How does genomic ancestry modulate the effects of APOE in cortical cell populations of admixed individuals?

• Grant number: 25/00999-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2025
• End date: June 30, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Michel Satya Naslavsky
• Grantee: Gabriel do Nascimento Santos
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 22/03102-8 - How genomic ancestry modulates APOE effects in admixed individuals?, AP.PNGP.PI

Abstract

APOE gene is consistently associated with risk of developing dementia, particularly Alzheimer's disease (AD), and ¿4 allele is the highest effect risk factor attributed to the most prevalent form of AD with multifactorial etiology. Recent studies showed that ¿4 contribution depends on global ancestry of the patient and local ancestry around the gene, with attenuated risk among Africans when compared to Europeans. The genomic context function of APOE in AD-related neuropathology (NP) is an open problem. This study intend to dissect (1) patterns of global (GA) and genome-wide local ancestry (LA) (including APOE locus and within genes involved in APOE expression in brain); (2) gene expression across cortical and subcortical cell populations; (3) modulation of common APOE alleles and respective regulators over AD-related NP and cognitive decline; (4) verify the association of APOE GA and LA, APOE regulatory genes and lipid metabolism genes, white matter and lipid profiles on brain tissue and plasma; and (5) test the hypothesis of APOE's involvement and ancestry in cognitive outcomes via myelin-related lipid alterations in the white matter. At least 400 post-mortem cases of clinicopathological BAS cohort (FMUSP) will be whole-genome sequenced at mid-coverage (MC-WGS) for detection of common and rare variation, ancestry inference and association with AD-related NP and cognitive decline outcomes. Next, we will select samples based on extreme distributions of local/global ancestry, NP and cognition for cell/nuclei isolation of frontal cortex to perform single cell RNA sequencing, in order to describe alterations in gene expression per cell population and local ancestry. We will select groups of samples based on APOE genotype, GA and LA for single-cell isolation followed by RNA sequencing. Association of variants within differentially expressed genes will be performed with NP and cognition outcomes. Lipidomic analysis will be performed in cortical and subcortical tissues. In the census-based elderly cohort SABE, with 500 subjects that were sequenced and submitted to DTI MRI, we will measure global and regional white matter integrity and investigate the association between APOE genotypes, GA and LA with neuroimaging and cognitive outcomes. Plasma lipidomic analyses will be performed in 64 or more individuals in a follow-up DTI MRI 8-12 years apart, to be collected by this proposal for measuring temporal alterations in brain structure. The hypothesis of ancestry-modulated lipid changes will be tested after integration of results of the above-mentioned experiments. We expect to bring light on the complex ancestry related APOE regulation to provide better risk estimation and potential therapeutic targets to this public health relevant condition.