PROJECT SUMMARY
Detecting early signs of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) during the prodromal stage of
AD is becoming increasingly important for cost-effective clinical trials, developing targeted intervention strategies, and
gaining maximum benefit from currently available treatment plans. However, because of substantial differences in the
manifestation of cognitive impairment, preclinical cognitive changes are not discernible from age-related cognitive
decline. Although a combined approach of using neuropsychological, fluid, and imaging biomarkers has relatively
improved the timely diagnosis of AD, measurement of these biomarkers is expensive and highly technology-
dependent, making these techniques impractical for use in many older adults across different settings. In addition,
assessment of cognitive functions through the use of neuropsychological batteries remains the gold-standard in clinical
trials and evaluation of intervention efficacy. Thus, it is critical to identify early detectors that are 1) sensitive to
pathologies of AD, 2) strongly predictive of future change in cognition, and 3) accessible and feasible across diverse
settings. Based on our recent findings, which have identified measures of speech motor control as a powerful aid in
indexing early stages of neurodegenerative diseases such as amyotrophic lateral sclerosis and primary progressive
aphasia, we propose assessment of speech markers as an alternative or complementary and ecologically valid
strategy for identifying adults at risk of developing cognitive impairment due to AD. Speech production is one of
humans’ most complex motor behaviors, as it relies on tight integration of cognition, sensory, and motor processes
which are all subject to change with advancing age. We hypothesize that the rate of age-related changes in speech
motor control of adults can be influenced by genetic susceptibility to develop AD. In addition, we hypothesize that
measures of speech elicited during cognitively-demanding speech tasks can differentiate carriers of APOE e4 (i.e., the
major gene known to increase AD risk) from noncarriers and that baseline speech acoustic and kinematic measures
can predict later cognitive decline. The proposed research will innovatively use acoustics and articulatory kinematics
in combination with neuroimaging to pursue three Aims. In Aim 1, we will determine the effect of aging on speech
motor control of adults with APOE e4 positive (e4+) and APOE e4 negative (e4-) genotypes matched in sex and
education. In Aim 2, we will identify the brain structural and resting-state functional bases for age-related changes in
speech measures of adults with e4+ and e4- genotypes. Finally, in Aim 3, we will determine 1) whether baseline speech
acoustic/ kinematic measures predict cognitive change over two years, as quantified by Hopkins Learning Test-
Revised (HVLT-R) and Trail Making Test (TMT) scores in e4+ and e4- groups and 2) if speech and cognitive changes
are mediated through alterations in brain structure and function. The findings of this study will provide critical information
about measures of speech motor control that can be efficiently incorporated into neuropsychological testing to optimize
the clinical assessment of AD.