Microvascular hemodynamics and speech function in adults at risk for Alzheimer's disease

Impaired microvascular function is increasingly recognized as a key contributor to Alzheimer’s disease (AD)- related neurodegeneration. Although apolipoprotein E ε4 (APOE-ε4) is a well-established genetic risk factor for both AD and cerebrovascular disease, the mechanistic relationships between APOE-ε4 status, cerebral hemodynamics, and cognitive-motor function remain poorly understood. This study aims to examine how speech motor control, captured through acoustic and kinematic measures, relates to cerebral microvascular physiology in individuals stratified by genetic risk for AD. There is growing evidence that microvascular dysregulation emerges during the preclinical stages of AD, preceding the accumulation of amyloid-β plaques and tau tangles. Our previous work has shown that speech motor control metrics are sensitive to early neurodegenerative changes, highlighting their potential as scalable, behaviorally grounded biomarkers. Given that both cerebral hemodynamic measures and speech features independently show promise in detecting early neurodegeneration, we propose to investigate their interaction as a complementary and ecologically valid approach to identifying individuals at elevated risk for AD. Speech production is among the most complex human motor behaviors, requiring the integration of cognitive, sensorimotor, and neuromuscular processes, all of which are affected in AD. In this project, we will collect noninvasive magnetic resonance imaging (MRI) data alongside detailed speech samples in a well-characterized cohort of older adults (aged 60–80) with and without the APOE- ε4 allele. Microvascular physiology will be assessed using multi-delay arterial spin labeling (ASL) MRI to quantify cerebral blood flow (CBF) and arterial transit time (ATT) in brain regions supporting speech motor function. Speech motor control will be evaluated using acoustic and kinematic features. We hypothesize that (1) objective speech acoustic and kinematic features will distinguish APOE-ε4 carriers from non-carriers with high classification accuracy and will outperform cognitive scores in identifying APOE-ε4 status; (2) compared to non- carriers, APOE-ε4 carriers will exhibit reduced CBF and ATT in brain regions supporting speech motor function, reflecting impaired neurovascular regulation; and (3) hemodynamic alterations in speech motor regions will mediate the relationship between speech performance and cognitive function in APOE-ε4 carriers, offering a mechanistic explanation for how vascular dysfunction contributes to early behavioral markers of AD risk. The findings from this research will advance our understanding of how genetic risk for AD influences cerebral microvascular function and its downstream impact on speech motor control. This work will also evaluate the potential of speech-based assessments as low-burden, objective tools for early detection and monitoring of AD progression. By integrating neuroimaging and speech biomarkers, this project aims to inform the development of more sensitive and accessible diagnostic strategies that can be incorporated into clinical and research settings to support timely intervention and improved disease tracking. Project Number: 1R15AG101712-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Marziye Eshghi | Institution: MGH INSTITUTE OF HEALTH PROFESSIONS, Charlestown, MA | Award Amount: $624,208 | Activity Code: R15 | Study Section: Cognitive Disorders and Brain Aging Study Section[CDBA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11360881