# Modeling Alzheimer's Disease in Hispanic Latino populations using human cortical organoids

> **NIH NIH F31** · UNIVERSITY OF TEXAS SAN ANTONIO · 2024 · $40,215

## Abstract

Project Summary/Abstract
Hispanic Latinos (HLs) have the highest risk of developing Alzheimer’s disease (AD) and related dementias, the
highest proportion of any ethnic group in the US. In genome-wide association studies (GWAS) conducted mostly
in non-Hispanic white (NHW) individuals, Apolipoprotein E4 (APOE4) was established as the leading AD genetic
risk factor, increasing risk 3-12 fold compared to the non-risk allele, APOE3. In HLs however, there is discordant
evidence about the association of APOE4 with AD which is at least partially attributed to the genetic diversity of
HLs stemming from widespread geographic origins. GWAS in large HL populations identified ancestry native to
Central America, the primary ancestry of Hispanic Mexican Americans (HMA), have little to no AD association
with APOE4. Studies further suggest that inheritance of APOE4 allele from native ancestor may not increase AD
risk to the same extent as that observed in NHW. It is postulated that genetic variation, possibly regulatory, either
local to APOE allele, or across the genome, modifies APOE4 biology. Recently, genetic variation local to APOE
was shown to dominantly influence gene transcription and APOE expression independent of APOE genotype.
Gaining insight on the molecular basis by which HMA background modifies APOE4 biology would identify
protective mechanisms against AD. My central hypothesis is that APOE4 will be associated with AD-related
phenotypes in cortical organoids with NHW ancestry, but not with HMA ancestry, or to a lesser extent. Since AD
develops decades before cognitive decline and ethnic variation is human-specific, I will test my hypothesis in 3D
cortical organoids. I will generate excitatory neuron-enriched human cortical organoids (hCO), and inhibitory
neuron-enriched human subpallial organoids (hSO) to explore neuron subtype-specific differences in AD-related
phenotypes. To investigate cellular phenotypes mediated by APOE4 with respect to genetic background, I will
1) characterize the effect of APOE4 on AD-related cellular phenotypes within NHW background, and 2)
determine the effect of HMA background on APOE4 mediated phenotypes and gene transcription. My preliminary
data suggests that the APOE4 allele reduces growth and upregulates APOE expression in both hCO and hSO
compared to organoids carrying the non-risk allele, APOE3. Aim 1 will explore the cellular basis contributing to
size (differentiation, maturation, and cell death) and characterize AD-related pathology by immunostaining and
protein expression assays. To control for patient background and assess the specific effects of APOE4 genotype
and genetic background, I will gene-edit APOE3 to APOE4 in iPSCs with NHW and HMA backgrounds. In Aim
2, I will determine the phenotypic and transcriptional changes associated with HMA background on APOE4-
mediated AD-related phenotypes. Under this fellowship, I will expand my molecular toolkit and in vitro disease
modeling and hone my skills as a molec...

## Key facts

- **NIH application ID:** 10873075
- **Project number:** 5F31AG082498-02
- **Recipient organization:** UNIVERSITY OF TEXAS SAN ANTONIO
- **Principal Investigator:** Karina K Meyer-Acosta
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,215
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873075

## Citation

> US National Institutes of Health, RePORTER application 10873075, Modeling Alzheimer's Disease in Hispanic Latino populations using human cortical organoids (5F31AG082498-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10873075. Licensed CC0.

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