Search

Highlights • We hypothesize that synaptic function is differentially affected by APOE isoforms. • CSF SNAP-25 levels were elevated in an APOE ε4 gene dose-dependent manner. • CSF SNAP-25 levels were substantially higher in APOE ε4 carriers than APOE ε4 noncarriers with MCI. • CSF SNAP-25 levels were associated with MMSE score, CSF Aβ42, t-tau, and p-tau levels. Abstract The underlying mechanism of apolipoprotein E ε4 (APOE ε4) in the pathogenesis of Alzheimer's disease (AD) remains elusive. We hypothesize that synaptic function is differentially affected by APOE isoforms. Levels of CSF SNAP-25 were compared between APOE ε4 carriers and noncarriers in 55 participants with normal cognition, 75 patients with mild cognitive impairment (MCI), and 16 patients with mild AD dementia. We investigated relationships between SNAP-25 levels and age, gender, education, CSF Aβ42, and tau protein. We found that levels of SNAP-25 in CSF were substantially greater in APOE ε4 carriers compared to noncarriers with MCI. There was no significant difference in SNAP-25 levels between APOE ε4 carriers and noncarriers with normal cognition or AD. CSF SNAP-25 levels were associated with MMSE and CSF Aβ and tau levels. In summary, APOE ε4 may affect CSF SNAP levels in MCI patients, suggesting an important role of APOE ε4 in synaptic dysfunction leading to AD. [ABSTRACT FROM AUTHOR]

Highlights • The relationship between APOE - 491 A/T, -427C/T, and −219 T/G SNP and AD was studied. • The −491 T allele and the −491 A/T genotype protect against AD. • The −219 T/G heterozygosity is a potential risk factor of AD. Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a complex aetiology. The ε4 allel of the apolipoprotein E gene (APOE) is the only confirmed genetic risk factor for the development of AD. In addition, polymorphisms at the promoter region of the APOE gene are assumed to modulate the susceptibility to AD by their different affinity to the transcription factors thus affecting the expression of the gene. In the presented study, we investigated the association between −491 A/T (rs449647), −427C/T, (rs769446) and −219 T/G (rs405509) single nucleotide polymorphisms (SNPs) of APOE gene and AD risk in the Polish population. We found that only the −491 T allele and −491 A/T genotype acted as protective factors against AD, whereas the −219 T/G heterozygosity increased risk for AD in APOE ε4 carriers but not in APOE ε4 non-carriers. What is more, haplotype frequency estimation showed significant positive for A-T-T-C-C and A-T-G-C-C haplotypes or negative for A-T-T-T-C and T-T-T-T-C haplotypes associations with AD. These results contribute to the evidence that APOE promoter polymorphisms modulate risk for AD. [ABSTRACT FROM AUTHOR]

Neuronal loss is a prominent phenomenon in Alzheimer’s disease (AD) and alcohol-induced brain damage. Alcohol abuse is associated with an increased risk of AD, regardless of the type of alcoholic beverage. Furthermore, the detrimental effect of excessive alcohol consumption on the risk of AD is exacerbated among people carrying apolipoprotein E (APOE) ε4 allele, the major genetic risk factor for AD. However, how APOE ε4 and alcohol abuse synergistically enhance the possibility of AD is unclear. Here we show that in N2a cells stably expressing human APP695 (N2a-APP), high-concentration ethanol-induced neurotoxicity was significantly augmented in the presence of apoE4 protein, compared with apoE3 protein. Early and late apoptotic cells were apparently more in cells treated with the combination of apoE4 and ethanol, compared with that of apoE3 and ethanol. Inhibition of apoptosis using a pan-caspase inhibitor z-vad resulted in abolishment of the apoE isoform-specific effect on high-concentration ethanol-induced neurotoxicity. Moreover, compared with apoE3, apoE4 augmented ethanol-induced cellular oxidative stress, and pre-incubation with a reactive oxygen species (ROS) scavenger NAC abrogated the specific effect of apoE4 on ethanol-induced neurotoxicity. Taken together, our results for the first time demonstrate that apoE4 and high-concentration ethanol synergistically enhance neurotoxicity through elevating cellular oxidative stress and increasing neuronal apoptosis, and support the notion that avoiding excessive alcohol consumption can help to prevent AD especially in APOE ε4 carriers. [ABSTRACT FROM AUTHOR]

About 30–70% of familial Alzheimer’s disease (AD) cases are related to mutations in presenilin-1 gene ( PSEN1 ). Although the role of mutations and common variants in AD had been extensively investigated, the contribution of rare or low frequency PSEN1 variants on AD risk remains unclear. In the current study, we performed a mutational screening of PSEN1 coding exons and flanking intronic sequences among 53 index cases with familial history of AD from Rio de Janeiro (Brazil). Two missense variants (rs63750592; rs17125721), one rare and a low frequency variant, and two intronic variants (rs3025786; rs165932) were identified. In silico tools were used to predict the functional impact of the variants, revealing no changes in protein functionality by exonic variants. Otherwise, all variants were predicted to alter splicing signals. Prediction results, together with previous reports, suggest a correlation between rs17125721 and AD. So, a subsequent case-control study to evaluate the role of rs1712572 on AD risk was performed in an additional sample of 120 AD sporadic cases and in 149 elderly healthy controls by TaqMan Genotyping Assay. Our data indicates a risk association for rs17125721 in familial AD cases (OR = 6.0; IC95% = 1.06–33.79; p = 0.042). In addition, we tested the multiplicative interaction between allele ε4 of the apolipoprotein E ( APOE ) and rs17125721 and no statistical association was found. Taken together, our findings provide new insight about the genetic relevance of low frequency PSEN1 variants for familial AD development. [ABSTRACT FROM AUTHOR]

The deficit of cholinergic activity is one of the main findings in Alzheimer’s disease (AD), and is related to the synthesis of acetylcholine, and the hydrolysing enzymes, acetylcholinesterase and butyrylcholinesterase (BuChE). Together with the Apolipoprotein E-ε4 allele (ApoE-ε4), the BuChE-K variant has been proposed to increase AD risk in certain populations. In addition, this polymorphism has been associated with a lower capacity to attenuate β-amyloid aggregation. In the present study we explored the interaction of the BuChE-K variant with its activity in CSF, conventional AD biomarkers and ApoE genotype. 217 AD patients and 200 age-matched controls were genotyped for the ApoE and the BuChE-K variant. BuChE activity in CSF, as well as the levels of the CSF-AD biomarkers amyloid-beta 42 (Aβ42), total and hyperphosphorylated tau (t-tau and p-tau) were determined in 88 of these patients. The results showed no significant differences in the BuChE-K variant distribution between patients and controls. No influence of the BuChE-K variant was seen neither in CSF BuChE activity, nor in the levels of Aβ42, t-tau and p-tau in AD patients. ApoE genotype also did not seem to influence CSF BuChE activity. Interestingly, in AD patients, an association between high CSF BuChE activity and increased levels of CSF Aβ42 was shown, particularly in ApoE-ε4 allele carriers. In our population, the BuChE-K variant does not seem to confer risk for AD or to influence the activity of the enzyme in CSF. However, we demonstrated an association between BuChE activity, ApoE-ε4 genotype and CSF Aβ42 levels, highlighting the importance of assessing BuChE activity as a possible modulator of Aβ load in the brain. [ABSTRACT FROM AUTHOR]

