# Establishing Genotype-to-Phenotype Relationships Between Alzheimer’s Related BIN1 Variants

> **NIH NIH R21** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2022 · $431,750

## Abstract

PROJECT SUMMARY ABSTRACT
Genome-wide association studies (GWAS) have identified several risk factors associated with altered probability
of late onset Alzheimer’s disease (LOAD). In this regard, variation in bridging integrator 1 (BIN1) have been
identified as being strongly associated with increased risk of AD. To that end, several preliminary studies have
suggested that BIN1 not only modulates amyloid and tau pathology but also modulates various inflammatory
and cell homeostatic pathways. Nonetheless, the mechanistic links between BIN1 and AD remain poorly defined.
Moreover, there is a paucity of research examining the effects of BIN 1 variation on the manifestation or
augmentation of AD-related phenotypes. In this proposal, we will use our collective expertise in stem cell
bioengineering, neurodegenerative disease modeling, and genome engineering to investigate the relationship
between specific BIN 1 variants and AD risk. In the first aim, we will using our highly efficient gene editing
approach to introduce BIN1 variants into isogenic hiPSCs from healthy non-demented control (NDC) and AD
patients. In the second aim, we will employ isogenic hiPSC lines in a 3-D co-culture model to test the hypothesis
that these BIN variants exert their risk-modifying effects through (i) modulation of amyloid precursor protein
(APP) processing and Aβ secretion and (ii) alteration in tau hyperphosphorylation and internalization. In addition,
we will use RNA-seq analysis to identify signaling pathways, gene regulatory networks, and transcriptional
targets that are independently influenced by the presence of BIN variation and disease status. In addition,
through the use of BIN1 knockout hiPSCs we will be able to determine if these BIN1 variants induce their effects
occur through gain- or loss-of-function mechanisms. Overall, a more thorough understanding of the mechanisms
by which variation in BIN1 contributes to the likelihood of AD onset will have a significant impact on the design
of therapeutic interventions.

## Key facts

- **NIH application ID:** 10525652
- **Project number:** 1R21AG079279-01
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** DAVID A BRAFMAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $431,750
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525652

## Citation

> US National Institutes of Health, RePORTER application 10525652, Establishing Genotype-to-Phenotype Relationships Between Alzheimer’s Related BIN1 Variants (1R21AG079279-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10525652. Licensed CC0.

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