Reduced hippocampal glutamate in Alzheimer disease

Altered neurometabolic profiles have been detected in Alzheimer disease (AD) using ¹H magnetic resonance spectroscopy (MRS), but no definitive biomarker of mild cognitive impairment (MCI) or AD has been established. This study used MRS to compare hippocampal metabolite levels between normal elderly controls (NEC) and subjects with MCI and AD. Short echo-time (TE = 46 ms) ¹H spectra were acquired at 4 T from the right hippocampus of 23 subjects with AD, 12 subjects with MCI and 15 NEC. Absolute metabolite levels and metabolite ratios were compared between groups using a multivariate analysis of covariance (covariates: age, sex) followed by post hoc Tukey's test (p < 0.05 significant). Subjects with AD had decreased glutamate (Glu) as well as decreased Glu/creatine (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to NEC. Subjects with AD also had decreased Glu/mI ratio compared to MCI. There were no differences between subjects with MCI and NEC. Therefore, in addition to NAA/Cr, decreased hippocampal Glu may be an indicator of AD.     

MCI patients’ EEGs show group differences between those who progress and those who do not progress to AD

The theta/gamma and alpha3/alpha2 ratio were investigated as early markers for prognosticating of progression to dementia. 76 subjects with mild cognitive impairment (MCI) underwent EEG recording, MRI scans and neuropsychological (NPS) tests. After 3 years of follow-up, three subgroups were characterized as converters to Alzheimer's disease (AD, N = 18), converters to non-AD dementia (N = 14) and non-converters (N = 44). The theta/gamma and alpha3/alpha2 ratio, performance on cognitive tests and hippocampal volume, as evaluated at the time of initial MCI diagnosis, were studied in the three groups. As expected, MCI to AD converters had the smallest mean hippocampal volume and poorest performance on verbal learning tests, whereas MCI to non-AD converters had poorest cognitive performance in non-verbal learning tests, abstract thinking, and letter fluency. Increased theta/gamma ratio was associated with conversion to both AD and non-AD dementia; increased alpha3/alpha2 ratio was only associated with conversion to AD.Theta/gamma and alpha3/alpha2 ratio could be promising prognostic markers in MCI patients. In particular, the increase of high alpha frequency seems to be associated with conversion in AD. EEG markers allow a mean correct percentage of correct classification up to 88.3%. Future prospective studies are needed to evaluate the sensitivity and specificity of these measures for predicting an AD outcome.     

Reduced levels of IgM autoantibodies against N-truncated pyroglutamate Aβ in plasma of patients with Alzheimer's disease

In the present work, we investigated the level of IgM autoantibodies directed against different Aβ epitopes as potential diagnostic biomarker for Alzheimer's disease (AD). Anti-Aβ autoantibody levels were measured in 75 plasma samples from patients with AD, individuals with mild cognitive impairment (MCI), and healthy age- and sex-matched controls (HC). To validate the presence of anti-Aβ IgMs, pooled plasma samples were subjected to gel-filtration analysis. The mean level of pGluAβ-IgM (N-terminal truncated starting at position three with pyroglutamate) was significantly decreased in AD patients as compared to HC. In the group of MCI patients there was a significant positive correlation between pGluAβ-IgM and cognitive decline analyzed by MMSE (rho = 0.58, d.f. = 13, p = 0.022). These observations indicate that the level of IgM autoantibodies against pGluAβ is a promising plasma biomarker for AD and correlates with the cognitive status of individuals at risk to develop AD.     

A comparative analysis of sensory visual evoked oscillations with visual cognitive event related oscillations in Alzheimer's disease

We compared visual evoked oscillatory responses of subjects with Alzheimer's disease (AD) (n = 22) to healthy elderly controls (n = 19) elicited by simple light stimuli. The visual evoked oscillatory responses in AD subjects without cholinergic treatment (n = 11) show significant differences (df = 2.38, F = 4.957, P = 0.012) from the controls and the AD subjects treated with a cholinesterase inhibitor (n = 11). Higher theta oscillatory responses in untreated AD subjects are seen on the electrode locations over bi-parietal and right occipital regions after simple light stimuli with less, if any, cognitive load. These changes were restricted to the theta frequency range only and are related to location, frequency bands and drug effects. In our previous work we observed that visual event related oscillations elicited after the visual stimuli with a higher cognitive load, i.e. an oddball target, display lower amplitudes: between controls and AD subjects in delta frequency band without a drug effect, over the left and mid-central region. These differences between the visual evoked oscillations and the visual event related oscillations imply that there are at least two different cognitive circuits that are activated upon visual stimuli in AD patients.     

