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.

Precuneus Failures in Subjects of the PSEN1 E280A Family at Risk of Developing Alzheimer’s Disease Detected Using Quantitative Electroencephalography

“…The homozygous presence of the AD risk variant CLU CC in asymptomatic subjects is associated with an increase of Alpha-3 (11-13 Hz) and Alpha-1 (7.5-9 Hz) power. The Alpha-3, which is close to our Alpha-2, is also higher in young subjects and lower in old subjects [65]. The Apolipoprotein E (ApoE) ε4 allele is the greatest genetic susceptibility factor for AD and has been studied in carriers with AD and MCI using EEG [66][67][68][69][70], having been also reported anomalies for Alpha and Theta band at resting state related to slowing of EEG [71,72].…”

“…Golob et al [64] reported differences in ERP acquired during a target detection task in asymptomatic subjects carriers of PSEN1 mutation (A431E substitution = 14, L235V substitution = 5) and APP mutation (V717I substitution). The CLU genotype, that is related to risk for AD, exerts a significant effect on Alpha absolute power in resting state for asymptomatic subjects [65]. The homozygous presence of the AD risk variant CLU CC in asymptomatic subjects is associated with an increase of Alpha-3 (11-13 Hz) and Alpha-1 (7.5-9 Hz) power.…”

“…The Apolipoprotein E (ApoE) ε4 allele is the greatest genetic susceptibility factor for AD and has been studied in carriers with AD and MCI using EEG [66][67][68][69][70], having been also reported anomalies for Alpha and Theta band at resting state related to slowing of EEG [71,72]. To our knowledge, only one study has used EEG in subjects within a wide range of age (18-56 years), including young asymptomatic carriers [65]. The study reported a significant effect between age and ERP, related to an olfactory task, for ApoE ε4 carriers, opening the possibility of finding significant effects over the EEG in asymptomatic APOE ε4 carriers.…”

Healthy and Pathological Brain Aging: From the Perspective of Oscillations, Functional Connectivity, and Signal Complexity

“…Recent evidence suggests that genetic factors of pathological aging like clusterin ( CLU ) gene polymorphisms and the apolipoprotein E ε4 ( APOE4 ) mutation may affect upper alpha absolute power in nondemented elderly individuals [27], or reduce the amplitude of the posterior-dominant alpha rhythm in early AD [28, 29]. Taken together, these alpha frequency findings suggest that the genotype is associated with age-related preclinical dysregulation of hippocampal function and contributes to AD pathophysiology.…”

Genetics and Functional Imaging: Effects of APOE, BDNF, COMT, and KIBRA in Aging

“…Behaviorally, this was reflected in faster response times in identifying happy faces for older A homozygotes. Further, an electroencephalography study examined the association between the AD-related clusterin (CLU; rs11136000) polymorphism and resting-state alpha-rhythm activity in healthy non-carriers of the APOE ε4 allele (Ponomareva et al 2013). The CLU CC risk variant was associated with an increase of alpha activity only in older adults (50-80 years), whereas there were no genetic effects in younger adults (20-50 years).…”