Genetic association of apolipoprotein E genotype with EEG alpha rhythm slowing and functional brain network alterations during normal aging

Abstract

The ε4 allele of the apolipoprotein E (APOE4+) genotype is a major genetic risk factor for Alzheimer's disease (AD), but the mechanisms underlying its influence remain incompletely understood. The study aimed to investigate the possible effect of the APOE genotype on spontaneous electroencephalogram (EEG) alpha characteristics, resting-state functional MRI (fMRI) connectivity (rsFC) in large brain networks and the interrelation of alpha rhythm and rsFC characteristics in non-demented adults during aging. We examined the EEG alpha subband's relative power, individual alpha peak frequency (IAPF), and fMRI rsFC in non-demented volunteers (age range 26-79 years) stratified by the APOE genotype. The presence of the APOE4+ genotype was associated with lower IAPF and lower relative power of the 11-13 Hz alpha subbands. The age related decrease in EEG IAPF was more pronounced in the APOE4+ carriers than in the APOE4+ non-carriers (APOE4-). The APOE4+ carriers had a stronger fMRI positive rsFC of the interhemispheric regions of the frontoparietal, lateral visual and salience networks than the APOE4- individuals. In contrast, the negative rsFC in the network between the left hippocampus and the right posterior parietal cortex was reduced in the APOE4+ carriers compared to the non-carriers. Alpha rhythm slowing was associated with the dysfunction of hippocampal networks. Our results show that in adults without dementia APOE4+ genotype is associated with alpha rhythm slowing and that this slowing is age-dependent. Our data suggest predominant alterations of inhibitory processes in large-scale brain network of non-demented APOE4+ carriers. Moreover, dysfunction of large-scale hippocampal network can influence APOE-related alpha rhythm vulnerability.

Keywords: APOE genotype; Alzheimer’s disease; aging; alpha rhythm; brain networks; functional MRI; functional connectivity; genetic predisposition.

FIGURE 1

EEG individual alpha peak frequency (IAPF) in non-demented APOE4– and APOE+ carriers. (A) Group-averaged EEG topographical plots of IAPF in individuals with APOE4+ and APOE4– genotypes. (B) IAPF (mean and SE) in individuals with APOE4+ and APOE4– genotypes. *p = 0.01; significant difference between APOE4+ vs. APOE4– subjects.

FIGURE 2

Log-transformed relative power (mean and SE) in the non-demented subjects with APOE4+ and APOE4– genotypes. *p < 0.05; significant difference between APOE4+ vs. APOE4– subjects of every 1-Hz subband of alpha band.

FIGURE 3

Log-transformed relative power (mean and SE) in the non-demented younger and older cohorts. *p < 0.01; significant difference between younger vs. older subjects of every 1-Hz subband of alpha band.

FIGURE 4

Correlation between age and EEG individual alpha peak frequency in APOE4+ and APOE4– healthy subjects. Abbreviations are the same as in Figure 1.

FIGURE 5

The patterns of functional links, corresponding to the fMRI resting-state functional connectivity (rsFC) differences in the non-demented APOE4+ carriers and non-carriers (p-FDR < 0.05). (A) Between groups contrast APOE4+ > APOE–. Only the networks with significant positive rsFC values in APOE4+ carriers or in non-carriers (p-FDR < 0.05) are presented. 1—Lateral PreFrontal Cortex left, LPFC l; 2—Subcallosal Cortex SubCalC; 3—Inferior Temporal Gyrus right, anterior division, aITG r; 4—Inferior Temporal Gyrus left, anterior division, aITG l; 5—Planum Polare left, PP l; 6—Anterior Parahippocampal Gyrus left, aPaHC l; 7—Parietal Operculum right, PO r; 8—Parietal Operculum left, PO l; 9—Salience Supramagrinal right, Salience SMG r; 10—Cerebellum9 right, Cereb9 r; 11—Visual Laterale right, VisLat r; 12—Lateral Occipital Cortex right iLOC r. (B) Between groups contrast APOE4– < APOE4+. Only the networks with significant negative rsFC values in APOE4– or APOE+ carriers (p-FDR < 0.05) are presented. 1—Superior Frontal Gyrus right, SFG r; 2—Middle Frontal Gyrus right, MFG, r; 3—Planum Polare left, PP l; 4—Amygdala; 5—Dorsal Attentional Network, Dor Att Net; 6—Anterior Parahippocampal Gyrus left, aPaHC l; 7—Hippocampus left; 8—Posterior Parietal Cortex right, PPC; 9—Lateral Occipital Cortex right, iLOC r.

FIGURE 6

Association between fMRI-derived resting-state functional connectivity in the network between the left hippocampus and the right posterior parietal cortex and EEG individual alpha peak frequency in non-demented adults. Abbreviations are the same as in Figure 1.