Genetic Association Between Alzheimer’s Disease Risk Variant of the PICALM Gene and EEG Functional Connectivity in Non-demented Adults

Abstract

Genome wide association studies (GWAS) have identified and validated the association of the PICALM genotype with Alzheimer's disease (AD). The PICALM rs3851179 A allele is thought to have a protective effect, whereas the G allele appears to confer risk for AD. The influence of the PICALM genotype on brain functional connectivity in non-demented subjects remains largely unknown. We examined the association of the PICALM rs3851179 genotype with the characteristics of lagged linear connectivity (LLC) of resting EEG sources in 104 non-demented adults younger than 60 years of age. The EEG analysis was performed using exact low-resolution brain electromagnetic tomography (eLORETA) freeware (Pascual-Marqui et al., 2011). We found that the carriers of the A PICALM allele (PICALM AA and AG genotypes) had higher widespread interhemispheric LLC of alpha sources compared to the carriers of the GG PICALM allele. An exploratory correlation analysis showed a moderate positive association between the alpha LLC interhemispheric characteristics and the corpus callosum size and between the alpha interhemispheric LLC characteristics and the Luria word memory scores. These results suggest that the PICALM rs3851179 A allele provides protection against cognitive decline by facilitating neurophysiological reserve capacities in nondemented adults. In contrast, lower functional connectivity in carriers of the AD risk variant, PICALM GG, suggests early functional alterations in alpha rhythm networks.

Alzheimer’s Disease: An Updated Overview of Its Genetics

“…According to the amyloid hypothesis, a wide variety of genes identified are involved in pathological Aβ processing ( Figure 2 and Table 1 ), such as the disintegrin and metalloproteinase domain-containing protein 10 ( ADAM10 ), which is the most important α-secretase in the brain that could cause increases in the Aβ42/Aβ40 ratio [ 33 , 34 , 35 ]. In the same way, the phosphatidylinositol-binding clathrin assembly protein ( PICALM ) initiates the polymerization of clathrin, which contributes to NP formation [ 36 , 37 , 38 ]; clustered mitochondria protein homolog ( CLU ), a chaperone that prevents the aggregation of foreign proteins, has been found to inhibit the formation of amyloid fibrils by APP and other genes involved [ 39 , 40 , 41 ].…”

A review of brain imaging biomarker genomics in Alzheimer’s disease: implementation and perspectives

“…For instance, alterations of brain rhythms and functional connectivity have been revealed in EEG and MEG studies [178][179][180]. Relationships between various AD genetic risk factors and EEG phenotypes have also been reported [181][182][183][184]. Hence, compared with a single omics category, integration of multiomics information allows systemic exploration at multiscale layers to better understand the comprehensive biological information flow that underlies the disease and to pave the way for precision medicine.…”

Modeling Brain Functional Connectivity Patterns during an Isometric Arm Force Exertion Task at Different Levels of Perceived Exertion: A Graph Theoretical Approach

“…For functional connectivity analysis, we utilized a method that applies a single voxel at the centroid of each BA using eLORETA software [ 109 , 110 , 135 , 136 ]. A connectivity analysis between pairs of 84 ROIs in two EEG frequency bands was conducted for all physical exertion levels using independent sample t-tests that were corrected for multiple comparisons using a nonparametric randomization method based on the “maximal statistic.” The same permutation test was applied with 5,000 randomizations to identify the critical probability thresholds at significant levels and to correct type 1 errors.…”