A Systematic Review of Altered P300 Event-Related Potential in Apolipoprotein E4 (APOE4) Carriers.

BACKGROUND: Apolipoprotein ε4 allele (APOE4) is the strongest genetic risk factor for Alzheimer's disease and seems to be related to cognitive decline and damaged event-related potential P300, which is a sensitive measure to assess cognitive processing. OBJECTIVE: This research aims to critically review the existing scientific evidence regarding the association between APOE4 and P300. METHODS: A systematic review was carried out up to January 2020 on the following databases: Web of Science, Scopus and Medline/PubMed. Articles were considered for inclusion if they are original research that provided information regarding the association between APOE4 and P300, available in English, Spanish, or Portuguese, and available in full text. The methodological quality of the studies selected was evaluated using the quality assessment tool for observational cohort and cross-sectional studies recommended by Cochrane. RESULTS: Out of 993 studies, 14 met the inclusion criteria. The results obtained showed that APOE4 is related to a longer P300 latency. However, the data supplied do not allow us to confirm if this relationship also occurs in amplitude measures. Moreover, it was observed that APOE genotype may influence P300 in different ages, from younger individuals to demented older people. CONCLUSION: Evidence shows that APOE4 negatively influences cortical activities related to cognitive functions, as indicated by P300.

What can time-frequency and phase coherence measures tell us about the genetic basis of P3 amplitude?

In a recent comprehensive investigation, we largely failed to identify significant genetic markers associated with P3 amplitude or to corroborate previous associations between P3 and specific single nucleotide polymorphisms (SNPs) or genes. In the present study we extended this line of investigation to examine time-frequency (TF) activity and intertrial phase coherence (ITPC) in the P3 time window, both of which are associated with P3 amplitude. Previous genome-wide research has reported associations between P3-related theta and delta activity and individual genetic variants. A large, population-based sample of 4211 subjects, comprising male and female adolescent twins and their parents, was genotyped for 527,828 single nucleotide polymorphisms (SNPs), from which over six million SNPs were accurately imputed. Heritability estimates were greater for TF energy than ITPC, whether based on biometric models or the combined influence of all measured SNPs (derived from genome-wide complex trait analysis). The magnitude of overlap in the specific SNPs associated with delta energy and ITPC and P3 amplitude was significant. A genome-wide analysis of all SNPs, accompanied by an analysis of approximately 17,600 genes, indicated a region of chromosome 2 around TEKT4 that was significantly associated with theta ITPC. Analysis of candidate SNPs and genes previously reported to be associated with P3 or related phenotypes yielded one association surviving correction for multiple tests: between theta energy and CRHR1. However, we did not obtain significant associations for SNPs implicated in previous genome-wide studies of TF measures. Identifying specific genetic variants associated with P3 amplitude remains a challenge.

Potential cognitive decline linked to angiotensin-converting enzyme gene but not hypertension: Evidence from cognitive event-related potentials.

OBJECTIVES: The aims of the present study were to investigate the effect of hypertension and angiotensin-converting enzyme (ACE) genotypes on cognitive event-related potentials (ERPs), and whether the impact of ACE genotypes on P300 is related to the influence of hypertension. METHODS: Using the Cognitive Abilities Screening Instrument (CASI), we recruited 97 mentally healthy middle-aged and older adults. Medical histories were collected, and blood pressure, ACE insertion/deletion polymorphisms and ERPs in an auditory oddball task were measured for all participants. RESULTS: When the participants were stratified according to the presence or absence of hypertension, there were no differences in CASI score, percentage of ACE genotypes and ERPs. The subjects with the D/D homozygote displayed lower amplitude and longer latency of P300, although there were no differences in CASI score and the percentage of hypertension. CONCLUSIONS: The subjects with the D/D genotype tended to have decreased amplitude and prolonged latency of P300 ERPs which reflected subtle cognitive impairment. There were no associations between hypertension, CASI score and P300 measurements. SIGNIFICANCE: Using ERPs, potential cognitive decline was linked to ACE genotypes, independently of the effect of hypertension.

Genome-wide scans of genetic variants for psychophysiological endophenotypes: introduction to this special issue of Psychophysiology.

