Regional Precuneus Cortical Hyperexcitability in Alzheimer's Disease Patients

Objective Neuronal excitation/inhibition (E/I) imbalance is a potential cause of neuronal network malfunctioning in Alzheimer's disease (AD), contributing to cognitive dysfunction. Here, we used a novel approach combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to probe cortical excitability in different brain areas known to be directly involved in AD pathology. Methods We performed TMS‐EEG recordings targeting the left dorsolateral prefrontal cortex (l‐DLPFC), the left posterior parietal cortex (l‐PPC), and the precuneus (PC) in a large sample of patients with mild‐to‐moderate AD (n = 65) that were compared with a group of age‐matched healthy controls (n = 21). Results We found that patients with AD are characterized by a regional cortical hyperexcitability in the PC and, to some extent, in the frontal lobe, as measured by TMS‐evoked potentials. Notably, cortical excitability assessed over the l‐PPC was comparable between the 2 groups. Furthermore, we found that the individual level of PC excitability was associated with the level of cognitive impairment, as measured with Mini‐Mental State Examination, and with corticospinal fluid levels of Aβ 42 . Interpretation Our data provide novel evidence that precuneus cortical hyperexcitability is a key feature of synaptic dysfunction in patients with AD. The current results point to the combined approach of TMS and EEG as a novel promising technique to measure hyperexcitability in patients with AD. This index could represent a useful biomarker to stage disease severity and evaluate response to novel therapies. ANN NEUROL 2023;93:371–383