Risk Variants in Three Alzheimer’s Disease Genes Show Association with EEG Endophenotypes

Abstract

Background: Dementia due to Alzheimer’s disease (AD) is a complex neurodegenerative disorder, which much of heritability remains unexplained. At the clinical level, one of the most common physiological alterations is the slowing of oscillatory brain activity, measurable by electroencephalography (EEG). Relative power (RP) at the conventional frequency bands (i.e., delta, theta, alpha, beta-1, and beta-2) can be considered as AD endophenotypes. Objective: The aim of this work is to analyze the association between sixteen genes previously related with AD: APOE, PICALM, CLU, BCHE, CETP, CR1, SLC6A3, GRIN2 β, SORL1, TOMM40, GSK3 β, UNC5C, OPRD1, NAV2, HOMER2, and IL1RAP, and the slowing of the brain activity, assessed by means of RP at the aforementioned frequency bands. Methods: An Iberian cohort of 45 elderly controls, 45 individuals with mild cognitive impairment, and 109 AD patients in the three stages of the disease was considered. Genomic information and brain activity of each subject were analyzed. Results: The slowing of brain activity was observed in carriers of risk alleles in IL1RAP (rs10212109, rs9823517, rs4687150), UNC5C (rs17024131), and NAV2 (rs1425227, rs862785) genes, regardless of the disease status and situation towards the strongest risk factors: age, sex, and APOE ɛ4 presence. Conclusion: Endophenotypes reduce the complexity of the general phenotype and genetic variants with a major effect on those specific traits may be then identified. The found associations in this work are novel and may contribute to the comprehension of AD pathogenesis, each with a different biological role, and influencing multiple factors involved in brain physiology.

Systematic analysis of cellular crosstalk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease

“…Several of these interactions warrant further investigation. For example, the interleukin receptor IL1RAP has been previously implicated in genetic studies of AD endophenotypes 3,[59][60][61] , and the contribution of IL-1 signaling to neurodegenerative diseases has been well-established [62][63][64] . In line with these previous findings, we identified the IL1RAP sub-network in microglia as the most negatively associated with Braak stage.…”

Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation

“…NAV2 that encodes Neuron Navigator 2, showed an opposite pattern of expression in oligodendrocytes from frontal cortex. Neuron Navigator 2 was suggested to be involved in CNS development, and the NAV2 gene has been implicated in Alzheimer’s disease 72 , 73 . These results suggest a distinct pattern of transcriptome dysregulation in C9-ALS and C9-FTD.…”

Recent studies of the genetics of complex diseases associated with impaired cognitive functions

“…Примером электрофизиологического ЭФ служит сенсомоторный дефицит, который характеризуется специфическими особенностями энцефалограммы у больных ШЗ [56] и больных БА [57]. Кроме того, снижение модуляции блуждающего нерва, приводящее к увеличению смертных случаев среди больных ШЗ, в настоящее время рассматривается как ЭФ данного заболевания [58].…”