This special issue addresses the heritability and molecular genetic basis of 17 putative endophenotypes involving resting EEG power, P300 event-related potential amplitude, electrodermal orienting and habituation, antisaccade eye tracking, and affective modulation of the startle eye blink. These measures were collected from approximately 4,900 twins and parents who provided DNA samples through their participation in the Minnesota Twin Family Study. Included are papers that detail the methodology followed, genome-wide association analyses of single nucleotide polymorphisms and genes, analysis of rare variants in the human exome, and a whole genome sequencing study. Also included are 11 articles by leading experts in psychophysiology and genetics that provide perspective and commentary. A final integrative report summarizes findings and addresses issues raised. This introduction provides an overview of the aims and rationale behind these studies.

Heritability and molecular-genetic basis of the P3 event-related brain potential: a genome-wide association study.

P3 amplitude is a candidate endophenotype for disinhibitory psychopathology, psychosis, and other disorders. The present study is a comprehensive analysis of the behavioral- and molecular-genetic basis of P3 amplitude and a P3 genetic factor score in a large community sample (N = 4,211) of adolescent twins and their parents, genotyped for 527,829 single nucleotide polymorphisms (SNPs). Biometric models indicated that as much as 65% of the variance in each measure was due to additive genes. All SNPs in aggregate accounted for approximately 40% to 50% of the heritable variance. However, analyses of individual SNPs did not yield any significant associations. Analyses of individual genes did not confirm previous associations between P3 amplitude and candidate genes but did yield a novel association with myelin expression factor 2 (MYEF2). Main effects of individual variants may be too small to be detected by GWAS without larger samples.

Genetic associations of nonsynonymous exonic variants with psychophysiological endophenotypes.

We mapped ∼85,000 rare nonsynonymous exonic single nucleotide polymorphisms (SNPs) to 17 psychophysiological endophenotypes in 4,905 individuals, including antisaccade eye movements, resting EEG, P300 amplitude, electrodermal activity, affect-modulated startle eye blink. Nonsynonymous SNPs are predicted to directly change or disrupt proteins encoded by genes and are expected to have significant biological consequences. Most such variants are rare, and new technologies can efficiently assay them on a large scale. We assayed 247,870 mostly rare SNPs on an Illumina exome array. Approximately 85,000 of the SNPs were polymorphic, rare (MAF < .05), and nonsynonymous. Single variant association tests identified a SNP in the PARD3 gene associated with theta resting EEG power. The sequence kernel association test, a gene-based test, identified a gene PNPLA7 associated with pleasant difference startle, the difference in startle magnitude between pleasant and neutral images. No other single nonsynonymous variant, or gene-based group of variants, was strongly associated with any endophenotype.

In search of rare variants: preliminary results from whole genome sequencing of 1,325 individuals with psychophysiological endophenotypes.

Whole genome sequencing was completed on 1,325 individuals from 602 families, identifying 27 million autosomal variants. Genetic association tests were conducted for those individuals who had been assessed for one or more of 17 endophenotypes (N range = 802-1,185). No significant associations were found. These 27 million variants were then imputed into the full sample of individuals with psychophysiological data (N range = 3,088-4,469) and again tested for associations with the 17 endophenotypes. No association was significant. Using a gene-based variable threshold burden test of nonsynonymous variants, we obtained five significant associations. These findings are preliminary and call for additional analysis of this rich sample. We argue that larger samples, alternative study designs, and additional bioinformatics approaches will be necessary to discover associations between these endophenotypes and genomic variation.

Decomposing P300 to identify its genetic basis.

In this commentary, I explore reasons why it has been difficult to associate P300 amplitude with a gene or a single nucleotide polymorphism (SNP). I suggest we decompose P300 into the factors that contribute to it to get better traction on its genetic basis. Specifically, I note that we can improve the measurement of P300 to remove state-dependent contributions by including more than one measurement occasion; we can identify and extract the neural components contributing to P300 amplitude by estimating EEG power in specific bands of the P300; we can adjust P300 for single-trial variability; we can extract single-trial variability; and we can refine the tasks to isolate the separate psychological processes that P300 reflects. In the end, each of these factors that contribute to the conglomerate P300 may be a separate endophenotype mapping onto a separate SNP or gene.