• In the APOE ɛ4 carriers, both females and males demonstrated a stronger significant correlation between plasma p-tau181 and Aβ levels. • Our study showed a significant three-way interaction between sex, APOE, and plasma p-tau181 for Aβ levels in non-demented older individuals. To evaluate the relationship between blood tau phosphorylated at threonine 181 (p-tau181) levels and β-amyloid (Aβ) levels, this study took the potential role of sex differences and apolipoprotein E (APOE)-ε4 status into account. We examined 620 participants with normal cognition (n = 178) and mild cognitive impairment (n = 442). Three-way interactions between sex, APOE ε4 status, and the levels of plasma p-tau181 were examined with linear regression models for Aβ levels adjusting for age, education, and diagnosis. The correlation analysis was performed to detect the association of the levels of plasma p-tau181 with brain Aβ stratified for APOE status and sex. Blood p-tau181 levels were higher in APOE ε4+ participants as compared to APOE ε4 – participants (p < 0.001). A comparison of APOE ε4 status within each gender showed that APOE ε4 carriers had higher levels of plasma p-tau181 and amyloid-β than APOE ε4 noncarriers in both men and women (p < 0.001). In sex/APOE-stratified analyses, individuals with the APOE ε4 allele showed stronger correlations between plasma p-tau181 and brain Aβ levels in both females (r = 0.49, p < 0.001 for APOE ε4 carriers vs r = 0.28, p < 0.001 for APOE ε4 noncarrier.) and males (r = 0.34, p < 0.001 for APOE ε4 carriers vs r = 0.21, p = 0.04 for APOE ε4 noncarriers.). In interactive analysis, the association of plasma p-tau181 and Aβ levels was significant in the female APOE ε4 carriers (p < 0.003). APOE ε4 status and female sex interact to impact the correlation between plasma p-tau181 and Aβ levels. Although the APOE ε4 genotype is one of the most important risky genes for AD, sex differences may also modify the degree of risk at critical times among non-demented older adults. [ABSTRACT FROM AUTHOR]

• Our findings suggested that the results were driven by the interaction between plasma p-tau181 and APOE ε4 status in non-demented elderly adults, where plasma p-tau181 levels had a significant correlation with cognition in the APOE ε4 carriers. • Plasma p-tau181 levels predicted cognitive performance, but only in the APOE ε4 carriers. In this study, we aimed to investigate the relationships among plasma p-tau181, APOE ε4, and cognitive performance in non-demented elderly individuals. We used individuals (n = 630) with cognitive normal (CN, n = 182) and mild cognitive impairment (MCI, n = 448). Multiple linear regression models were performed to test the effects of APOE ε4 × plasma p-tau181 interaction on MMSE, CDR-SOB, ADAS-cog13, and RAVLT immediate recall. All models adjusted for age, sex, and education. In total, our study comprised 630 samples including 364 APOE ε4 non-carriers and 266 APOE ε4 carriers. In APOE ε4 carriers, plasma p-tau181 was significantly associated with MMSE (B = −0.04, p = 0.003), ADAS-Cog13 (B [unstandardized coefficient] = 0.21, p < 0.001), CDR-SB (B = 0.02, p = 0.003) and RAVLT immediate recall ((B = −0.17, p = 0.035). After correcting for Aβ status and diagnosis, the interaction between APOE ε4 and plasma p-tau181 was significant or marginally significant associations for RAVLT immediate recall (p = 0.076), MMSE (p = 0.011), CDR (p = 0.008), and ADAS-Cog13 (p < 0.001). Our findings suggested that plasma p-tau181 levels predicted cognitive performance among non-demented older adults, but only in the APOE ε4 carriers. [ABSTRACT FROM AUTHOR]

This study investigated the neuroprotective effects of COG1410, an apoliporotein E (apoE)-derived mimic peptide, against early brain injury (EBI) after subarachnoid hemorrhage (SAH). SAH was induced in C57BL/6 J mice (n = 68) by endovascular perforation. Mice received intravenous injection of COG1410 (2 mg/kg) or equal volume of vehicle (saline). The mortality rate, neurological score, rotarod latencies, cell apoptosis, microglial activation, pro-inflammatory cytokines production and protein levels of apoptotic and inflammatory markers were assessed at 24 h after sham operation or SAH. Results showed that COG1410 alleviated the neurological deficits associated with SAH. Compared with vehicle treatment group, the number of apoptotic cells and activated microglia decreased significantly in the COG1410 treated group. COG1410 enhanced Akt activation and suppressed caspase-3 cleavage. The imbalance of Bax and Bcl-2 induced by SAH was regulated by COG1410. Additionally, COG1410 attenuated cytokines production of IL-1β, IL-6 and TNF-α and suppressed the activation of JNK/c-Jun and NF-κB. Taken together, COG1410 protected against EBI via reducing apoptosis and neuroinflammation, through mechanisms that involve the regulation of apoptotic signaling and microglial activation. COG1410 is a potential neuroprotective agent for SAH treatment. [ABSTRACT FROM AUTHOR]

Amnestic mild cognitive impairment (aMCI) is a transitional stage between normal aging and Alzheimer’s disease (AD). Possession of the apolipoprotein E (APOE) ε4 genotype is a major predictor of progression to AD, particularly in patients with aMCI. However, the use of APOE genotyping in the diagnosis of aMCI that evolves into AD is limited due to its low sensitivity and specificity. In this study, we found that there was a notable increase in plasma homocysteine (HCY) and significant decrease in serum brain-derived neurotrophic factor (BDNF) in aMCI that converts to AD in patients with the APOE ε4 allele. Both plasma HCY and serum BDNF had higher positive predictive values and were more sensitive biomarkers of aMCI. Additionally, a testing strategy employing plasma HCY and serum BDNF revealed increases in sensitivity, specificity, and predictive ability compared with the use of either biomarker alone. The present study demonstrates that MCI that evolves into AD in patients with the APOE ε4 genotype may be predicted by plasma HCY and serum BDNF. [ABSTRACT FROM AUTHOR]

Parkinson’s disease is a progressive brain disorder due to the degeneration of dopaminergic neurons in the substantia nigra. The accumulation of aggregated forms of α-synuclein protein into Lewy bodies is one of the characteristic features of this disease although the pathological role of any such protein deposits in causing neurodegeneration remains elusive. Here, the effects of different apolipoprotein E isoforms (apoE2, apoE3, apoE4) on the aggregation of α-synuclein in vitro were examined using thioflavin T assays and also an immunoassay to detect the formation of multimeric forms. Our results revealed that the aggregation of α-synuclein is influenced by apoE concentration. At low concentrations of apoE (<15 nM), all of the isoforms were able to increase the aggregation of α-synuclein (50 μM), with apoE4 showing the greatest stimulatory effect. This is in contrast to a higher concentration (>15 nM) of these isoforms, where a decrease in the aggregation of α-synuclein was noted. The data show that exceptionally low levels of apoE may seed α-syn aggregation, which could potentially lead to the pathogenesis of α‐synuclein-induced neurodegeneration. On the other hand, higher levels of apoE could potentially lower the degree of α-synuclein aggregation and confer protection. The differential effects noted with apoE4 could explain why this particular isoform results in an earlier age of onset for Parkinson’s disease. [ABSTRACT FROM AUTHOR]

