Functional network disruption in cognitively unimpaired autosomal dominant Alzheimer's disease: a magnetoencephalography study.

Understanding the nature and onset of neurophysiological changes, and the selective vulnerability of central hub regions in the functional network, may aid in managing the growing impact of Alzheimer's disease on society. However, the precise neurophysiological alterations occurring in the pre-clinical stage of human Alzheimer's disease remain controversial. This study aims to provide increased insights on quantitative neurophysiological alterations during a true early stage of Alzheimer's disease. Using high spatial resolution source-reconstructed magnetoencephalography, we investigated regional and whole-brain neurophysiological changes in a unique cohort of 11 cognitively unimpaired individuals with pathogenic mutations in the presenilin-1 or amyloid precursor protein gene and a 1:3 matched control group ( = 33) with a median age of 49 years. We examined several quantitative magnetoencephalography measures that have been shown robust in detecting differences in sporadic Alzheimer's disease patients and are sensitive to excitation-inhibition imbalance. This includes spectral power and functional connectivity in different frequency bands. We also investigated hub vulnerability using the hub disruption index. To understand how magnetoencephalography measures change as the disease progresses through its pre-clinical stage, correlations between magnetoencephalography outcomes and various clinical variables like age were analysed. A comparison of spectral power between mutation carriers and controls revealed oscillatory slowing, characterized by widespread higher theta (4-8 Hz) power, a lower posterior peak frequency and lower occipital alpha 2 (10-13 Hz) power. Functional connectivity analyses presented a lower whole-brain (amplitude-based) functional connectivity in the alpha (8-13 Hz) and beta (13-30 Hz) bands, predominantly located in parieto-temporal hub regions. Furthermore, we found a significant hub disruption index for (phase-based) functional connectivity in the theta band, attributed to both higher functional connectivity in 'non-hub' regions alongside a hub disruption. Neurophysiological changes did not correlate with indicators of pre-clinical disease progression in mutation carriers after multiple comparisons correction. Our findings provide evidence that oscillatory slowing and functional connectivity differences occur before cognitive impairment in individuals with autosomal dominant mutations leading to early onset Alzheimer's disease. The nature and direction of these alterations are comparable to those observed in the clinical stages of Alzheimer's disease, suggest an early excitation-inhibition imbalance, and fit with the activity-dependent functional degeneration hypothesis. These insights may prove useful for early diagnosis and intervention in the future.