Towards a neurophysiological diagnostic marker of Alzheimer's disease using transcranial magnetic stimulation combined with electroencephalography

Background A scalable, objective measure of cortical function that differentiates Alzheimer's disease (AD) from other causes of cognitive impairment is still lacking. Transcranial magnetic stimulation combined with electroencephalography (TMS–EEG) enables direct assessment of cortical reactivity. Objective To test whether left primary motor cortex (M1L) P30 amplitude captures AD-related excitability changes, distinguishes biomarker-confirmed AD patients from controls (CN) and from other non-AD causes of cognitive impairment. Methods Ninety participants underwent M1L TMS-EEG with Delphi-MD: biomarker-confirmed AD (n = 22), other cognitively impaired (n = 27: vascular/mixed n = 12; frontotemporal dementia n = 4; unknown etiology n = 11), and CN (n = 41). Results P30 differed across biomarker-confirmed AD, other cognitively impaired, and CN (Quade F(2,80) = 4.989, p = 0.009, ηp 2 = 0.11). Pairwise tests showed higher P30 in biomarker-confirmed AD versus other cognitively impaired (t = 2.117, p = 0.037, d = 0.61) and versus CN (t = 3.14, p = 0.002, d = 0.80). Among 27 clinically suspected AD tested for biomarkers, P30 was higher in biomarker + (22/27) versus biomarker− (5/27) (p = 0.035, d = 0.98), had good discriminatory performance for biomarker-confirmed AD (ROC = 0.853 [95% CI boot 0.627–1.000], p < 0.001), and was not associated with cerebrovascular changes (p = 0.455, d = 0.24). Conclusions P30 amplitude is elevated in biomarker-confirmed AD relative to CN and other causes of cognitive impairment, aligning with amyloid-associated cortical hyperexcitability. These findings support P30 as a promising, non-invasive physiological biomarker to aid differential diagnosis and, potentially, disease monitoring in AD. Trial registry name and URL: https://clinicaltrial.health.gov.il/clinicaltrials/?MOHResearchId=MOH_2022-04-13_010726