The CYP17A1 gene encodes cytochrome P450c17α, an enzyme that catalyzes the formation of sex hormones, which have been linked to the pathogenesis of Alzheimer’s disease (AD). An association between the CYP17A1 rs743572 single nucleotide polymorphism (SNP) and AD has been reported; however, the findings are controversial. In the present study, we investigated the association between rs743572 and another SNP, rs3824755, and AD risk in a Chinese Han population (n = 207 patients and 239 controls), and their interaction with the apolipoprotein E ( APOE ) e4 allele. We found that the C allele and GC + CC genotypes of rs3824755 conferred protection against AD only in APOE e4 carriers. Both rs3824755 and rs743572 polymorphisms showed interactions with APOE e4. The C allele and GC + CC genotypes of rs3824755 acted as protective factors that decreased the risk of APOE e4 in AD. The CYP17A1 rs743572 G allele and AG + GG genotypes were found to be potential risk factors that act synergetically with APOE e4. Moreover, the CA and GG haplotypes were protective and conferred a slight risk, respectively, in APOE e4 carriers. These results indicate that CYP17A1 rs3824755 and rs743572 are associated with AD in the Chinese Han population and act in combination with APOE e4. [ABSTRACT FROM AUTHOR]

Background Serum levels of apolipoprotein E (apoE) have been suggested as potential biomarker for dementia, but the long-term association between apoE and risk of dementia is uncertain. Methods Between 1990 and 1993, we measured serum apoE by immunoassay in 1042 non-demented individuals (mean ± SD age 68.4 ± 7.3 years; 59.3% women) from the population-based Rotterdam Study. Follow-up for dementia was complete until 2014. We used Cox models to determine the risk of dementia and Alzheimer’s disease in relation to apoE, adjusting for age, sex, educational level, cardiovascular risk factors, and additionally APOE genotype. Results Serum apoE was associated to APOE genotype (p-trend = 1.0E-51, r 2 = 0.21). In men, apoE tended to be lower with age, whereas in women the opposite was observed (p-trend = 0.07 and 0.08, respectively). During a median follow-up of 15.7 years (IQR 9.7–21.7), 220 participants developed dementia, of whom 180 had Alzheimer’s disease. Lower serum apoE was associated with an increased risk of dementia (HR, 95%CI, per SD decrease: 1.25, 1.05–1.48) and in particular Alzheimer’s disease (1.51, 1.23–1.86), which remained statistically significant for Alzheimer’s disease after additionally adjusting for APOE genotype (1.28, 1.01–1.62). When stratifying analyses in 5-year time frames, risk estimates were similar throughout the study period. Serum apoE tended to marginally improve 20-year prediction of Alzheimer’s disease (IDI 0.008, 95%CI −0.001–0.026, p = 0.086), but not all dementia. Conclusion Serum apoE is associated with long-term risk of Alzheimer’s disease in the general population, independent of APOE genotype. Additional predictive value of serum apoE was limited. [ABSTRACT FROM AUTHOR]

Aim Polymorphisms in the apolipoprotein E and CYP2D6 genes are widely reported to be related to Alzheimer's disease. However, few studies have focused on the relationship between polymorphisms in apolipoprotein E and CYP2D6 (rs1065852) genes and therapeutic responses to donepezil (DNP). This study explored the influence of apolipoprotein E3 and CYP2D6 (rs1065852) gene polymorphisms on therapeutic responses to donepezil in Han Chinese patients with Alzheimer's disease. Materials and methods A total of 85 patients with mild to moderate Alzheimer's disease who were treated with 2.5–10 mg of DNP per day for at least 3 months were enrolled. Mini-Mental State Examination scores were measured before and after DNP treatment, and the apolipoprotein E3 and CYP2D6 (rs1065852) genotypes of the patients were determined. Results We found that ApoE E3 non-carriers responded better to DNP treatment than E3 carriers ( p = 0.000) and that CYP2D6*10/*10 patients (MMSE score change: 0.29 ± 3.27) exhibited better therapeutic responses to DNP than did CYP2D6*1/*1 and CYP2D6*1/*10 patients ( p = 0.033). Patients who were ApoE E3 non-carriers and who had the CYP2D6*10/*10 genotype exhibited a trend toward better clinical responses to DNP therapy. Conclusions The ApoE E3 allele and the CYP2D6 rs1065852 polymorphism may provide clinically relevant information for predicting therapeutic responses to DNP therapy. [ABSTRACT FROM AUTHOR]

CD33 and MS4A cluster variants have been identified to modulate the risk of Alzheimer’s disease (AD) in several recent genome-wide association studies (GWAS) in Caucasians. In the present study, we first conducted a case-control study to investigate the CD33 single nucleotide polymorphisms (SNPs) rs3865444 and rs3826656 and the MS4A cluster SNPs rs610932 and rs670139 in a cohort from eastern China that comprised 126 late-onset Alzheimer’s disease (LOAD) patients and 129 healthy controls. The results revealed that the frequency of rs3826656 major (G) allele carriers was higher among the LOAD patients than among the controls [ P = 0.005; odds ratio (OR), 1.760; 95% confidence interval (CI), 1.185–2.615]. In apolipoprotein E ( APOE ) ε4 allele carriers, the G allele of the SNP rs3865444 was found to be associated with an increased risk of LOAD ( P = 0.002; OR, 3.391; 95% CI, 1.512–7.605). Next, we re-evaluated the association between these variants and LOAD by conducting a meta-analysis using data from studies of East Asian populations, including the present case-control study, and confirmed that rs3826656 increased the risk of LOAD. In addition, we identified a significant association between rs610932 and LOAD ( P = 0.035; OR, 0.79; 95% CI, 0.63–0.98). Note that heterogeneity should be considered during the interpretation of these results; significant heterogeneity was identified among studies on rs3865444, even in a subgroup analysis based on stratification of studies by the country of origin. In summary, our results suggest that CD33 and MS4A cluster variants are associated with LOAD susceptibility in East Asian populations. [ABSTRACT FROM AUTHOR]

We aimed to examine the association between Apolipoprotein E ( APOE ) and sleep disturbances. This is a cross-sectional study, from the Washington Heights-Inwood Community Aging Project (WHICAP). A total of 1944 non-demented older adults took part in the study. Sleep dysfunction was measured using sleep categories derived from the Medical Outcomes Study Sleep Scale. Genetic association between APOE -ϵ4 genotype and sleep disturbances was assessed using unadjusted linear regression models. Secondary analyses were conducted adjusting for age, sex, education, ethnicity and body mass index (BMI) . In the unadjusted model, individuals carrying the APOE -ϵ4 allele showed lower levels of snoring ( β = −0.02, SE = 0.01, p = 0.010) and sleep apnea ( β = −0.01, SE = 0.01, p = 0.037) when compared to non-ϵ4 carriers. After covariates' adjustment, ϵ4 carriers demonstrated stronger association with lower levels of both snoring ( β = −0.02, SE = 0.01, p = 0.006), and sleep apnea ( β = −0.01, SE = 0.01, p = 0.018). Our results suggest that APOE- ϵ4 is associated with decreased problems in snoring and sleep apnea, in non-demented older adults. [ABSTRACT FROM AUTHOR]

