Neurophysiological correlates of network dysfunction in prodromal Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by a long prodromal phase in which subtle functional alterations precede overt cognitive decline and structural neurodegeneration. Identifying sensitive markers of early network dysfunction and short-term disease progression remains a major clinical challenge. The present doctoral thesis investigated functional neurophysiological alterations in patients with biomarker-confirmed mild cognitive impairment due to Alzheimer’s disease (MCI-AD), with the aim of identifying biomarkers of early network dysfunction, prognostic stratification, and potential targets for therapeutic modulation. Across three complementary studies, a multimodal neurophysiological approach was adopted, combining conventional and high-frequency components of somatosensory evoked potentials (SEPs), together with transcranial magnetic stimulation (TMS). Study 1 demonstrated that MCI-AD patients exhibit marked alterations in high-frequency SEP components (HFOs) despite preserved conventional SEP parameters, suggesting early disruption of fast thalamocortical and intracortical network dynamics. Study 2 showed that baseline prolongation of early HFO duration independently predicted short- term cognitive decline, supporting the prognostic value of SEP-derived functional markers. Study 3 explored the effects of chronic genistein supplementation on cognitive and neurophysiological outcomes, revealing subtle, time-dependent patterns in high-frequency SEP components, consistent with modulation of network-level processes. Taken together, the findings of this thesis support the view that SEP-derived HFOs capture early alterations in network dynamics that are clinically relevant in prodromal AD. These results highlight the potential role of advanced neurophysiological measures as functional biomarkers for risk stratification and for the evaluation of early-stage interventions targeting network dysfunction in Alzheimer’s disease.