APOE- ε4 Modulates Facial Neuromuscular Activity in Nondemented Adults: Toward Sensitive Speech-Based Diagnostics for...

The APOE-ε4 allele is a genetic risk factor for late-onset Alzheimer's disease (AD). Beyond cognitive decline, APOE-ε4 affects motor function, reducing muscle strength and coordination, potentially through mitochondrial dysfunction and oxidative stress. This study examined the influence of the APOE- ε4 allele on neuromuscular function in oral muscles involved in speech production, using surface electromyography (EMG); and assessed the predictive power of EMG measures in differentiating APOE- ε4 carriers from noncarriers. Forty-two cognitively intact adults (16 APOE- ε4 carriers, 26 noncarriers) completed speech tasks while EMG was recorded from seven craniofacial muscles. Seventy EMG features including amplitude, frequency, complexity, regularity, and functional connectivity were extracted. Statistical analyses assessed genotype effects, sex differences, and correlations with blood metabolic biomarkers. APOE- ε4 carriers exhibited increased motor unit recruitment and synchronization, suggesting accelerated muscle fatigue. EMG-based measures outperformed cognitive tests in distinguishing carriers (AUC = 0.90) and correlated with metabolic biomarkers. Sex differences emerged, with female carriers showing reduced and male carriers showing increased functional connectivity. These findings highlight speech-based neuromuscular changes as potential early biomarkers of Alzheimer's risk before cognition is affected.