The present study assessed the mechanisms by which nerve growth factor (NGF) increased the level of apolipoprotein E (apoE) in PC12 cells. NGF (50 ng/mL) significantly increased apoE protein levels following 72 h of treatment. Similarly NGF increased luciferase activity in cells transfected with a luciferase reporter construct containing a 500 bp fragment of the apoE promoter, indicating NGF-induced apoE expression is regulated, at least in part, at the level of transcription. The non-selective nitric oxide synthase (NOS) inhibitor N ɷ -nitro- L -arginine methylester (L-NAME; 20 mM) did not attenuate the NGF-mediated increase in luciferase activity, while the inducible NOS inhibitor s-methylisothiourea (S-MIU; 2 mM) partially attenuated this action of NGF. Inhibition of MAP kinase activation with 50 μM U0126 or pre-treatment with the PKC inhibitor bisindolylmaleimide 1 (BIS-1; 10 μM) prevented the NGF-mediated activation of the apoE promoter. Pre-treatment with the phospholipase C (PLC) inhibitor U73122 (5 μM) partially inhibited the NGF-induced increase in luciferase activity while the Akt inhibitor LY294002 (10 μM) had no effect. These data suggest NGF-induced apoE transcription requires MAP kinase and PKC activation and that these TrkA signaling pathways may be modulated by NO. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive dysfunction and memory loss. Increasing evidence indicates that inflammation in the brain is a powerful factor in AD progression. Epoxyeicosatrienoic acids, the biologically active derivatives of arachidonic acid, synthesized by cytochrome P450 (CYP) epoxygenases, have been proven to have powerful anti-inflammatory effects. The aim of this study was to examine whether polymorphism in CYP2J2 , encoding one of the most common CYP epoxygenase isoforms, is associated with late-onset AD (LOAD). This case-control study genotyped 672 representatives of the Chinese Han population, including 321 LOAD patients and 351 healthy controls matched for age and gender, for the functional rs890293 polymorphism within CYP2J2 by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI–TOF MS). The CYP2J2 rs890293 T allele and GT + TT genotype were significantly associated with an increased risk of LOAD. Further data stratification according to the presence of the apolipoprotein E ( APOE ) e4 allele confirmed a strong association between CYP2J2 rs890293 and LOAD, and indicated that the involvement of CYP2J2 in LOAD was independent of ApoE-ϵ4. Our study demonstrated that CYP2J2 rs890293 is a possible predisposing genetic factor for progression of LOAD. [ABSTRACT FROM AUTHOR]

• Childbearing at older ages affects the health and wellbeing of the mother. • Cognitive performance in long-live families was reported as an indicator of healthy aging. • Women with extended maternal age at last childbirth exhibited better cognitive profile compared to younger mothers. • The association between later maternal age and better cognitive profile in a long-life cohort supports the potential use of later age at childbirth as a marker for healthy aging. Extended maternal age has been suggested as marker of delayed age-associated disabilities. We use the Long Life Family Study (LLFS) offspring generation to investigate the association between extended maternal age at last childbirth and healthy-aging endophenotypes. We hypothesize that women with extended maternal age at last childbirth will exhibit healthier endophenotype profiles compared to younger mothers. The association between maternal age and age-related endophenotypes previously derived in LLFS was assessed using Generalized Estimating Equations to adjust for relatedness. The quartiles of the maternal age at last childbirth were modeled as the independent variables. Univariate analyses tested the association between maternal age at last childbirth and age at clinical assessment, education, field center, Apolipoprotein E (APOE) genotype, depression, stress, smoking and successful pregnancies. Only the variables significantly associated in the univariate analyses were considered in secondary multivariate analyses. Univariate analyses showed that compared to older mothers (age at last birth ≥35), mothers 30 years old or younger at last childbirth are less educated (12 ± 3 years versus 13 ± 3 years) and have a higher frequency of smoking (9% versus 3% for maternal age ≥35). Results showed that older mothers (age at last birth ≥31–34 or ≥ 35) demonstrated significantly better cognitive profiles (p = 0.017 and p = 0.021 respectively) compared with mothers with last childbirth age ≤30. Later maternal age among women from long-life families is associated with a better cognitive profile, supporting the hypothesis that later age at childbirth may be a marker for healthy aging. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (APOE) gene polymorphism has been reported to be associated with cognitive dysfunction in healthy individuals, however the results were controversial in the very old elderly. The aim of this study is to assess the possible association of the APOE polymorphism with cognitive dysfunction in people aged 75 years and over. Four hundred and twenty-five aged Chinese veteran men without dementia were enrolled for APOE genotyping and neuropsychological tests including Mini-Mental Status Examination (MMSE), Digit Span Forward and Backward, and Cognitive Ability Screening Instrument Chinese language version (CASI C-2.0) were evaluated in these subjects. Among the elderly veterans, people who carry APOE ε4 were found to have worse performance on the total CASI scores, the abstraction/judgment subscores and the list-generating fluency subscores. This study suggests that the APOE ε4 alleles contributed detrimental effects on cognitive function in the very old veterans who do not have dementia. [ABSTRACT FROM AUTHOR]

Highlights: [•] APOE*4 allele is associated with increased risk of dementia in Pakistani population. [•] Stressful life events are also associated with dementia risk in Pakistani population. [•] No significant interaction was observed between APOE*4 and stress in Pakistani population. [ABSTRACT FROM AUTHOR]

Highlights: [•] The interactive effects of APOE and ERT after OVX on Aβ accumulation were determined in EFAD mice. [•] ERT decreased extracellular amyloid plaque and Aβ deposition with APOE2 and APOE3. [•] ERT increased extracellular amyloid plaque and Aβ deposition, but lowered soluble Aβ42 with APOE4. [•] First in vivo evidence that hAPOE differentially regulates the effects of ERT on Aβ deposition. [•] Aβ42 levels may be a critical read-out for APOE4 carriers enrolled in ERT trials. [Copyright &y& Elsevier]

Highlights: [•] SORL1 (rs2070045) polymorphism was examined in Alzheimer's disease (AD) in Chinese. [•] An increased susceptibility to AD associated with SORL1 T/T genotype was found. [•] SORL1 T/T genotype and ApoEɛ4 allele didn’t show an interaction effect on AD risk. [ABSTRACT FROM AUTHOR]

• PGLYRP2 gene rs892145, rs3813135 and rs733731 polymorphisms were examined in a Chinese Han cohort. • The rs892145 AT heterozygote in PGLYRP2 gene is a risk factor for PD and early-onset PD. • The rs3813135 C allele in PGLYRP2 gene might be a risk factor for PD. • No association was found between genotype or allele in rs733731 polymorphism and PD. Gut inflammation is increasingly corroborated to take part in the pathogenesis of Parkinson's disease (PD). The PGLYRP2 gene has been proven to increase susceptibility to inflammatory bowel disease (IBD). The present study aimed to explore the genetic relationship between single nucleotide polymorphism (SNP) of the PGLYRP2 gene and the risk of sporadic PD in the Han population of northern China. The genotypes of the rs3813135 T/C, rs733731 C/T and rs892145 A/T polymorphisms of the PGLYRP2 gene in 400 Chinese Han patients with PD and 400 healthy age-and sex-matched individuals were identified by the Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR–RFLP) method. The results showed that the frequency of the rs892145 AT heterozygote significantly differed between the PD and control groups (OR = 1.459, 95%CI = 1.459–1.039, P = 0.029), as well as the early-onset PD and control groups (P = 0.024). The rs3813135 polymorphism yielded only one significant result: C allele was more common in the male PD group than in the male control group (P = 0.045). Conversely, no significant difference in the genotype frequency of rs733731 was found between the PD and control groups. Five common haplotypes were assessed, of which the TTA and TCA haplotypes were related to PD susceptibility. In summary, our results indicated that the PGLYRP2 gene is associated with sporadic PD in the Chinese Han population, in which the rs892145 AT heterozygote might increase the risk of PD and possibly the risk of early-onset PD. Moreover, linkage disequilibrium (LD) analysis showed these three PGLYRP2 polymorphisms has a strong linkage in causing mutations. [ABSTRACT FROM AUTHOR]

