Abstract: M. Eshghi, P. Rong, M. Dadgostar, H. Shin, B. D. Richburg, N. V. Barnett, D. H. Salat, S. E. Arnold, J. R. Green (2026)

Introduction: The APOE-epsilon 4 allele is a genetic risk factor for late-onset Alzheimer's disease (AD). Beyond cognitive decline, APOE-epsilon 4 affects motor function, reducing muscle strength and coordination, potentially through mitochondrial dysfunction and oxidative stress. This study examined the influence of the APOE-epsilon 4 allele on neuromuscular function in oral muscles involved in speech production, using surface electromyography (EMG); and evaluated the preliminary discriminatory performance of EMG-based multivariable models in differentiating APOE-epsilon 4 carriers from noncarriers.

Methods: Forty-two cognitively intact adults (16 APOE-epsilon 4 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, alongside group comparisons on cognitive measures to confirm preserved cognition in this sample.

Results: APOE-epsilon 4 carriers exhibited descriptive patterns consistent with increased motor unit recruitment and synchronization, indicating altered neuromuscular control and possible compensatory adjustments. Multivariable EMG-based models showed promising internal discrimination between carriers and noncarriers, whereas standard cognitive measures did not demonstrate significant APOE-epsilon 4-related differences in this cohort. EMG-based measures also showed correlation with metabolic biomarkers. Genotype and genotype-by-sex effects on the EMG-derived factors were not statistically significant. However, descriptive sex-stratified patterns suggested reduced functional connectivity in female carriers and increased functional connectivity in male carriers.

Discussion: These findings suggest that speech-based neuromuscular changes may serve as exploratory candidate indicators of neuromuscular vulnerability associated with APOE-epsilon 4 carrier status in cognitively intact adults. While this study distinguishes APOE-epsilon 4 carriers from noncarriers, further work is needed to determine whether these EMG features can diagnose AD, predict progression to mild cognitive impairment (MCI) or dementia, or serve as early diagnostic or prognostic biomarkers. Additionally, their prognostic value and relationship to standard cognitive measures should be confirmed in equivalent models and in larger, independent longitudinal cohorts.

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Exploratory associations between APOE-Îµ4 carrier status and facial neuromuscular activity in cognitively intact adults: a cross-sectional surface electromyography study