Verbal fluency performance in amnestic MCI and older adults with cognitive complaints

Verbal fluency tests are employed regularly during neuropsychological assessments of older adults, and deficits are a common finding in patients with Alzheimer's disease (AD). Little extant research, however, has investigated verbal fluency ability and subtypes in preclinical stages of neurodegenerative disease. We examined verbal fluency performance in 107 older adults with amnestic mild cognitive impairment (MCI, n = 37), cognitive complaints (CC, n = 37) despite intact neuropsychological functioning, and demographically matched healthy controls (HC, n = 33). Participants completed fluency tasks with letter, semantic category, and semantic switching constraints. Both phonemic and semantic fluency were statistically (but not clinically) reduced in amnestic MCI relative to cognitively intact older adults, indicating subtle changes in the quality of the semantic store and retrieval slowing. Investigation of the underlying constructs of verbal fluency yielded two factors: Switching (including switching and shifting tasks) and Production (including letter, category, and action naming tasks), and both factors discriminated MCI from HC albeit to different degrees. Correlational findings further suggested that all fluency tasks involved executive control to some degree, while those with an added executive component (i.e., switching and shifting) were less dependent on semantic knowledge. Overall, our findings highlight the importance of including multiple verbal fluency tests in assessment batteries targeting preclinical dementia populations and suggest that individual fluency tasks may tap specific cognitive processes.     

Metabolic syndrome, mild cognitive impairment, and progression to dementia. The Italian Longitudinal Study on Aging

We investigated the relationship of metabolic syndrome (MetS) and its individual components with incidence of mild cognitive impairment (MCI) and its progression to dementia in a large longitudinal Italian population-based sample with a 3.5-year follow-up. A total of 2097 participants from a sample of 5632 65-84-year-old subjects from the Italian Longitudinal Study on Aging were evaluated. MetS was defined according to the Third Adults Treatment Panel of the National Cholesterol Education Program criteria. MCI, dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were classified using current published criteria. Among MCI patients those with MetS (N = 49) had a higher risk of progression to dementia (HR, 4.40; 95% CI, 1.30-14.82) compared with those without MetS (N = 72). After a multivariate adjustment, the risk in MCI patients with MetS approximately doubled (multivariate adjusted HR, 7.80, 95% CI 1.29-47.20) compared with those MCI without MetS. Finally, among non-cognitively impaired individuals there were no significant differences in risks of developing MCI in those who were affected by MetS (N = 608) in comparison with those without MetS (N = 837), as well as excluding those individuals with undernutrition or low inflammatory status with or without undernutrition. In our population, among MCI patients the presence of MetS independently predicted an increased risk of progression to dementia over 3.5 years of follow-up.     

Cingulum fiber diffusivity and CSF T-tau in patients with subjective and mild cognitive impairment

Diffusion tensor imaging (DTI) and CSF biomarkers are useful diagnostic tools to differentiate patients with mild cognitive impairment (MCI) from normal controls, and may help predict conversion to dementia. Total Tau protein (T-tau) and DTI parameters are both markers for axonal damage, thus it is of interest to determine if DTI parameters are associated with elevated CSF T-tau levels in patients with cognitive impairment. For this purpose, patients with subjective cognitive impairment (SCI) and MCI were recruited from a university based memory clinic.Regions of interest were used to determine fractional anisotropy (FA), radial diffusivity (DR) and axial diffusivity (DA) in known white matter tracts in patients with MCI (n = 39) and SCI (n = 8) and 26 cognitively healthy controls. Significant lower FA and higher DR values were observed in patients with pathological vs. patients with normal CSF T-tau levels and vs. controls in left posterior cingulum fibers. T-tau values were negatively correlated with FA and positively correlated with DR values in the posterior cingulum fibers.Cingulum fiber diffusivity was related to T-tau pathology in SCI/MCI patients and altered DR may suggest that loss of myelin contributes to early white matter changes in patients at risk of developing Alzheimer's disease (AD).     