Effects of ZNF804A on auditory P300 response in schizophrenia.

The common variant rs1344706 within the zinc-finger protein gene ZNF804A has been strongly implicated in schizophrenia (SZ) susceptibility by a series of recent genetic association studies. Although associated with a pattern of altered neural connectivity, evidence that increased risk is mediated by an effect on cognitive deficits associated with the disorder has been equivocal. This study investigated whether the same ZNF804A risk allele was associated with variation in the P300 auditory-evoked response, a cognitively relevant putative endophenotype for SZ. We compared P300 responses in carriers and noncarriers of the ZNF804A risk allele genotype groups in Irish patients and controls (n=97). P300 response was observed to vary according to genotype in this sample, such that risk allele carriers showed relatively higher P300 response compared with noncarriers. This finding accords with behavioural data reported by our group and others. It is also consistent with the idea that ZNF804A may have an impact on cortical efficiency, reflected in the higher levels of activations required to achieve comparable behavioural accuracy on the task used.

Analysis of schizophrenia-related genes and electrophysiological measures reveals ZNF804A association with amplitude of P300b elicited by novel sounds.

Several genes have recently been identified as risk factors for schizophrenia (SZ) by genome-wide association studies (GWAS), including ZNF804A which is thought to function in transcriptional regulation. However, the downstream pathophysiological changes that these genes confer remain to be elucidated. In 143 subjects (68 clinical high risk, first episode or chronic cases; 75 controls), we examined the association between 21 genetic markers previously identified by SZ GWAS or associated with putative intermediate phenotypes of SZ against three event-related potential (ERP) measures: mismatch negativity (MMN), amplitude of P300 during an auditory oddball task, and P300 amplitude during an auditory novelty oddball task. Controlling for age and sex, significant genetic association surpassing Bonferroni correction was detected between ZNF804A marker rs1344706 and P300 amplitude elicited by novel sounds (beta=4.38, P=1.03 × 10(-4)), which is thought to index orienting of attention to unexpected, salient stimuli. Subsequent analyses revealed that the association was driven by the control subjects (beta=6.35, P=9.08 × 10(-5)), and that the risk allele was correlated with higher novel P300b amplitude, in contrast to the significantly lower amplitude observed in cases compared to controls. Novel P300b amplitude was significantly correlated with a neurocognitive measure of auditory attention under interference conditions, suggesting a relationship between novel P300b amplitude and higher-order attentional processes. Our results suggest pleiotropic effects of ZNF804A on risk for SZ and neural mechanisms that are indexed by the novel P300b ERP component.

Age and apolipoprotein E ε4 effects on neural correlates of odor memory.

Alzheimer's disease (AD) affects 5.4 million Americans. Evidence suggests that individuals who are positive for the apolipoprotein E (ApoE) ε4 allele are at higher risk for developing the disease. Studies have also shown that the ε4 allele is linked to olfactory decline. Olfactory functioning may be investigated using olfactory event-related potentials (OERPs). The high temporal resolution of OERPs enables an understanding of the neural correlates of olfactory processing and functioning. This study investigated the effects of age, ApoE ε4 status, response type, and electrode site on OERP latency and amplitude during encoding and retrieval in an odor recognition memory task. The 60 participants were equally divided into 3 age groups matched on ε4 status: younger, middle, and older. Odors were presented using a computer-controlled olfactometer. Participants were notified during encoding that this was a task of odor memory. Results indicated differences in OERP activity as a function of age, ApoE ε4 status, response type, and electrode site. These findings highlight the potential of OERPs to distinguish ε4- and ε4+ individuals and to contribute to an earlier diagnosis of AD.

Cholinergic receptor gene (CHRM2) variation and familial loading for alcohol dependence predict childhood developmental trajectories of P300.