Highlights: [•] Dab1 mediates VEGF-induced regulation of NR2B in cortical neurons. [•] VEGF treatment led to the association of VEGF receptor-2 (Flk1) and reelin receptor (apolipoprotein E receptor 2, ApoER2). [•] VEGF-induced Dab1 activation is Flk1-dependent. [•] VEGF treatment could significantly rescue the deficits in phospho-Dab1 levels in reeler (Reln−/−) neurons. [ABSTRACT FROM AUTHOR]

Highlights: [•] TACE activity and sTNFRs levels were increased in plasma of AD and aMCI patients. [•] The levels of TACE activity and sTNFRs correlated with Aβ in AD and aMCI patients. [•] ApoE genotype impacted on the levels of TACE activity and sTNFRs. [•] Combined TACE activity or sTNFRs, Aβ and APOE may help with the diagnosis of AD. [ABSTRACT FROM AUTHOR]

Abstract: APOE genotype is a risk factor for Alzheimer''s disease (AD) and cerebral amyloid angiopathy (CAA). The risk and severity of CAA increase with possession of APOE ɛ4, whereas APOE ɛ2 increases the risk of vessel rupture. Uptake of Aβ by cerebrovascular smooth muscle cells (CVSMCs) is mediated by low-density lipoprotein receptor-related protein-1 (LRP1). To determine whether APOE influences CAA by altering LRP1 expression, particularly by CVSMCs, we analysed APOE genotype, CAA severity, and LRP1 levels in post-mortem cerebral cortex, choroid plexus and meningeal vessels. LRP1 mRNA and protein were not related to CAA severity and presence. LRP1 mRNA was increased in meningeal vessels, but not cortex or choroid plexus, in AD and in association with APOE ɛ4, and was decreased in association with APOE ɛ3. In brains with CAA, APOE ɛ2 was associated with decreased LRP1 protein in meningeal vessels, and ɛ3 with increased LRP1 in choroid plexus. These findings suggest that APOE may influence the severity of CAA through altered expression of LRP1. [Copyright &y& Elsevier]

Abstract: To explore the possible cellular source and mechanism of apolipoprotein E (apoE) expression in mechanical injured neuronal cultures. Primary cultured mouse cortical neurons were subjected into mechanical injury by needle scratching. The conditioned medium of wild type (WT) primary mouse astrocytes was collected and added into cultured injured apoE knockout (KO) neurons. Separately, the conditioned medium of injured apoE KO neurons was collected and added into cultured WT astrocytes. We used a specific inhibitor of extracellular signal-regulated kinase (ERK) to block the possible apoE-associated pathway between injured neurons and astrocytes. The apoE expression levels of the cells and secreted into medium were measured by Western blot, respectively. The apoE expression was increased in neurons after mechanically injury, and the injured neurons uptook the astrocyte-secreted apoE, as well. Furthermore, the injured neurons stimulated astrocytes to express more apoE through the ERK signaling pathway. Mechanical injury triggered the neurons to increasingly synthesized apoE and uptook exogenous apoE, while stimulators released from injured neurons elevated astrocytes in apoE expression and secretion. [Copyright &y& Elsevier]

Abstract: It remains controversial regarding the association between Apolipoprotein E (ApoE) gene polymorphism and the risk of vascular dementia (VaD). The present meta-analysis was performed to derive a more precise estimation of the relationship. The meta-analysis was performed by searching PubMed, Embase and Web of Science databases. A total of 29 studies included 1763 VaD cases and 4534 controls were identified. The results showed evidence for significant association between ApoE ɛ4 mutation and VaD risk (for ɛ3/ɛ4 vs. ɛ3/ɛ3: OR=1.65, 95% CI=1.40–1.94, p-value<0.00001; for ɛ4/ɛ4 vs. ɛ3/ɛ3: OR=3.17, 95% CI=2.09–4.80, p-value<0.00001; for ɛ4 allele vs. ɛ3 allele: OR=1.72, 95% CI=1.40–2.12, p-value<0.00001). The similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta-analysis suggests an association between ApoE ɛ4 mutation and increased risk of VaD. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution. [Copyright &y& Elsevier]

Abstract: Recently, an international genome-wide association study (GWAS) additionally found rs597668 near EXOC3L2/BLOC1S3/MARK4 was a new genome-wide significance locus associated with late-onset Alzheimer''s disease (LOAD) in Caucasians. Follow-up replication studies were conducted almost exclusively in Caucasians, and the effects of the risk locus in other populations are as yet unknown. This study investigated the GWAS-associated locus near EXOC3L2 in 1205 unrelated Northern Han Chinese subjects comprising 598 LOAD patients and 607 healthy controls matched for gender and age. The results showed no significant differences in the genotypic or allelic distributions of rs597668 polymorphism between LOAD cases and healthy controls (genotype: P =0.653; allele: P =0.603), even after stratification for apolipoprotein E (APOE) ɛ4 status and statistical adjustment for age, gender and APOE ɛ4 status. This study suggests that the rs597668 polymorphism near EXOC3L2 may not play a major role in the susceptibility to LOAD in the Northern Han Chinese population. [Copyright &y& Elsevier]

Abstract: Previously, we reported that apolipoprotein E (apoE) deficiency increased the susceptibility to experimental autoimmune neuritis (EAN), an inflammatory autoimmune disorder of the peripheral nervous system (PNS) and an animal model for human Guillain-Barré syndrome (GBS) by affecting the antigen-presenting function of Schwann cells (SCs) via influence upon IL-6 production. To further elucidate the role of apoE in inflammation of the PNS, here we studied the effect of different isoforms of apoE on SCs in response to inflammatory stimulation. SCs from apoE2, E3 and E4 transgenic (Tg) and wild type (WT) mice were cultured, and their responses to stimulation by lipopolysaccharide (LPS) plus interferon (IFN)-γ were compared. Upon stimulation, the morphology of cultured SCs changed. Pronounced production of interleukin (IL)-6 and IL-10 within SCs, and of IL-6 and nitric oxide (NO) in the supernatants were found in an isoform-dependent manner (apoE3>apoE2≈apoE4). Further results indicated that both nuclear factor (NF) κB and Akt signaling pathways were involved in the process by the same isoform-dependent pattern. However, the expression of co-stimulatory molecules as showing the antigen-presenting capacity of SCs was not significantly different among these groups. In conclusion, SCs respond to inflammatory insults accompanied by increased productions of IL-6, IL-10 and NO in an apoE-isoform-dependent manner. SCs from apoE2 and apoE4 Tg mice seem to bear some dysfunction in producing cytokines (IL-6 and IL-10) and NO as compared with their apoE3 counterparts, probably resulting from their insufficiency to suppress the activation of NFκB and Akt pathways. Our findings may help to understand the role of different isoforms of apoE in inflammatory disorders of the PNS. [Copyright &y& Elsevier]