Ubc9 gene polymorphisms and late-onset Alzheimer's disease in the Korean population: A genetic association study

Ubiquitin-conjugating enzyme E2I (Ubc9) ligates small ubiquitin-related modifier (SUMO) to target proteins, resulting in changes of their localization, activity, or stability. Sumoylation of amyloid precursor protein (APP) was reported to be associated with decreased levels of beta amyloid (Aβ) aggregates, suggesting that sumoylation may play a role in the pathogenesis of Alzheimer's disease (AD). We investigated the association between genetic variations of Ubc9 gene (UBE2I) and late-onset Alzheimer's disease (AD). Five single nucleotide polymorphisms (SNPs) in UBE2I were genotyped in the DNA samples of 312 AD patients, 347 subjects with mild cognitive impairment (MCI), and 489 cognitively healthy controls. The genotype distribution of a polymorphism in intron 7 (rs761059) differed between AD cases and controls, with an adjusted odds ratio (OR) of 1.45 (p = 0.046, 95% CI: 1.01–2.08). One haplotype (ht2 CAGAG) was found in 14.0% of the AD patients and in 11.1% of the controls (p = 0.04, OR = 1.43. 95% CI; 1.01–2.01). Stratification by the ApoE-?4 allele gave no significant difference between the groups. When the samples were stratified by gender, the genotypes of two SNPs (rs8052688, rs8063) were significantly associated with the risk of MCI among women. Our investigation suggests that UBE2I polymorphisms might be associated with a risk of AD and MCI.     

Visual contrast sensitivity in Alzheimer’s disease,mild cognitive impairment,and older adults with cognitive complaints

Deficits in contrast sensitivity (CS) have been reported in Alzheimer’s disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology in older adults with AD (n = 10), amnestic MCI (n = 28), cognitive complaints without performance deficits (CC; n = 20), and healthy controls (HC; n = 29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated. CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, frequency doubling technology-based measures of CS may have promise as a novel AD biomarker.     

Early event-related potentials changes during simple mental calculation in Chinese older adults with mild cognitive impairment: A case–control study

The aim was to examine early event-related potential (ERP) changes during mental arithmetic calculation task in mild cognitive impairment patients compared to healthy elderly. 16 mild cognitive impairment (MCI) subjects and 16 healthy Chinese older adults were studied. Event-related potentials were elicited using a simple mental calculation task. Performance on arithmetic calculation task, and the latency and amplitude of early event-related potential components (N1, P1, N170, and P2) were compared between the two groups. The reaction time of MCI group was significantly longer than that of control group (1691.03 ± 94.59 vs. 1539.55 ± 27.76, P < 0.01). The correct rate of MCI group (0.9463 ± 0.04) was significantly lower than that of control group (0.9776 ± 0.02, P < 0.01). The latency of temporal–occipital N170 and central–prefrontal P2 of MCI group were significantly prolonged compared to controls. MCI subjects presented significantly higher P2 amplitude. Compared with healthy controls, N170 was significantly lower at left temporal–occipital region and higher at right temporal–occipital region in mild cognitive impairment. Mild cognitive impairment patients had deficit on simple calculation. The early arithmetic calculation processing mechanism of mild cognitive impairment patients may be different from normal people.     

Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease

To test the effects of the PPAR-γ agonist pioglitazone on cognition, regional cerebral blood flow (rCBF), and plasma levels of Aβ40 and Aβ42, we conducted a 6-month, randomized, open-controlled trial in patients with mild Alzheimer disease (AD) accompanied with type II diabetes mellitus. We randomly assigned 42 patients to either the group treated with 15-30 mg pioglitazone daily (n = 21, pioglitazone group) or not (n = 21, control group). The pioglitazone group improved cognition and rCBF in the parietal lobe, while the control group showed no such improvement. The plasma Aβ40/Aβ42 ratio increased in the control group, but showed no significant change in the pioglitazone group. Both groups showed good control of diabetes during the study. In addition, pioglitazone treatment resulted in a decrease in fasting plasma insulin levels, indicating enhanced insulin sensitivity. The results of this pilot study demonstrated that pioglitazone exhibited cognitive and functional improvements, and stabilization of the disease in diabetic patients with AD. Pioglitazone may offer a novel strategy for the treatment of AD.     

