transformative research on somatic gene recombination in the normal and Alzheimer's disease-related dementia brain

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2023 · $924,514

## Abstract

Project Summary/Abstract
Understanding the human brain and its diseases represents an enormous challenge but also an opportunity for
improving human health. One of the many remarkable attributes of the normal brain is its ability to store and
retrieve information for a lifetime of learning and memories. Alzheimer’s disease (AD) and related dementias
(ADRDs) disrupt these cognitive functions and have enormous personal, familial, and societal costs,
compounded by a disturbing absence of disease-modifying therapies despite scores of scientific theories, billions
of dollars, decades of research, and hundreds of failed clinical trials. This transformative proposal will meet
these challenges through studies on a newly identified molecular mechanism within the brain: somatic gene
recombination (SGR). SGR may alter individual genomes within each neuron by linking neural activity – both
normal and abnormal – to functional DNA gene sequences present within the genomes of post-mitotic neurons.
We hypothesize that through retro-insertion of RNA sequences, genomic cDNAs (gencDNAs) are formed. We
identified thousands of gene variants for just a single gene – the AD gene, APP – which offers new explanations
for disease progression and the failure of AD therapeutics thus far. This proposal will explore the links between
SGR acting on other known or unknown disease loci in ADRDs and test the hypothesis that SGR dysregulation
represents a common pathogenic mechanism shared by AD and ADRDs.
Three areas of study will be pursued by a team of proven investigators empowered by world class ADRD,
neuroscience, and bioinformatics experts. First, we will define the machinery of SGR in the human brain by
identifying the involved genes and biochemically characterizing their function. Second, we will use targeted and
unbiased approaches to identify new genes undergoing SGR in ADRDs and characterize neuroanatomical
expression in relation to the classical hallmarks of the disease. Third, we will explore possible targets to be used
as biomarkers and for therapeutics in cell culture and human fluid samples. Importantly, these studies will
examine a potential near-term therapy for AD and ADRDs by studying FDA-approved reverse transcriptase
inhibitors. These proposed studies are the first to examine SGR in ADRDs and represent a new line of research.
The scope of this proposal presents a truly transformational study of the brain, its diseases, and the enormous
challenge of understanding and treating ADRDs.

## Key facts

- **NIH application ID:** 10640064
- **Project number:** 5R01AG071465-04
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** JEROLD CHUN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $924,514
- **Award type:** 5
- **Project period:** 2020-09-11 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10640064

## Citation

> US National Institutes of Health, RePORTER application 10640064, Transformative research on somatic gene recombination in the normal and Alzheimer's disease-related dementia brain (5R01AG071465-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10640064. Licensed CC0.

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