Higher soluble ADAM10 plasma levels are associated with decreased cognitive performance in older adults carrying APOEε4

Author(s)

Pelegrini, Lucas Nogueira de Carvalho ; Manzine, Patricia Regina ; Popolin, Cecilia Patricia ; Dorta, Sabrina ; Grigoli, Marina Mantellatto ; Alexandre-Silva, Vanessa ; Pedroso, Renata ; Ramos, Ari Alex ; Pott, Henrique ; Cominetti, Marcia Regina

• Document type: Journal article
• Source: NEUROBIOLOGY OF AGING; v. 151, p. 6-pg., 2025-04-15.

Abstract

The APOE gene, particularly its epsilon 4 allele, is a significant genetic risk factor for Alzheimer's disease (AD) and influences amyloid-beta (A beta) pathology and cognitive decline. This study explores the relationship between APOE epsilon 4 genotype, plasma levels of soluble ADAM10 (sADAM10), and cognitive performance in cognitively unimpaired (CU) older adults and those with AD dementia. It is a cross-sectional analysis that included 85 participants assessed for cognitive function, APOE genotype, and plasma sADAM10 levels. ADAM10, a key enzyme in the non-amyloidogenic pathway of A beta precursor protein (APP) processing, has emerged as a promising biomarker due to its altered levels in AD patients. Our findings revealed significantly higher plasma sADAM10 levels in AD participants compared to CU individuals, with APOE epsilon 4 carriers exhibiting a nearly twofold increase in sADAM10 levels. A negative correlation was observed between plasma sADAM10 concentrations and cognitive performance, independent of APOE epsilon 4 status. Notably, the study highlights the potential of sADAM10 as a blood-based biomarker, emphasizing its relevance in APOE epsilon 4-mediated AD pathology. Importantly, most studies exploring ADAM10 and APOE interactions have been conducted in high-income countries, limiting the generalizability of their findings to diverse populations. This study is the first to be conducted in a Global South country, offering critical insights into underrepresented populations and underscoring the need for more inclusive research in AD. Future research should include larger cohorts and longitudinal designs to validate these findings and explore targeted interventions leveraging sADAM10 activity in the context of APOE epsilon 4-associated AD progression. (AU)

• FAPESP's process: 21/01863-9 - Biology and function of ADAM10 isoforms for differential diagnosis of Alzheimer's Disease by electrochemical sensors
• Grantee: Márcia Regina Cominetti
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/14673-3 - Multi-user equipment approved in grant 2021/01863-9: Real time PCR system QuantStudio qPCR
• Grantee: Márcia Regina Cominetti
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 23/08952-2 - Training and technical training for the project 'Biology and function of ADAM10 isoforms for the differential diagnosis of Alzheimer's disease through electrochemical sensors'
• Grantee: Marina Mantellatto Grigoli
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 24/23624-4 - Multi-user equipment approved in grant 2021/01863-9: EVOS M7000 imaging system
• Grantee: Márcia Regina Cominetti
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 24/10955-2 - Effects of single nucleotide polymorphisms (SNPs) on ADAM10 levels and activities in patients with dementia of Alzheimer's disease compared to cognitively healthy older adults
• Grantee: Ari Alex Ramos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 22/15314-0 - Effects of single nucleotide polymorphisms (SNPs) on ADAM10 levels and activities in patients with dementia of Alzheimer's disease compared to cognitively healthy older adults
• Grantee: Lucas Pelegrini Nogueira de Carvalho
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 23/00868-2 - Structural bases of the ADAM10 isoforms proteolytic activity
• Grantee: Sabrina Dorta de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate