# Determining the genetic drivers of ancestry-specific differential penetrance of APOE4 in sporadic Alzheimer’s Disease > **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $41,324 ## Abstract PROJECT SUMMARY AND ABSTRACT Alzheimer’s disease (AD) is a heritable and debilitating progressive neurological disease and the most common form of dementia. Among the AD risk loci identified by decades of AD genetics research, the APOE locus encoding for Apolipoprotein E, specifically the APOE4 isoform, is the strongest known genetic risk factor for sporadic AD (sAD). Thus, APOE4 represents a prime therapeutic target. However, APOE4 is differentially penetrant across genetically-defined ancestral populations, increasingly so across African (AFR), Non-Finnish European (NFE) and East Asian (EAS) ancestries. This suggests that other common genetic factors may modify its penetrance and therefore protect or predispose certain individuals to its pathological effects. Yet, the definitive sources of these differences remain undefined. This highlights a crucial gap in our understanding of sAD heritability that will be essential to effectively prognosticate, stratify, and treat diverse patient populations. Recent trans-ancestry transcriptional profiling suggests that APOE4 expression in the AD brain differs across ancestries and thus could be a key modifier of AD risk from APOE4. These expression differences could be attributed to noncoding genetic variants within the APOE locus that influence cis-regulatory element activity, leading to context-specific transcriptional dysregulation of APOE that drivies cell type- and state-specific molecular phenotypes. Indeed, increased APOE expression has been linked to sAD phenotypes. Further supporting this, reporter assays in cell lines suggest a subset of variants nearby APOE are functional. However, it is yet to be definitively confirmed which, if any, of these APOE locus noncoding variants underlie differential penetrance across AFR, NFE and EAS ancestries. This work aims to pinpoint functional ancestry-specific genetic modifiers of APOE4 penetrance in human cells. Massively parallel reporter assays in iPSC-derived brain cell types will functionally prioritize from a comprehensive set of 10,661 analytically-nominated variants (Aim 1). Transcriptomic and epigenomic profiling of ancestry-diverse iPSC-derived brain cell types will create ancestry- and cell type-specific gene-regulatory maps of the APOE locus necessary to functionally interpret prioritized variants (Aim 2). In turn, employing scarless genome editing in iPSC-derived models will determine the sufficiency of analytically nominated high-priority variants to alter gene expression in the APOE locus (Aim 3). This proposed work will accompany training goals centered around structured coursework in bioinformatics, leadership and management training, and improving science communication towards leading an independent research group in the future. Presenting this work at both broad and specific meetings will foster interdisciplinary crosstalk core to these goals. All experiments and training will be jointly guided by sponsors Dr. Ryan Corces and Dr. Yadong Hua... ## Key facts - **NIH application ID:** 10901747 - **Project number:** 1F31AG087658-01 - **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO - **Principal Investigator:** Zachary A Gardell - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $41,324 - **Award type:** 1 - **Project period:** 2024-06-15 → 2027-06-14 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10901747 ## Citation > US National Institutes of Health, RePORTER application 10901747, Determining the genetic drivers of ancestry-specific differential penetrance of APOE4 in sporadic Alzheimer’s Disease (1F31AG087658-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10901747. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*