Polymorphism C in the serotonin transporter gene (SLC6A4) in questionable dementia and Alzheimer's disease

The promoter region of the serotonin transporter gene (SLC6A4) shows a 22-bp tandem repeat polymorphism, indicated as polymorphism C, that has been associated to depression, obsessive-compulsive disorder, memory impairment, and anxiety. Less clear are data regarding its association with Alzheimer's disease (AD). No data were reported regarding its association with questionable dementia (QD). In this study we investigate for polymorphism C in the SLC6A4 gene 302 elderly subjects with a clinical diagnosis of AD (n = 105), QD (n = 88) and no cognitive impairment (n = 114) attending a geriatric ward. A community-dwelling sample of 390 healthy subjects was also included in the analysis. A significant higher prevalence of the C16/C16 genotype in AD than in QD was observed (37.14% vs. 3%; p = 0.041, OR 2.001, 95%CI 1.018–4.024), while no differences in the C16/C14 and C14/C14 genotypes as well as in the estimated allele frequencies were found. No further differences among the three groups of subjects were found, also when they were compared with the community-dwelling sample. These findings suggest that SLC6A4 gene variation may have only a minor role, if any, in AD or QD.     

Measurements of medial temporal lobe atrophy for prediction of Alzheimer's disease in subjects with mild cognitive impairment

Our aim was to compare the predictive accuracy of 4 different medial temporal lobe measurements for Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Manual hippocampal measurement, automated atlas-based hippocampal measurement, a visual rating scale (MTA-score), and lateral ventricle measurement were compared. Predictive accuracy for AD 2 years after baseline was assessed by receiver operating characteristics analyses with area under the curve as outcome. Annual cognitive decline was assessed by slope analyses up to 5 years after baseline. Correlations with biomarkers in cerebrospinal fluid (CSF) were investigated. Subjects with MCI were selected from the Development of Screening Guidelines and Clinical Criteria for Predementia AD (DESCRIPA) multicenter study (n = 156) and the single-center VU medical center (n = 172). At follow-up, area under the curve was highest for automated atlas-based hippocampal measurement (0.71) and manual hippocampal measurement (0.71), and lower for MTA-score (0.65) and lateral ventricle (0.60). Slope analysis yielded similar results. Hippocampal measurements correlated with CSF total tau and phosphorylated tau, not with beta-amyloid 1–42. MTA-score and lateral ventricle volume correlated with CSF beta-amyloid 1–42. We can conclude that volumetric hippocampal measurements are the best predictors of AD conversion in subjects with MCI.     

Genetic variation in APOE cluster region and Alzheimer's disease risk

We report the fine mapping/sequencing results of promoter and regulatory regions of APOE cluster genes (APOE, APOC1, APOC4, APOC2, and TOMM40) in Alzheimer's disease (AD) risk as well as in the progression from mild cognitive impairment (MCI) to AD. Long-range sequencing in 29 MCI subjects who progressed to dementia revealed 7 novel variants. Two potentially relevant novel variants and 34 single nucleotide polymorphisms (SNPs) were genotyped in a large sample of AD, MCI, and control subjects (n = 1453). Globally, very little association signal was observed in our sample in the absence of APOE ε4. Rs5158 (APOC4 intron 1) and rs10413089 (3′ to APOC2) showed a trend toward an increase in AD risk independently from APOE ε4 associated risk though it did not survive multiple test correction (uncorrected p = 0.0099 and 0.01, respectively). Interestingly, rs10413089 showed a similar effect in an independent series. The analysis of the discovery sample showed an association of TOMM40 single nucleotide polymorphisms with progression from MCI stage to AD (rs59007384 and rs11556510), as well as with a shorter time to progression from MCI status to AD (rs10119), though these results could not be replicated in independent series. Further studies are needed to investigate the role of APOE cluster variants in AD risk.     

Baroreflex function is reduced in Alzheimer’s disease: a candidate biomarker?