P300 amplitude in childhood predicts substance use disorders by young adulthood. Trajectories of visual P300 amplitude show an association between low amplitude P300 and familial risk for alcohol dependence (AD). Variation in the cholinergic muscarinic receptor gene (CHRM2) has previously been associated with P300 amplitude and AD. The present study used group based trajectory modeling of auditory P300 data collected longitudinally from offspring in families with and without familial loading for AD to determine if specific trajectories would be associated with familial risk and CHRM2 variation. Trajectory modeling confirms previous reports of an association between the low visual P300 trajectory with high familial risk in male offspring. This association was detected in offspring in the 8-12 age range, but not in 13-18 or 19-29 year olds or in high-risk female offspring. CHRM2 association analysis with P300 finds 8-12 year olds who are homozygous for the T allele of rs1824024 are 2.6 times more likely to follow a P300 trajectory characterized by lower and slower change regardless of familial loading. Combining the odds for being male and having a TT genotype results in odds of 6.5 that individuals will follow the low P300 trajectory.

Auditory event-related potentials (P3a, P3b) and genetic variants within the dopamine and serotonin system in healthy females.

The late positive components of the human event-related brain potential comprise electrocortical reflections of stimulus-driven attentional capture (the anteriorly distributed P3a) and top-down control detection of relevant events (the posteriorly distributed P3b). As of yet, the neuropharmacologic and neurogenetic origin of the P3a and P3b is not fully understood. In this study, we address the contribution of dopaminergic and serotoninergic mechanisms. Sixty healthy females completed an active auditory novelty oddball paradigm while EEG was recorded. In all subjects, genetic polymorphisms within the dopamine system (dopamine transporter [DAT1], catecholamine-O-methyltransferase val158met [COMT val158met]) and the serotonin system (serotonin transporter [5HTTLPR]) were assessed. Across genotypes, novels (relative to standards) elicited a fronto-centrally distributed P3a, and targets (relative to standards) a parieto-centrally distributed P3b. Genotypes effects were observed for both P3a (COMT, 5HTTPLR) and P3b (DAT1, COMT, 5HTTLPR) only at prefrontal electrode location (Fz). Specifically, the frontal P3a was enhanced in COMT met/met homozygotes, but not in DAT1 9R. The target-related P3b was enhanced in COMT met/met and DAT1 9R relative to its genetic counterparts, but only at frontal electrodes. This 'anteriorized' enhancement may reflect either an additional frontal component in the target-related P3 dependent on dopamine, or a more subtle shift in the neural ensemble that generates the target-related P3. Results for 5HTTLPR short allele homozygotes mimicked those in COMT met/met homozygotes. In all, the present findings suggest involvement of frontal-cortical dopaminergic and serotoninergic mechanisms in bottom-up attentional capture (COMT val158met, 5HTTLPR), with an additional top-down component sensitive to striatal signals (DAT1).

DBH -1021C>T and COMT Val108/158Met genotype are not associated with the P300 ERP in an auditory oddball task.

OBJECTIVE: The amplitude and latency of the P300 may be associated by variations in dopaminergic genes. The current study was conducted to determine whether functional variants of the catechol-O-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) gene were associated with P300 amplitude and latency in an auditory oddball task. METHODS: The P300 ERP was assessed by a two-tone auditory oddball paradigm in a large sample of 320 healthy volunteers. The Val108/158Met polymorphism (rs4680) of the COMT gene and the -1021C>T polymorphism (rs1611115) of the DBH gene were genotyped. P300 amplitude and latency were compared across genotype groups using analysis of variance. RESULTS: There were no differences in demographic characteristics in subjects for genotypic subgroups. No genotype associations were observed for the P300 amplitude and latency on frontal, central and parietal electrode positions. CONCLUSIONS: COMT Val108/158Met and DBH -1021C>T polymorphisms do not show evidence of association with characteristics of the P300 ERP in an auditory oddball paradigm in healthy volunteers. SIGNIFICANCE: We failed to find evidence for the association between dopaminergic enzymatic polymorphisms and the P300 ERP in healthy volunteers, in the largest study undertaken to date.

Effect of DISC1 on the P300 waveform in psychosis.