Abstract: Tau-tubuline kinase 1 (TTBK1) is a recently discovered brain-specific protein kinase involved in tau phosphorylation at AD-related sites. A recent large study has identified significant association of two single nucleotide polymorphisms (SNPs) (rs2651206 and rs7764257) in the TTBK1 gene with late-onset Alzheimer''s disease (LOAD) in Spanish. Here, we performed a case–control study to clarify whether the risk for LOAD might be influenced by these polymorphisms in a large Chinese cohort consisting of 400 patients and 388 healthy controls. The minor alleles of the rs2651206 polymorphism within TTBK1 was significantly associated with a reduced risk of LOAD (odds ratio/OR=0.69, P =0.011). Furthermore, rs2651206 polymorphism was still strongly associated with LOAD (OR=0.72, P =0.05) after adjusted for age, gender, and the apolipoprotein E (APOE) ɛ4 status. Haplotype analysis identified the TG haplotype, deriving from the two minor alleles, to decrease the risk of LOAD (OR=0.78, P =0.037). This study provides the evidence that variations in the TTBK1 gene may play an important role in the pathogenesis of sporadic LOAD in a Han Chinese population. [Copyright &y& Elsevier]

Abstract: Background: Down syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimer''s disease (DAD) compared with the general population. Many studies have investigated genetic susceptibility to AD in the general population, resulting in a number of potential candidate genes that may influence the development of DAD. The majority of these variants, however, have not been investigated in subjects with DS. Aim: The aim of this study was to determine whether genetic variants previously associated with AD in the general population, were also associated with DAD in individuals with DS. Methods: Genotyping of 43 SNPs within 28 genes was undertaken in 187 individuals with Down syndrome with and without dementia of Alzheimer''s disease, using the SNPlex platform. Results: Significant associations of SNPs in five genes with DAD in DS were found, namely APOE, SORL1, BACE1, RUNX1 and ALDH18A1. As expected, the most strongly associated SNP was the APOE ɛ4 rs429358 variant (HR=2.47 [1.58, 3.87], p =7.52×10−5), although variants within the more recently implicated SORL1 and RUNX1 genes were also strongly associated with DAD in DS (HR=0.54 [0.37, 0.80], p =0.002 and HR=1.61 [1.15, 2.26], p =0.006 respectively). Conclusions: Our study demonstrates that a number of variants previously associated with AD in the general population are also associated with DAD in DS. To enable us to determine whether these variants, as well as other more recently revealed AD susceptibility variants, truly contribute to the development of DAD in DS, further multi-centre collaborative studies comprising large number of individuals with DS are needed. [Copyright &y& Elsevier]

Abstract: The major Alzheimer''s disease susceptibility genes (APOE, clusterin, complement receptor 1 (CR1) and phosphatidylinositol binding clathrin assembly protein, PICALM) can be implicated directly (APOE, CR1) or indirectly (clusterin and PICALM) in the herpes simplex life cycle. The virus binds to proteoliposomes containing APOE or APOA1 and also to CR1, and both clusterin and PICALM are related to a mannose-6-phosphate receptor used by the virus for cellular entry and intracellular transport. PICALM also binds to a nuclear exportin used by the virus for nuclear egress. Clusterin and complement receptor 1 are both related to the complement pathways and play a general role in pathogen defence. In addition, the amyloid precursor protein APP is involved in herpes viral transport and gamma-secretase cleaves a number of receptors used by the virus for cellular entry. APOE, APOA1 and clusterin, or alpha 2-macroglobulin, insulysin and caspase 3, which also bind to the virus, are involved in beta-amyloid clearance or degradation, as are the viral binding complement components, C3 and CR1. There are multiple ways in which the products of key susceptibility genes might be able to modify the viral life cycle and in turn the virus interacts with key proteins involved in APP and beta-amyloid processing. These interactions support a role for the herpes simplex virus in Alzheimer''s disease pathology and suggest that antiviral agents or vaccination might be considered as viable therapeutic strategies in Alzheimer''s disease. [Copyright &y& Elsevier]

Abstract: Inflammatory response is involved in the etiopathology of Alzheimer''s disease (AD). Interleukin-6 (IL-6), a pleiotropic inflammatory cytokine, was reported to be associated with both increased Aβ aggregation and the appearance of hyperphosphorylated tau in AD brain. To explore the association of genetic variants in the promoter of IL-6 gene with sporadic AD (SAD), a case–control study was conducted in a North Chinese Han population. A systematic screening of IL-6 promoter was performed using direct sequencing and two polymorphisms were obtained including −572C/G (rs1800796) and −384A/T (rs7802308). Definitive genotyping of these markers and apolipoprotein E (APOE) polymorphism were surveyed in 341 SAD patients and 421 controls. The results revealed no significant differences in the distributions of alleles or genotypes between SAD and control groups. However, there was an interaction between −572C/G and APOE genotypes (P =0.016) using logistic analysis. In the subjects with APOE ɛ4, there were significant differences in the allele (P =0.004) and genotype (P =0.004) distributions of −572C/G polymorphism between SAD and control groups. The −572CC genotype increased risk for AD by 3.301-fold (Wald=11.093, adjust OR=3.301, 95% CI=1.635–6.665, P =0.001) compared to CG+GG genotype. The present results suggest the −572 polymorphism could modify the risk for SAD in APOE ɛ4 carriers. [Copyright &y& Elsevier]

Abstract: Alzheimer disease (AD) has a heterogeneous aetiology, involving genetic and environmental factors. Low-density lipoprotein receptor-related protein 1 (LRP1), alpha-2-macroglobulin (A2M) and apolipoprotein E (APOE) are involved in molecular pathways leading to beta-amyloid deposition. Three polymorphic sites in these genes (APOE-ɛ2/ɛ3/ɛ4, A2M-Ile/Val and LRP1-C/T) have been associated with AD, but the results were not univocal. We carried out a case-control study to investigate the association between these polymorphisms and the risk of developing AD and their possible interaction. We recruited 125 AD patients who fulfilled the diagnostic criteria proposed by NINCDS-ADRDA for probable or possible AD and 310 controls subjects. PCR was used to detect the polymorphisms. ORs and 95% CIs were estimated using logistic regression analysis. The OR for subjects carrying at least one allele Val (A2M-Val+) in their genotypes was 1.52 (95% CI 1.00–2.31; p =0.05); for subjects carrying at least one allele C (LRP1-C+), 1.58 (95% CI 1.00–2.50; p =0.05); for subjects carrying at least one allele ɛ4 (APOE-ɛ4+), 3.1 (95%CI 1.87–5.00; p <0.001). The coexistence of at least one allele Val (A2M-Val+) and one allele C (LRP1-C+) increased up two times the risk of AD (OR 2.32; 95% CI 1.23–4.35; p <0.009). No evidence of significant interaction has been found between the studied polymorphisms (p >0.05). In conclusion our study suggests that LRP1-C/T, A2M-Ile/Val and APOE-ɛ2/ɛ3/ɛ4 polymorphisms are associated with AD. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies have consistently suggested that the ɛ4 allele of apolipoprotein E (APOE) gene is a major risk factor for Alzheimer''s disease (AD). However, whether the ɛ2 allele, a possible protective factor for AD, will express its protective effect in terms of cortical thickness in healthy elderly carriers is unclear. The goal of this study is to clarify the effects of APOE genotypes on cortical thickness in nondemented elderly subjects. We used 164 healthy, cognitively normal, elderly subjects, who were grouped into ɛ2 carriers, ɛ3 homozygotes, and ɛ4 carriers respectively. The APOE ɛ2 carriers had a significant thicker (corrected p <0.05) cortical thickness in the superior temporal cortex compared with the ɛ3 homozygotes. In addition to this area, the APOE ɛ2 carriers had a significantly thicker region in the dorsolateral prefrontal cortex (corrected p <0.05) than did the ɛ4 carriers. These findings suggest that the different alleles of the APOE gene have distinct neuroanatomic effects in elderly healthy subjects and may play specific roles in the development of AD. [Copyright &y& Elsevier]

