Age-dependent effect of Alzheimer's risk variant of CLU on EEG alpha rhythm in non-demented adults

Abstract

Polymorphism in the genomic region harboring the CLU gene (rs11136000) has been associated with the risk for Alzheimer's disease (AD). CLU C allele is assumed to confer risk for AD and the allele T may have a protective effect. We investigated the influence of the AD-associated CLU genotype on a common neurophysiological trait of brain activity (resting-state alpha-rhythm activity) in non-demented adults and elucidated whether this influence is modified over the course of aging. We examined quantitative electroencephalography (EEG) in a cohort of non-demented individuals (age range 20-80) divided into young (age range 20-50) and old (age range 51-80) cohorts and stratified by CLU polymorphism. To rule out the effect of the apolipoprotein E (ApoE) genotype on EEG characteristics, only subjects without the ApoE ε4 allele were included in the study. The homozygous presence of the AD risk variant CLU CC in non-demented subjects was associated with an increase of alpha3 absolute power. Moreover, the influence of CLU genotype on alpha3 was found to be higher in the subjects older than 50 years of age. The study also showed age-dependent alterations of alpha topographic distribution that occur independently of the CLU genotype. The increase of upper alpha power has been associated with hippocampal atrophy in patients with mild cognitive impairment (Moretti etal., 2012a). In our study, the CLU CC-dependent increase in upper alpha rhythm, particularly enhanced in elderly non-demented individuals, may imply that the genotype is related to preclinical dysregulation of hippocampal neurophysiology in aging and that this factor may contribute to the pathogenesis of AD.

Keywords: Alzheimer’s disease; EEG; aging; alpha rhythm; clusterin; genetic predisposition.

FIGURE 1

Absolute power (mean and SE) of alpha1 (A), alpha2 (B), and alpha3 (C) bands in the young and old cohorts, for occipital (O), frontal (F), frontal poles (Fp), temporal posterior (Tp), and temporal (T) areas. Black asterisks (*) indicate a P < 0.01 significant difference in absolute spectral power between two cohorts in the same region of interest (ROI). The arrows labeled with green (for the young cohort) and purple (for the old cohort) asterisks compare different ROI in the same cohort. The ROI at the start of the arrow has either (+) P < 0.05 or (*) P < 0.01 significant differences in absolute spectral power compared the ROIs at the ends of the arrow.

FIGURE 2

Alpha1, alpha2, and alpha3 absolute power (mean and SE) in the healthy young and old cohorts. *P í 0.01, significant differences between the alpha bands in the young (green) and old (purple) cohorts.

FIGURE 3

The average absolute power of alpha1 (A), alpha2 (B), and alpha3 (C) bands (mean and SE) in young and old subjects with CLU CC and CLU CT&TT genotypes. Triangle indicates significant differences between the CLU CC and CLU CT&TT carriers P < 0.05.

FIGURE 4

Topographic distribution of alpha1 (A), alpha2 (B), and alpha3 (C) absolute power (mean and SE) in young and old carriers of CLU CC an CLU CT&TT genotypes in occipital O, frontal F, frontal poles Fp, temporal posterior Tp, and temporal T areas. Triangle indicates significant differences between the CLU CC and CLU CT&TT carriers P < 0.05.