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

Natalya Ponomareva,Vitaly Fokin,Rodion Konovalov,Andrey Mitrofanov,Daria Malina,Evgeny Rogaev,Marina Krotenkova,Tatiana Andreeva,Sergey Illarioshkin,Maria Protasova

doi:10.3389/fnins.2020.00324

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 non-demented adults. In contrast, lower functional connectivity in carriers of the AD risk variant, PICALM GG, suggests early functional alterations in alpha rhythm networks.

Highlights

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by progressive impairment of memory and other cognitive functions
There were no significant differences in functional connectivity in other frequency bands between the carriers of different PICALM genotypes
Control analysis showed that no significant correlation between lagged linear connectivity (LLC) characteristics and age was observed in the groups of PICALM AA&AG and PICALM GG genotype carriers as well as in the whole sample

Summary

INTRODUCTION

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by progressive impairment of memory and other cognitive functions. Neurophysiological and neuroimaging studies have revealed the effect of genetic risk factors for AD on brain functional connectivity in clinical and even preclinical stages of the disease. The effect of PICALM genotype on functional connectivity in brain networks, in particular DMN, was found in aMCI patients and in healthy subjects in fMRI studies (Zhang et al, 2015; Sun et al, 2017). We suggested that the EEG connectivity would differ depending on PICALM polymorphism, even in clinically healthy people To test this hypothesis we applied exact low-resolution electromagnetic tomography (eLORETA) freeware, which is widely used to study EEG alterations in AD, aMCI and other neurodegenerative disorders. The present study aimed to determine whether, in nondemented subjects younger than 60 years of age, polymorphism rs3851179 of the PICALM genotype is associated with the LLC characteristics of rsEEG cortical sources assessed by eLORETA. We analyzed the association of the PICALM genotype with CC size, the correlation between LLC characteristics and CC size, and the correlations between LLC and CC size with cognitive performance scores

Participants

RESULTS

Findings

ETHICS STATEMENT