Abstract: Clusterin is a secreted molecular chaperone, also called apolipoprotein J. Recent genetic studies have demonstrated that clusterin is a significant susceptibility gene for late-onset Alzheimer''s disease (AD). Clusterin shares several properties with apolipoprotein E, a well-known risk gene for AD, i.e. they bind to amyloid-β peptides and are present in neuritic plaques, enhance the clearance of amyloid-β peptides in brain, and are included in lipid particles and thus regulate cholesterol traffic. Biochemical studies indicate that clusterin can prevent the progress of AD pathogenesis. We have observed earlier that histone deacetylase (HDAC) inhibitors can induce the expression of clusterin in several neuroblastoma and glioma cell lines. Recent studies have revealed that valproic acid, a common and well-tolerated drug for epilepsy and bipolar disorders, is a potent HDAC inhibitor. In this study, we examined whether valproic acid can induce the expression of clusterin in human astrocytes. Our results demonstrated that valproic acid is a potent inducer of clusterin expression and secretion in human astrocytes at the therapeutical concentrations. Another clinically used HDAC inhibitor, the cancer drug, Vorinostat (SAHA, suberoylanilide hydroxamic acid), also robustly stimulated the expression of clusterin in human astrocytes. One could postulate that valproic acid may be able to prevent amyloid-β aggregation in AD, as observed in transgenic AD mice, by increasing clusterin expression. [Copyright &y& Elsevier]

Abstract: Alzheimer''s Disease (AD) is a neurodegenerative disorder with a complex aetiology displayed by multiple pathogenic factors. The APOE ɛ4 allele represents the only established genetic risk factor for sporadic AD; in addition, previous findings on three single nucleotide polymorphisms (SNPs) located on the APOE promoter region, have led to a growing interest in their potential role in AD pathogenesis. The −491 A/T promoter polymorphism has been the one most frequently shown to be associated with AD, as it influences the APOE coding region transcription. The aim of this study was to evaluate the possible effect of the −491 A/T polymorphism on the cognitive profile of sporadic AD patients with a disease severity ranging from mild to moderate. Our results showed that patients carrying the −491 AA genotype had poorer cognitive performances than the −491 AT ones, statistically significant in demanding tests of visual attention, especially for the late-onset AD (LOAD). No further differences on cognitive profile were observed when stratifying AA and AT patients according to their APOE genotype. These results suggest a possible functional effect of the −491 A/T promoter on the neuropsychological performances of AD. This role seems to be independent of APOE genotype. In fact the effect of −491 A/T occurs predominantly on attention while the APOE ɛ4 allele mainly affects memory performances. According to the biological effect exerted on APOE transcription, the −491 A/T polymorphism could be considered a disease modifier more than a risk factor for sporadic AD. [Copyright &y& Elsevier]

Abstract: Recent evidences indicate that polymorphisms within the promoter region of the vascular endothelial growth factor (VEGF) gene may elevate the risk for Alzheimer''s disease (AD). To further investigate, we have analyzed association between promoter polymorphisms of the VEGF gene in 93 AD patients and age and sex matched 113 controls from Tunisian population. The distribution of genotype and allele frequencies of the VEGF (−2578C/A) and (−1154G/A) polymorphisms did not differ significantly between AD and control groups (p >0.05). In the subgroup of ApoE ɛ4 carriers, the −2578A was observed to be significantly higher in the AD patients than in the control individuals. After adjusting the data by gender, age and the ApoE ɛ4 status using logistic regression, the −2578A allele was found to increase the risk for sporadic AD by 1.7-fold. The present study provides the evidence that the −2578A allele may be associated with the development of AD in the individuals with ApoE ɛ4 allele. In addition, AD patients carrying the −2578A allele had lower Aβ42 (p =0.029) levels than those without this allele, particularly in subjects with ApoE ɛ4 allele. [Copyright &y& Elsevier]

Abstract: α-Synuclein (α-syn) is an abundant neuronal protein expressed at the synapse. In neurodegenerative disease α-syn accumulates in the extracellular space. Astrocytes present at neural synapses are thought to contribute to synaptogenesis through cholesterol release and normally exhibit increased glial fibrillary acid protein (GFAP) reactivity and apolipoprotein E (apoE) expression in neurodegenerative disease states. We proposed that extracellular α-syn treatment of human astrocytes would impact cholesterol levels and expression of GFAP and apolipoprotein E (apoE). Human astrocytes were treated with α-syn at different concentrations and time points to determine the effective membrane permeability of the peptide. After α-syn treatment, we analyzed apoE and cholesterol levels in the astrocyte membrane. Lastly, we performed immunocytochemistry for GFAP in control and α-syn treated cells. Our results indicate membrane apoE was reduced and redistributed from a nuclear and membranous dominated expression to the cytosol. Cholesterol levels were also reduced in the astrocyte cell membrane. GFAP expression was sharply increased in α-syn treated cells indicating that α-syn may contribute to reactive gliosis. Our results support the conclusion that astrocytes play a role in pathological mechanisms in synucleinopathies. [Copyright &y& Elsevier]

Abstract: The ɛ4 version of the Apolipoprotein E gene has been proved to be a risk factor for the development of Alzheimer''s disease (AD). Furthermore, another gene mitochondrial aldehyde dehydrogenase (ALDH2) has also been proposed to be potentially associated with AD, based on its possible relations toward acetaldehyde accumulation which further damage brain cells. Yet this observation had been limited in several groups of Oriental populations. In this study we gathered 106 unrelated Mongolian SAD (sporadic Alzheimer disease) patients and 100 controls in performing an analysis of ALDH2 genotyping. Nevertheless, the results showed that neither genotype nor allele distribution of ALDH2 between patients and controls presents significant differences. Further study on the ALDH2 correlation with APOE ɛ4 displays no disparity. Hereby gene ALDH2 may not represent a risk factor in the development of AD among Mongolian population. [Copyright &y& Elsevier]

Abstract: Apolipoprotein E (ApoE) 4 is a potent risk factor for Alzheimer''s disease (AD). However, the mechanism underlying ApoE4 function in the pathology of AD is not well understood. We report here that, in comparison with ApoE2 and ApoE3, ApoE4 significantly reduces levels of insulin-degrading enzyme (IDE), which is responsible for the cellular clearance of Aβ in neurons. This differential regulation of IDE by various ApoE isoforms was blocked by coincubation with N-methyl-d-aspartic acid (NMDA) receptor inhibitors and receptor-associated protein (RAP), which blocked the interaction between ApoE and members of the low-density lipoprotein (LDL) receptor family. Moreover, inhibition of the NMDA receptor increased IDE levels in neurons, while activation of the NMDA receptor-reduced IDE expression. Further studies demonstrate that, as a pathway downstream of the NMDA receptor, cAMP-dependent protein kinase (PKA) contributes to the NMDA receptor-reduced IDE expression. These results suggest that ApoE4 down-regulates IDE expression in neurons by binding to its receptor and stimulating the NMDA receptor pathway, which may account for its role in AD pathogenesis. [Copyright &y& Elsevier]

