Functional connectivity (FC) alterations represent a key feature in Alzheimer's Disease (AD) and provide a useful tool to characterize and predict the course of the disease. Those alterations have been also described in Mild Cognitive Impairment (MCI), a prodromal stage of AD. There is a growing interest in detecting AD pathology in the brain in the very early stages of the disorder. Subjective Cognitive Decline (SCD) could represent a preclinical asymptomatic stage of AD but very little is known about this population. In the present work we assessed whether FC disruptions are already present in this stage, and if they share any spatial distribution properties with MCI alterations (a condition known to be highly related to AD). To this end, we measured electromagnetic spontaneous activity with MEG in 39 healthy control elders, 41 elders with SCD and 51 MCI patients. The results showed FC alterations in both SCD and MCI compared to the healthy control group. Interestingly, both groups exhibited a very similar spatial pattern of altered links: a hyper-synchronized anterior network and a posterior network characterized by a decrease in FC. This decrease was more pronounced in the MCI group. These results highlight that elders with SCD present FC alterations. More importantly, those disruptions affected AD typically related areas and showed great overlap with the alterations exhibited by MCI patients. These results support the consideration of SCD as a preclinical stage of AD and may indicate that FC alterations appear very early in the course of the disease.

The consideration of Subjective Cognitive Decline (SCD) as a preclinical stage of AD remains still a matter of debate. Alpha band alterations represent one of the most significant changes in the electrophysiological profile of AD. In particular, AD patients exhibit reduced alpha relative power and frequency. We used alpha band activity measured with MEG to study whether SCD and MCI elders present these electrophysiological changes characteristic of AD, and to determine the evolution of the observed alterations across AD spectrum. The total sample consisted of 131 participants: 39 elders without SCD, 41 elders with SCD and 51 MCI patients. All of them underwent MEG and MRI scans and neuropsychological assessment. SCD and MCI patients exhibited a similar reduction in alpha band activity compared with the no SCD group. However, only MCI patients showed a slowing in their alpha peak frequency compared with both SCD and no SCD. These changes in alpha band were related to worse cognition. Our results suggest that AD-related alterations may start in the SCD stage, with a reduction in alpha relative power. It is later, in the MCI stage, where the slowing of the spectral profile takes place, giving rise to objective deficits in cognitive functioning.

Mild cognitive impairment (MCI) has been described as an intermediate stage between normal aging and dementia. Previous studies characterized the alterations of brain oscillatory activity at this stage, but little is known about the differences between single and multidomain amnestic MCI patients. In order to study the patterns of oscillatory magnetic activity in amnestic MCI subtypes, a total of 105 subjects underwent an eyes-closed resting-state magnetoencephalographic recording: 36 healthy controls, 33 amnestic single domain MCIs (a-sd-MCI), and 36 amnestic multidomain MCIs (a-md-MCI). Relative power values were calculated and AGE (2014) compared among groups. Subsequently, relative power values were correlated with neuropsychological tests scores and hippocampal volumes. Both MCI groups showed an increase in relative power in lower frequency bands (delta and theta frequency ranges) and a decrease in power values in higher frequency bands (alpha and beta frequency ranges), as compared with the control group. More importantly, clear differences emerged from the comparison between the two amnestic MCI subtypes. The a-md-MCI group showed a significant power increase within delta and theta ranges and reduced relative power within alpha and beta ranges. Such pattern correlated with the neuropsychological performance, indicating that the a-md-MCI subtype is associated not only with a "slowing" of the spectrum but also with a poorer cognitive status. These results suggest that a-md-MCI patients are characterized by a brain activity profile that is closer to that observed in Alzheimer disease. Therefore, it might be hypothesized that the likelihood of conversion to dementia would be higher within this subtype.

Subjects with mild cognitive impairment (MCI) have an increased risk of developing Alzheimer’s disease (AD), and their functional brain networks are presumably already altered. To test this hypothesis, we compared magnetoencephalography (MEG) eyes-closed resting-state recordings from 29 MCI subjects and 29 healthy elderly subjects in the present exploratory study. Functional connectivity in different frequency bands was assessed with the phase lag index (PLI) in source space. Normalized weighted clustering coefficient (normalized Cw) and path length (normalized Lw), as well as network measures derived from the minimum spanning tree [MST; i.e., betweenness centrality (BC) and node degree], were calculated. First, we found altered PLI values in the lower and upper alpha bands in MCI patients compared to controls. Thereafter, we explored network differences in these frequency bands. Normalized Cw and Lw did not differ between the groups, whereas BC and node degree of the MST differed, although these differences did not survive correction for multiple testing using the False Discovery Rate (FDR). As an exploratory study, we may conclude that: (1) the increases and decreases observed in PLI values in lower and upper alpha bands in MCI patients may be interpreted as a dual pattern of disconnection and aberrant functioning; (2) network measures are in line with connectivity findings, indicating a lower efficiency of the brain networks in MCI patients; (3) the MST centrality measures are more sensitive to detect subtle differences in the functional brain networks in MCI than traditional graph theoretical metrics.

Objective: Although, the apolipoprotein E (APOE) genotype is widely recognized as one of the most important risk factors for Alzheimer's disease (AD) development, the neural mechanisms by which the ε4 allele promotes the AD occurring remain under debate. The aim of this study was to evaluate neurobiological effects of the APOE-genotype on the pattern of the structural covariance in mild cognitive impairment (MCI) subjects. Methods: We enrolled 95 MCI subjects and 49 healthy controls. According to APOE-genotype, MCI subjects were divided into three groups: APOEε4 non-carriers (MCIε4−/−, n = 55), APOEε4 heterozygous carriers (MCIε4+/−, n = 31), and APOEε4 homozygous carriers (MCIε4+/+, n = 9) while all controls were APOEε4 non-carriers. In order to explore their brain structural pattern, T1-weighted anatomical brain 1.5-T MRI scans were collected. A whole-brain voxel-based morphometry analysis was performed, and all significant regions (p < 0.05 family-wise error, whole brain) were selected as a region of interest for the structural covariance analysis. Moreover, in order to evaluate the progression of the disease, a clinical follow-up was performed for 2 years. Results: The F-test showed in voxel-based morphometry analysis a strong overall difference among the groups in the middle frontal and temporal gyri and in the bilateral hippocampi, thalami, and parahippocampal gyri, with a grading in the atrophy in these latter three structures according to the following order: MCIε4+/+ > MCIε4+/− > MCIε4−/− > controls. Structural covariance analysis revealed a strong structural association between the left thalamus and the left caudate and between the right hippocampus and the left caudate (p < 0.05 family-wise error, whole brain) in the MCIε4 carrier groups (MCIε4+/+ > MCIε4+/−), whereas no significant associations were observed in MCIε4−/− subjects. Of note, the 38% of MCIs enrolled in this study developed AD within 2 years of follow-up. Novellino et al. Structural Covariance in MCI APOEε4 Carriers Conclusion: This study improves the knowledge on neurobiological effect of APOE ε4 in early pathophysiological phenomena underlying the MCI-toAD evolution, as our results demonstrate changes in the structural association between hippocampal formation and thalamo-striatal connections occurring in MCI ε4 carriers. Our results strongly support the role of subcortical structures in MCI ε4 carriers and open a clinical window on the role of these structures as early disease markers.