The baroreflex (BR) reflects autonomic blood pressure control. Alzheimer’s disease (AD) affects the autonomic system. Detailed properties of BR in AD are unknown. We hypothesized that BR is reduced in AD, and is influenced by autonomic effects of cholinesterase inhibitors (ChEI). BR was determined in 18 AD patients, 11 patients with mild cognitive impairment (MCI) and 19 healthy control subjects. In AD, BR was measured again after ChEI treatment. Receiver operating characteristic analysis was used to define a BR cutoff value, which was then tested in an independent validation sample of 16 AD, 18 MCI, and 18 control subjects. BR was lower in AD compared with MCI (p < 0.05) and in MCI compared with healthy control subjects (p < 0.01). Receiver operating characteristic analysis between AD and healthy control subjects yielded a sensitivity of 89% and a specificity of 94%. ChEI treatment increased BR with 66% (p < 0.01). BR was reduced in AD and increased after treatment with ChEI. BR might be a good biomarker to further explore the link between cardiovascular disease and AD.     

Urine formaldehyde level is inversely correlated to mini mental state examination scores in senile dementia

It is widely known that exogenous formaldehyde exposure induces human cognitive impairment and animal memory loss; and recent studies show that formaldehyde at pathological levels induces Aβ deposition and misfolding of tau protein to form globular amyloid-like aggregates. Endogenous formaldehyde may be a marker for progressive senile dementia.The aim of this study was to investigate the correlation of endogenous formaldehyde in urine of senile dementia and mini mental state examination (MMSE) scores.Formaldehyde level was analyzed by high-performance liquid chromatography (with fluorescence detection) in human urine from dementia patients (n = 141), patients with hypertension (n = 33) or diabetes (n = 16) and healthy individuals (n = 38), autopsy hippocampus samples from Alzheimer's disease (AD) patients and brains of three types of AD animal model: namely, senescence accelerated mice (SAMP8), APP-transgenic mice and APP/PS1-transgenic mice.In a double-blind study, there was marked elevation of urine formaldehyde levels in patients (n = 91) with dementia, and a slight increase in patients (n = 50) with mild cognitive impairment. Urine formaldehyde level was inversely correlated with mini mental state examination scores (Rs = −0.441, p < 0.0001). Furthermore, formaldehyde levels were significantly increased in the autopsy hippocampus from Alzheimer's patients (n = 4). In SAMP8 brains the formaldehyde level was significantly increased, suggesting that the endogenous formaldehyde is related to aging in mice. The brain formaldehyde level in APP/PS1-transgenic (n = 8) mice at age of 3 months and APP-transgenic (n = 8) mice at age of 6 months was increased (0.56 ± 0.02 mM), respectively, as compared with their respective age-matched controls, when these two types of AD-like animals, respectively, started to form Aβ deposits and memory loss obviously. According to the level of formaldehyde in the brain of the transgenic mice, we treated normal mice with formaldehyde (0.5 mM, intraperitoneal administration) and observed the memory loss of the animal in Morris water maze trial.Cognitive impairments for the senile dementia are probably related to endogenous formaldehyde levels; and the mini mental state examination scores referred to the evaluation of urine formaldehyde level in dementia patients may be used as a non-invasive method for the investigation and diagnosis of senile dementia.     

Olfactory loss and nigrostriatal dopaminergic denervation in the elderly

Olfactory dysfunction may precede common neurodegenerative disorders in the elderly, such as Alzheimer (AD) or Parkinson disease (PD). However, pathobiological mechanisms of olfactory loss in the elderly are poorly understood. Although nigrostriatal dopaminergic denervation is a key patholobiological feature of PD, age-associated nigrostriatal denervation (AASDD) occurs also with normal aging and can be more prominent in some elderly. We investigated the relationship between AASDD and olfactory performance in community-dwelling subjects. Community-dwelling subjects (n = 73, 44 F/29 M, mean age 64.0 ± 16.4, range 20–85) underwent brain dopamine transporter (DAT) [¹¹C]2-β-carbomethoxy-3β-(4-fluorophenyl) tropane (β-CFT) positron emission tomography (PET) imaging and olfactory assessment using the 40-odor University of Pennsylvania Smell Identification Test (UPSIT). Subjects with clinical or DAT PET evidence of Parkinson disease (PD) were not eligible for the study. AASDD was defined based on normative data in young and middle-aged subjects. Compared to a mild and general linear decline in odor identification observed in most subjects (R² = 0.18, P = 0.0002), there were 13 subjects who deviated below the 5% confidence interval level in age-predicted UPSIT scores. Analysis limited to elderly subjects 60 years and over demonstrated a significant association between poor smell (n = 10 out of 49, 20.4%) and AASDD (χ² = 4.4, P < 0.05). There is a significant association between olfactory dysfunction and more prominent nigrostriatal denervation in the elderly. Olfactory assessment may have potential as a screening tool to detect age-accelerated neurodegeneration in the elderly.     

