Abstract
BackgroundThe apolipoprotein E epsilon 4 (APOE-4) is associated with a genetic vulnerability to Alzheimer's disease (AD) and with AD-related abnormalities in cortical rhythms. However, it is unclear whether APOE-4 is linked to a specific pattern of intrinsic functional disintegration of the brain after the development of the disease or during its different stages. This study aimed at identifying spatial patterns and effects of APOE genotype on resting-state oscillations and functional connectivity in patients with AD, using a physiological connectivity index called “lagged phase synchronization”.Methodology/Principal FindingsResting EEG was recorded during awake, eyes-closed state in 125 patients with AD and 60 elderly controls. Source current density and functional connectivity were determined using eLORETA. Patients with AD exhibited reduced parieto-occipital alpha oscillations compared with controls, and those carrying the APOE-4 allele had reduced alpha activity in the left inferior parietal and temporo-occipital cortex relative to noncarriers. There was a decreased alpha2 connectivity pattern in AD, involving the left temporal and bilateral parietal cortex. Several brain regions exhibited increased lagged phase synchronization in low frequencies, specifically in the theta band, across and within hemispheres, where temporal lobe connections were particularly compromised. Areas with abnormal theta connectivity correlated with cognitive scores. In patients with early AD, we found an APOE-4-related decrease in interhemispheric alpha connectivity in frontal and parieto-temporal regions.Conclusions/SignificanceIn addition to regional cortical dysfunction, as indicated by abnormal alpha oscillations, there are patterns of functional network disruption affecting theta and alpha bands in AD that associate with the level of cognitive disturbance or with the APOE genotype. These functional patterns of nonlinear connectivity may potentially represent neurophysiological or phenotypic markers of AD, and aid in early detection of the disorder.
Highlights
Alzheimer’s disease (AD) is characterized by a marked desarborization of synaptic contacts and neuronal loss, leading to progressive memory deficits and cognitive decline [1]
Given that characterizing brain activity purely in terms of anatomically segregated responses is not sufficient to explain the complexity of AD symptomatology, recent studies have focused their attention on functional connectivity between brain regions using functional Magnetic Resonance Imaging [10,11,12,13,14,15,16], electroencephalography (EEG) [17,18,19] or magnetoencephalography (MEG) [20,21,22]
There was a greater proportion of apolipoprotein E epsilon 4 (APOE-4) carriers in the patient group (n = 60/48%) compared with controls (n = 12/20%), and the opposite was true for APOE-4 noncarriers (AD: n = 65/52%; healthy controls (HC): n = 48/80%)
Summary
Alzheimer’s disease (AD) is characterized by a marked desarborization of synaptic contacts and neuronal loss, leading to progressive memory deficits and cognitive decline [1]. This is supported by reports of white matter structural abnormalities in AD, using diffusion tensor imaging or MRI tractography, as measures of anatomical connectivity [26,27,28]. The apolipoprotein E epsilon 4 (APOE-4) is associated with a genetic vulnerability to Alzheimer’s disease (AD) and with AD-related abnormalities in cortical rhythms. It is unclear whether APOE-4 is linked to a specific pattern of intrinsic functional disintegration of the brain after the development of the disease or during its different stages. This study aimed at identifying spatial patterns and effects of APOE genotype on resting-state oscillations and functional connectivity in patients with AD, using a physiological connectivity index called ‘‘lagged phase synchronization’’
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