INTRODUCTION: Abnormalities in the neurophysiological measures P300 amplitude and latency constitute endophenotypes for psychosis. Disrupted-in-Schizophrenia-1 (DISC1) has been proposed as a promising susceptibility gene for schizophrenia, and a previous study has suggested that it is associated with P300 deficits in schizophrenia. METHODS: We examined the role of variation in DISC1 polymorphisms on the P300 endophenotype in a large sample of patients with schizophrenia or psychotic bipolar disorder (n = 149), their unaffected relatives (n = 130), and unrelated healthy controls (n = 208) using linear regression and haplotype analysis. RESULTS: Significant associations between P300 amplitude and latency and DISC1 polymorphisms/haplotypes were found. Those homozygous for the A allele of single-nucleotide polymorphism (SNP) rs821597 displayed significantly reduced P300 amplitudes in comparison with homozygous for the G allele (P = .009) and the heterozygous group (P = .018). Haplotype analysis showed a significant association for DISC1 haplotypes (rs3738401|rs6675281|rs821597|rs821616|rs967244|rs980989) and P300 latency. Haplotype GCGTCG and ACGTTT were associated with shorter latencies. DISCUSSION: The P300 waveform appears to be modulated by variation in individual SNPs and haplotypes of DISC1. Because DISC1 is involved in neurodevelopment, one hypothesis is that disruption in neural connectivity impairs cognitive processes illustrated by P300 deficits observed in this sample.

Familiality of neural preparation and response control in childhood attention deficit-hyperactivity disorder.

BACKGROUND: Patients with attention deficit-hyperactivity disorder (ADHD) exhibit difficulties in multiple attentional functions. Although high heritability rates suggest a strong genetic impact, aetiological pathways from genes and environmental factors to the ADHD phenotype are not well understood. Tracking the time course of deviant task processing using event-related electrophysiological brain activity should characterize the impact of familiality on the sequence of cognitive functions from preparation to response control in ADHD. Method Preparation and response control were assessed using behavioural and electrophysiological parameters of two versions of a cued continuous performance test with varying attentional load in boys with ADHD combined type (n = 97), their non-affected siblings (n = 27) and control children without a family history of ADHD (n = 43). RESULTS: Children with ADHD and non-affected siblings showed more variable performance and made more omission errors than controls. The preparatory Cue-P3 and contingent negative variation (CNV) following cues were reduced in both ADHD children and their non-affected siblings compared with controls. The NoGo-P3 was diminished in ADHD compared with controls whilst non-affected siblings were located intermediate but did not differ from both other groups. No clear familiality effects were found for the Go-P3. Better task performance was further associated with higher CNV and P3 amplitudes. CONCLUSIONS: Impairments in performance and electrophysiological parameters reflecting preparatory processes and to some extend also for inhibitory response control, especially under high attentional load, appeared to be familially driven in ADHD and may thus constitute functionally relevant endophenotypes for the disorder.

Genetic association study of the P300 endophenotype in schizophrenia.

OBJECTIVE: Although reduced amplitude of the P300 event-related potential is a well-documented intermediate phenotype of schizophrenia, little is known about its genetic underpinnings in patients with schizophrenia. This study aims to examine associations between P300 and a range of candidate genetic variants, selected from either candidate gene studies or genome-wide association studies, in a large sample of patients with schizophrenia. METHODS: P300 amplitude at the midline parietal electrode and 193 single nucleotide polymorphisms (SNPs) in 67 genes were assessed in 336 patients with schizophrenia. The association between each SNP and P300 amplitude, controlled for illness duration and gender, was evaluated. Associations at p<.01 were considered of potential relevance, while Bonferroni correction was applied to determine formal statistical significance (Bonferroni-corrected threshold of significance p=.0003). RESULTS: Of the 193 selected SNPs, 4 SNPs showed potentially relevant association with P300 amplitude at a significance level of p<.01. One of these SNPs, rs1045642 in ABCB1, was most convincingly associated with P300 amplitude, reaching formal (Bonferroni-corrected) significance, while there was evidence for possible association with rs1572899 in DISC-1, rs6265 in BDNF and rs1625579 in MIR137. CONCLUSION: Genetic variation in ABCB1 may be associated with P300 amplitude in patients with schizophrenia. This result may encourage further efforts to elucidate the genetic underpinnings of P300 generation.

Association study of neuregulin 1 gene polymorphisms with auditory P300 in schizophrenia.