Amyloid load in nondemented brains correlates with APOE e4

179 cognitively healthy adults enrolled in the Sun Health Brain Donation program between 7/91 and 12/07 were at least 60 years old and nondemented at the time of death (21 had developed mild cognitive impairment [MCI]). Amyloid plaque density, congophilic amyloid angiopathy (CAA), and neurofibrillary tangle (NFT) density scores were based on CERAD criteria and compared in apolipoprotein E (APOE) e4 carriers (n = 42) and noncarriers (NC) (n = 137). Mean age (83.4 ± .6), gender (45% women), interval between death and brain harvest (3.1 ± 2.4 h), and brain weight (1200 ± 119 g) did not differ between e4 carriers (n = 42) and NC. Total plaque density was higher in e4 carriers than NC (6.8 ± 4.9 vs. 4.3 ± 4.4, p = .002), and this was true in each of 5 subregions examined. Total CAA (p = .002) and all subregion CAA burden was also higher in e4 carriers. Total neuritic plaque density (1.2 ± 1.0 vs. 1.0 ± 1.0, p = .18) and total NFT density (3.9 ± 2.4 vs. 3.6 ± 2.3, p = .50) did not differ between e4 carriers and NC, nor in any subregion. Eliminating the 21 with MCI did not alter these results. Nondemented APOE e4 carriers over age 60 have a higher burden of total parenchymal and vascular amyloid neuropathology than NC, but no difference in neuritic plaque and NFT pathology.     

Study of thyroid hormone receptor alpha gene polymorphisms on Alzheimer's disease

Because the action of thyroid hormone (T3) is involved in adult cognitive functions, we wanted to assess the association between THRA gene polymorphisms, which encodes the T3 nuclear receptor TRα1, and Alzheimer's disease (AD) risk.We analysed 5 single nucleotide polymorphisms (SNPs) of THRA, covering the known common genetic variability of the gene, in the Lille AD case-control study (710 cases/597 controls). We observed that subjects bearing the rs939348 TT genotype had a tendency to have a higher risk of developing AD (adjusted OR [95%CI] = 1.71 [0.99-2.95] p = 0.06). We extended our finding to three other independent AD case-control studies and observed similar trends. When combining the 4 studies (1749 cases/1339 controls), we observed an overall significant higher risk of AD in TT subjects (adjusted OR [95%CI] = 1.42 [1.03-1.96], p = 0.03) compared with C allele bearers. However, when combining our data with the available data coming from 2 American genome wide association studies on AD, we observed a weak and not significant association (OR = 1.19 [0.97-1.45], p = 0.10).The relationship between the genetic variability of the THRA gene and AD risk remains uncertain but cannot be entirely excluded.     

Apolipoprotein E modulates auditory event-related potentials in healthy aging

42 individuals ranging from 47 to 73 years of age underwent an auditory three-stimulus oddball task while their event-related potentials (ERPs) were recorded. Half were APOE ?3 homozygotes and the remaining participants were either ?3/?4 heterozygotes (n = 13), or ?4 homozygotes (n = 8). Analyses of variance showed that the heterozygotes had lower N1 amplitudes than the ?3 homozygotes, consistent with a previous study of participants with mild cognitive impairment (MCI) [I. Reinvang, T. Espeseth, L. Gjerstad, Cognitive ERPs are related to ApoE allelic variation in mildly cognitively impaired patients, Neuroscience Letters 382 (3) (2005) 346–351]. APOE genotype also significantly modulated N2 latency. ?4 homozygotes had longer N2 latencies, and importantly, longer N2 latencies predicted decline in verbal learning after 3.5 years follow up. These findings indicate a potential clinical significance of individual differences in ERP components N1 and N2.