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