Cortical excitability has been proposed as a novel neurophysiological marker of neurodegeneration in Alzheimer’s dementia (AD). However, the link between cortical excitability and structural changes in AD is not well understood.

To assess the relationship between cortical excitability and motor cortex thickness in AD.

In 62 participants with AD (38 females, mean ± SD age = 74.6 ± 8.0) and 47 healthy control (HC) individuals (26 females, mean ± SD age = 71.0 ± 7.9), transcranial magnetic stimulation resting motor threshold (rMT) was determined, and T1-weighted MRI scans were obtained. Skull-to-cortex distance was obtained manually for each participant using MNI coordinates of the motor cortex (x = −40, y = −20, z = 52).

The mean skull-to-cortex distances did not differ significantly between participants with AD (22.9 ± 4.3 mm) and HC (21.7 ± 4.3 mm). Participants with AD had lower motor cortex thickness than healthy individuals (t(92) = −4.4, p = <0.001) and lower rMT (i.e., higher excitability) than HC (t(107) = −2.0, p = 0.045). In the combined sample, rMT was correlated positively with motor cortex thickness (r = 0.2, df = 92, p = 0.036); however, this association did not remain significant after controlling for age, sex and diagnosis.

Patients with AD have decreased cortical thickness in the motor cortex and higher motor cortex excitability. This suggests that cortical excitability may be a marker of neurodegeneration in AD.

Pilot randomized double-blind-controlled trial of repetitive paired associative stimulation (rPAS), a paradigm that combines transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) with peripheral median nerve stimulation.

To study the impact of rPAS on DLPFC plasticity and working memory performance in Alzheimer’s disease (AD).

Thirty-two patients with AD (females = 16), mean (SD) age = 76.4 (6.3) years were randomized 1:1 to receive a 2-week (5 days/week) course of active or control rPAS. DLPFC plasticity was assessed using single session PAS combined with electroencephalography (EEG) at baseline and on days 1, 7, and 14 post-rPAS. Working memory and theta–gamma coupling were assessed at the same time points using the N-back task and EEG.

There were no significant differences between the active and control rPAS groups on DLPFC plasticity or working memory performance after the rPAS intervention. There were significant main effects of time on DLPFC plasticity, working memory, and theta–gamma coupling, only for the active rPAS group. Further, on post hoc within-group analyses done to generate hypotheses for future research, as compared to baseline, only the rPAS group improved on post-rPAS day 1 on all three indices. Finally, there was a positive correlation between working memory performance and theta–gamma coupling.

This study did not show a beneficial effect of rPAS for DLPFC plasticity or working memory in AD. However, post hoc analyses showed promising results favoring rPAS and supporting further research on this topic. (Clinicaltrials.gov-NCT01847586)