Transcranial magnetic stimulation measures of corticospinal excitability and their association with Alzheimer's disease biomarkers in cognitively unimpaired older adults

Abstract Neuronal hyperexcitability is a recognized feature of Alzheimer’s disease (AD), but whether it is present even during the preclinical stage remains unclear. We investigated transcranial magnetic stimulation (TMS) measures of corticospinal excitability in relation to plasma AD biomarkers in 59 cognitively unimpaired older adults. Individuals with lower plasma amyloid-β42/40 (Aβ42/40) ratios (high amyloid risk) had significantly reduced resting motor threshold (rMT) with monophasic posterior–anterior stimulation (p = 0.045) and steeper corticospinal recruitment gain (p = 0.033), indicating increased excitability. No group differences were found for short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), or intracortical facilitation (ICF). Across the whole sample, higher plasma phosphorylated tau181 to non-phosphorylated tau181 ratio (pTau181/npTau181) was associated with lower rMT (p = 0.026), while phosphorylated tau217, Alzheimer’s Disease Cortical Signature thickness, and cognition measured with the Preclinical Alzheimer’s Cognitive Composite (PACC5) showed only trending associations. These findings indicate that motor cortex hyperexcitability is detectable in cognitively unimpaired individuals with elevated amyloid burden. Association with resting motor threshold and corticospinal recruitment, but not with SICI, LICI, or ICF, reinforces the hypothesis that in this population Aβ interferes with voltage-gated sodium channel activity and the balance of glutamatergic receptors to produce hyperexcitability. These findings support the potential utility of TMS-derived measures as accessible biomarkers for detecting preclinical neurophysiological changes and monitoring disease impact on the brain. Future longitudinal studies in larger samples will be essential to validate these preliminary findings and establish the prognostic utility of corticospinal excitability measures in AD.