Abstract: A recent study reported that variants of the neuronal sortilin-related receptor gene (SORL1) increased the risk of late-onset Alzheimer disease (AD) in several populations. Here, we examined the risk effect in a large, well-characterized group of 437 late-onset AD patients and 451 control subjects in a Japanese population. Among eight single-nucleotide polymorphisms (SNPs) of the SORL1 gene for which association has been reported, we found a significant association for four of them, located between exon 24 and intron 37. This risk was evident in non-carriers of the apolipoprotein E-ɛ4 allele, but not in its carriers. Our results support the evidence that genetic variants of SORL1 affect susceptibility to late-onset AD. [Copyright &y& Elsevier]

Abstract: 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 ɛ3 homozygotes and the remaining participants were either ɛ3/ɛ4 heterozygotes (n =13), or ɛ4 homozygotes (n =8). Analyses of variance showed that the heterozygotes had lower N1 amplitudes than the ɛ3 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. ɛ4 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. [Copyright &y& Elsevier]

Abstract: Amyloid beta peptide (Aβ) accumulation is the major event in the brain of cases with Alzheimer''s disease (AD). The serine protease plasmin, which is generated from the inactive zymogen plasminogen, could accelerate Aβ degradation, and thus may play a role in AD pathogenesis. It has been reported that the increasing of plasminogen activator inhibitor-1 (PAI-1) inhibits the activity of plasminogen activator and thus reduces the generation of plasmin in vivo. For seeking the correlation of the PAI-1 promoter with sporadic AD (SAD), we performed a case–control study in a group of Chinese Han population. In the study, we detected two polymorphisms, a G/A single base substitution polymorphism at −844bp (rs2227631) and a single guanosine deletion/insertion 4G/5G polymorphism at −675bp (rs1799889) upstream from the start of transcription. Direct sequencing was used for genotyping in 324 SAD patients and 278 controls. We failed to find any associations between these two polymorphisms and SAD even after stratified by age of onset, gender and apolipoprotein E (APOE) ɛ4 status. Our data do not support that there is an association between the PAI-1 promoter polymorphisms and SAD in the Chinese Han population. [Copyright &y& Elsevier]

Abstract: Some APOE or tau gene polymorphisms have been associated with Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and Parkinson’s disease (PD). The reports of a possible association between the APOE 4 allele and dementia in PD are controversial, and some studies suggest that the tau H1/H1 genotype may increase the risk of dementia in PD. Here we analysed these APOE and tau polymorphisms in 86 clinically diagnosed PD patients with dementia (PDD), in 138 clinically diagnosed non-demented PD (PDND) patients, and in 91 healthy controls. Genomic DNA isolated from blood was used for PCR and subsequent RFLP analysis. We examined the possible genetic association of these polymorphisms with dementia in PD, but found no differences in genotypic distributions between the PDND, PDD, and control groups. The effects of tau and APOE polymorphisms on the age at dementia onset were studied using Kaplan–Meier survival analysis but no significant association were found. The lack of association between the APOE 4 allele and PDD suggests that the pathological process involved in the development of dementia in PD is different from the one that occurs in AD. [Copyright &y& Elsevier]

Abstract: In this study we examined the role of apoE on the rate of synaptic recovery in the olfactory bulb (OB) following olfactory epithelium (OE) lesioning in mice. We used both immunoblotting and immunohistochemical techniques to compare the density of OB synaptophysin (Syn, a synaptic marker) in apoE-gene deficient/knockout (KO) mice and wild-type (WT) mice following OE lesion. We found that the whole bulb concentrations of Syn, measured by immunoblotting, declined sharply following injury in both WT and KO mice during the degenerative phase (3–7 days). After this initial decline, the Syn concentration gradually increased to normal levels by 56 days in WT mice. In contrast, Syn concentration in KO mice did not recover by day 56 when Syn density in WT was essentially normal. Glomerular Syn density, measured by immunohistochemistry, found a lower density in KO mice at all time points post-lesion. This lower concentration of whole bulb Syn parallels the slower recovery of glomerular area in KO mice. The data indicate that apoE deficiency in KO mice is associated with a delayed recovery of the glomerular area and a slower recovery in Syn concentration in the OB. [Copyright &y& Elsevier]

Abstract: Alzheimer''s disease (AD) is the leading cause of dementia. Currently, no definitive diagnostic test for AD exists. An accurate, convenient and objective test to detect AD is urgently needed for efficient drug development and effective clinical use of emerging therapies. The aim of the present work is to investigate the usefulness of cerebrospinal fluid (CSF) β-amyloid protein (Aβ1–42) and total tau protein (t-tau) analyses in the diagnosis of AD and whether apolipoprotein E (ApoE) ɛ4 allele is a factor for AD affecting Tunisian people. Aβ1–42 and t-tau levels were measured in CSF from AD patients (n =73), non-Alzheimer dementia (nAD, n =35) and healthy controls (HC, n =38) by sandwich enzyme-linked immunosorbent assay. Aβ1–42 levels were decreased and t-tau increased in AD patients. The combination of Aβ1–42 and t-tau at baseline yielded a sensitivity of 87.4% for detection of AD. The specificities were 97.3% for controls and 82.7% for other dementia. The ApoE ɛ4 allele frequency (29.5%) was significantly higher in the AD patients than in the nAD patients (17.1%) or in the control groups (9.5%). AD patients carrying ApoE ɛ4 allele had lower Aβ1–42 (p <0.001) levels than those without a ɛ4 allele. The combination of t-tau and Aβ1–42 is a robust and reliable assay that may be useful in discriminating cases at risk for AD such as ApoE ɛ4 allele carriers from nAD patients or from age-matched control subjects. [Copyright &y& Elsevier]

Abstract: Genetic factors for inter-individual variation in cognition have been arousing great interest among researchers. Among the many associated genes, brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE), as two of the most frequently studied, might be good prospects for cognitive genetics. Thus, the aim of this study was to investigate both the isolated and cooperative effect of BDNF and APOE on normal cognitive ageing. A homogeneous population of Chinese aged males (N =161) were genotyped for functional genetic variants of BDNF (BDNF-G196A) and APOE (APOE-ɛ4) and assessed by a comprehensive neuropsychological measurement (Cognitive Abilities Screening Instrument Chinese version; CASI C-2.0). Thereafter genotypic group differences of BDNF and APOE in CASI cognitive profiles were tested. Results from the present study suggest the possible influence of APOE on specific cognitive domains (CASI orientation and language domains; p =0.010 and 0.028, respectively), whereas there was no significant role of BDNF, either solely or with APOE, in cognition in the elderly. Our findings suggest a possible association between APOE-ɛ4 and specific cognitive domains in the aged male, whereas the functional genetic variant of BDNF (BDNF-G196A) played no significant role in normal cognitive ageing. [Copyright &y& Elsevier]