Correlation of genetic variants within the topologically associated domain surrounding the APOE gene with Alzheimer's disease risk: a comparative analysis across Brazilian ancestries

• Grant number: 25/22755-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2025
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Michel Satya Naslavsky
• Grantee: Átila Oliveira Bastos
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Dementia is one of the main conditions associated with population aging, with Alzheimer's disease (AD) being its most prevalent form. AD affects approximately 55 million people worldwide, and its prevalence is expected to increase further due to rising life expectancy, particularly in countries such as Brazil, where this trend is even more pronounced. One of the clinical manifestations of AD is cognitive decline, which is frequently assessed using the Mini-Mental State Examination (MMSE), a standardized tool for rapid cognitive screening. The etiology of late-onset AD is multifactorial, with a polygenic genetic component and high heritability (estimated at 80%). Among the genetic factors associated with AD, variants in the Apolipoprotein E (APOE) gene are particularly prominent. This gene is involved in lipid transport and other pathways related to AD neuropathology. The ¿2, ¿3, and ¿4 alleles derive from haplotypes defined by two non-synonymous variants and exhibit different associations with the clinical features of AD. The presence of the ¿4 allele is associated with an increased risk of developing the disease, and this risk is modulated by genetic ancestry. While European ancestry tends to confer a higher risk, African ancestry appears to attenuate this effect. Risk estimation in admixed individuals requires consideration of both global ancestry (the overall proportion of each ancestry across the genome) and local ancestry (the ancestral origin at specific genomic loci, such as the APOE region). In this context, the present study aims to investigate how different ancestries found in the Brazilian population, the APOE ¿4 allele, and nearby genomic regions influence cognitive performance, as measured by the MMSE. To this end, previously identified variants located in topologically associated regions near APOE will be analyzed using genomic data from the SABE (acronym for Health, Well-being, and Aging Study) cohort, complemented by publicly available databases. These variants will be incorporated into regression analyses to evaluate their interaction with the APOE ¿4 allele across distinct local ancestry contexts. This study seeks to elucidate how the ancestry of genomic regions surrounding APOE contributes to cognitive decline in AD, considering the genetic diversity of the Brazilian population resulting from its complex history of admixture. (AU)