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

The APOE gene, particularly its ε4 allele, is a significant genetic risk factor for Alzheimer's disease (AD) and influences amyloid-β (Aβ) pathology and cognitive decline. This study explores the relationship between APOEε4 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 Aβ 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 APOEε4 carriers exhibiting a nearly twofold increase in sADAM10 levels. A negative correlation was observed between plasma sADAM10 concentrations and cognitive performance, independent of APOEε4 status. Notably, the study highlights the potential of sADAM10 as a blood-based biomarker, emphasizing its relevance in APOEε4-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 APOEε4-associated AD progression.