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Alzheimer Disease / Alzheimer’s Disease / Disease Progression · Journal article
Neurobiology of Aging · August 22, 2026
Encouraging direction, but not yet definitive.
This cross-sectional study provides evidence that early-stage Alzheimer's disease is associated with increased motor cortical hyperexcitability measured by TMS, with a dose–response relationship to cognitive decline. The finding that higher excitability correlates with worse MMSE and ADAS-Cog scores in AD participants supports the hypothesis that cortical hyperexcitability is mechanistically linked to cognitive impairment, though the cross-sectional design does not establish causation or predict clinical progression.
Cross-sectional comparative study. Biomarker-positive early-AD participants (ranging from mild cognitive impairment to mild dementia) and cognitively unimpaired age-matched adults; specific demographic details, enrollment site, and eligibility criteria not specified in abstract. Intervention: Transcranial magnetic stimulation with electromyography recording; single-pulse stimulation and input-output curve protocol (10 pulses each at 8 different intensities of maximum stimulator output). Compared with: Cognitively unimpaired age-matched controls. n = 135.
Early-AD participants show lower resting motor threshold (rMT, p < 0.001) compared to cognitively unimpaired controls, indicating increased excitability Input-Output curve Inflection Point is lower in AD (p = 0.007) and Dynamic Range is higher (p = 0.035) In AD, higher excitability (lower rMT) correlates with worse cognition on MMSE (p = 0.008) and lower Inflection Point correlates with worse performance on both MMSE (p = 0.030) and ADAS-Cog (p = 0.041)
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If validated longitudinally, TMS-based input-output curves could serve as a non-invasive biomarker of disease progression and target engagement in early AD, potentially enabling stratification or monitoring in clinical trials. The cross-sectional association between excitability and cognition should prompt prospective studies to establish whether baseline excitability predicts cognitive decline.
A well-designed cross-sectional study with biomarker-confirmed early AD and matched controls, demonstrating a mechanistic link between motor cortical hyperexcitability and cognitive impairment, but limited by cross-sectional design and lack of longitudinal or clinical outcome validation.
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If validated longitudinally, TMS-based input-output curves could serve as a non-invasive biomarker of disease progression and target engagement in early AD, potentially enabling stratification or monitoring in clinical trials. The cross-sectional association between excitability and cognition should prompt prospective studies to establish whether baseline excitability predicts cognitive decline.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Recent studies suggest that cortical hyperexcitability in Alzheimer's disease (AD) may accelerate disease progression. However, the field lacks validated non-invasive methods to assay excitability in humans. In this study we used transcranial magnetic stimulation with electromyography to investigate mechanisms of motor cortical excitability in 63 biomarker-positive early-AD (ranging from mild cognitive impairment to mild dementia) participants and 72 cognitively unimpaired age-matched adults (CU). Single-pulse stimulation was applied to motor cortex to record resting motor thresholds (rMT) and motor-evoked potentials. An Input-Output curve was generated by delivering 10 pulses each at eight different intensities of maximum stimulator output (%MSO). Linear models or equivalent non-parametric tests 1) compared excitability metrics between groups, 2) tested correlations with cognition (mini-mental state exam, MMSE; Alzheimer's disease assessment scale-cognitive, ADAS-Cog), and 3) tested the impact of APOE4. Results show that early-AD participants have increased motor cortical excitability than CU, with lower rMT (p < 0.001), lower Input-Output curve Inflection Point (p = 0.007), and higher Dynamic Range (p = 0.035). An analysis of the Input-Output curve adjusting for rMT showed larger responses in AD specifically in the 135-150% rMT range (p = 0.023). In AD, higher excitability was related to worse cognition (rMT: MMSE p = 0.008, Inflection Point: MMSE p = 0.030 and ADAS-Cog p = 0.041). There was no relationship between APOE4 and excitability. In conclusion, AD participants have increased motor cortical excitability, related to cognition. This is evident both at lower and higher stimulation intensities. TMS may provide a useful measure of target engagement for therapies aimed at preserving cognition or slowing decline in early-AD.
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