Neuregulin 1 (NRG1), a gene involved with myelin production has been shown to have a positive correlation with schizophrenia. Event-related potentials (ERPs) studies provide the evidence of disturbed electrophysiologic marker in schizophrenia. The present study investigated the association of NRG1 genotypes with P300 in schizophrenia. Three polymorphisms in NRG1 gene were detected in 287 Chinese Han schizophrenics and 120 healthy control subjects. Among the total sample, 140 patients and 96 controls underwent P300. There were no significant differences for genotype distributions and allele frequencies between schizophrenic group and the control. A significant difference was observed between the schizophrenic patients and controls in the AT haplotype, with Odds Ratio 0.304 (P = 0.000882, 95% CI = 0.145-0.636). P300 amplitude in the schizophrenic group was significantly lower than that of the controls at Fz, Cz, Pz. P300 latency in the schizophrenic group was also significantly longer than that of the controls at Cz, Pz, Fz. Significant differences of P300 latency between three genotypes of rs3924999 were found at Cz and Pz both in schizophrenic group and the controls. The G/G carriers of rs3924999 tended to perform worse in the P300 latency as compared to A/A or A/G carriers both in the schizophrenia and controls. There were no significant differences for P300 latency and amplitude between schizophrenic group and controls for AT haplotype. NRG1 gene is a susceptible gene for Chinese Han schizophrenia and AT haplotype might have the protective role in the schizophrenia. Rs3924999 in NRG1 gene might functionally impact cognitive processing.

[Neurophysiological endophenotypes and schizophrenic disorder: emergence and evolution of a clinical concept]. / Endophénotypes neurophysiologiques et trouble schizophrénique : naissance et évolution d'un concept clinique.

It is proposed an historical approach to concepts leading to the development of operational paradigms for measuring objectives neurophysiological endophenotypes. It is hypothesized that psychiatric interest for paradigms measuring Event-Related Potential (ERP) come from Bleuler (1911) and McGhie and Chapman (1961) phenomenological and clinical descriptions. They noted, first that patients with schizophrenia generally feel as if they are being flooded by an overwhelming mass of sensory input combined with a heightened sensory perception, second that they were distractible to irrelevant sensory stimuli. These subjective abnormalities may be related, first to inability to filter incongruent information measured in a double click paradigm by a deficit in P50 amplitude gating, and second to an inability to select a stimulus of interest measured in the oddball paradigm by a deficit in P300 amplitude. The analysis of these P50 and P300 ERP in cohorts of patients with schizophrenia found most of Gottesman endophenotype criteria. P50 and P300 ERP are therefore relevant neurophysiological endophenotypes. However, from a clinical point of view, these endophenotypes lack specificity. The hypothesis of this article leads us to formulate ways of research. It is shown the value of combining objective neurophysiological measures with subjective measures using self-administered questionnaires ("offline") or psychophysiological tests ("online") to develop rigorous neurophysiological experimental paradigms especially as clinical observations of their origins are not forgotten.

Adiposity measures predict olfactory processing speed in older adult carriers of the apolipoprotein E ε4 allele.

OBJECTIVE: The current study investigated the relationship between adiposity and P3 latency. METHODS: Fifty-one adults in two age groups (18-25 and 65+) participated. Odor stimuli were delivered via olfactometer as participants focused on a computer screen. Each stimulus was followed by presentation on the screen of four odor identification choices. Participants attempted identification by button press. Olfactory event-related potentials (OERPs) were recorded. BMI and waist circumference were measured as indicators of adiposity. RESULTS: In bivariate analyses with all participants included, positive correlations for P3 latency with both BMI and waist circumference were observed, indicating that as adiposity increased latencies also increased. When each age group was separately examined, correlations between adiposity measures and latency remained statistically significant for older adults. Furthermore, ApoE ε4 allele status was examined. Latencies remained positively correlated with adiposity in older adult ε4 carriers; but not in non-carriers. CONCLUSIONS: This study indicates that adiposity predicts olfactory processing speed in older adults, specifically in ε4 carriers. SIGNIFICANCE: The results suggest that olfactory processing speed may be a useful measure for detecting and following the effects of adiposity on brain integrity and cognitive function in those at genetic risk for AD.