Lack of association between apolipoprotein E genotype and sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neuro-degenerative disorder with both sporadic and familial forms. Approximately 20% of autosomal dominant ALS is caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. The causes of the remaining forms of ALS are unknown. The apolipoprotein E (APOE) gene is a known genetic risk factor for Alzheimer disease (AD), another neuro-degenerative disease. The APOE-4 allele increases risk and decreases age at onset in AD. Studies examining ALS and APOE have failed to show a significant effect of APOE on overall risk in ALS. Studies examining the effect of APOE-4 on site of onset in ALS (bulbar or limb) have been contradictory, with some studies showing an APOE association with bulbar onset and others showing no effect. Sample size was limited in these previous reports, particularly with respect to the number of bulbar onset cases (n = 33, 34 and 53). The present study examines a large collaborative data set of ALS patients (n = 363; 95 with bulbar onset) and age-matched neurologically normal controls. The results for these data showed no significant differences in the percentage of subjects with the APOE-4/4 and APOE-4/X genotypes (X = APOE-2 or APOE-3) when comparing cases and controls in both the overall data set or in the data set stratified by site of onset. Similarly, logistic regression analysis in the overall and stratified data set while controlling for sex showed no increase or decrease in risk of ALS associated with the APOE-4 allele. In addition, there were no significant differences in age at onset between patients with APOE-X/X, and APOE-4/4 or APOE-4/X genotypes, overall or stratified by site of onset. We conclude based on these data that the APOE gene is not a major genetic risk factor for site of onset in ALS. Received: June 30, 1997 / Accepted: August 10, 1997     

Association between APOE genotype, neuropathology and dementia in the older population of England and Wales

J. A. R. Nicoll, G. M. Savva, J. Stewart, F. E. Matthews, C. Brayne and P. Ince (2011) Neuropathology and Applied Neurobiology 37, 285–294
Association between APOE genotype, neuropathology and dementia in the older population of England and Wales Aims: Apolipoprotein E (APOE) genotype is the major genetic risk factor for sporadic Alzheimer's disease (AD) but it is unclear how this is mediated. Most studies of APOE genotype have used case–control design to compare groups differing by two variables: i.e. dementia and AD pathology, so it is unclear to which of these variables APOE genotype is more strongly related. The prospective Medical Research Council Cognitive Function and Ageing Study neuropathology cohort is population‐based sample in which donations are unbiased by dementia status. Methods: We investigated the association between APOE genotypes and neuropathological and cognitive data in this cohort (n = 310). Results: APOEε4 was associated with an increased risk of diffuse plaques, neuritic plaques, tangles and cerebral amyloid angiopathy. APOEε4 was not associated with infarcts, lacunes, haemorrhages or small vessel disease. APOEε2 appeared to have a protective effect on AD pathology and also on the risk of cortical atrophy. APOE genotype had a non‐significant effect on the presence of dementia after adjusting for AD pathology. Conclusions: APOE genotype is associated with each of the key features of AD pathology but not with cerebrovascular disease other than cerebral amyloid angiopathy. The excess risk of dementia in those with an APOEε4 allele is explained by the pathological features of AD. However, it remains unclear to what extent cognitive dysfunction is caused by these specific pathological features or more directly by closely related APOE‐associated mechanisms.     

Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE ε4 allele

Cholesterol regulates the production of amyloid beta (Aβ), which is central to the pathogenesis of Alzheimer's disease (AD), with high cellular cholesterol promoting and low cellular cholesterol reducing Aβ in vitro and in vivo. High density lipoprotein (HDL) plays a central role in the removal of excess cholesterol from cells, and cholesteryl ester transfer protein (CETP) is a crucial protein involved in the regulation of HDL levels. Two common polymorphisms in the promoter region (C–629A) and exon 14 I405V of the CETP gene are associated with CETP activity and HDL levels. To investigate if these sequence variants in CETP might be of importance in mediating susceptibility to AD, independently or in concert with apolipoprotein E (APOE) ε4 allele, we studied a sample of 286 Spanish AD patients and 315 healthy controls. In APOE ε4 carriers, homozygous for the CETP (–629) A allele had approximately a three times lower risk of developing AD (odds ratio 2.33, 95% CI 1.01–5.37), than homozygous and heterozygous carriers of the CETP (–629) C allele (odds ratio 7.12, 95% CI 4.51–11.24, P for APOE ε4/CETP (–629) AA genotype interaction < 0.001). Our data suggest that CETP behaves as a modifier gene of the AD risk associated with the APOE ε4 allele, possibly through modulation of brain cholesterol metabolism.     

Apolipoprotein E is associated with age at onset of amyotrophic lateral sclerosis

Apolipoprotein E (APOE) is a confirmed risk factor for Alzheimer disease. APOE is also involved in several other neurodegenerative disorders, including Parkinson disease and multiple sclerosis. Previous studies of amyotrophic lateral sclerosis (Lou Gehrig disease, ALS) have investigated the effect of APOE on the risk of developing ALS, age at onset, site of onset, and duration of the disease. The results have been inconsistent, possibly due to small sample sizes and complete reliance on case-control data. No family-based association studies were performed. To address these limitations, we investigated the relationship between APOE functional polymorphisms and age at onset of ALS in a large set of 508 families. We treated age at onset as a quantitative trait and performed family-based association analysis using the TDT _Q5 method. APOE-2 is protective against earlier onset ( P =0.001) with an average age at onset of APOE-2 carriers approximately 3 years later than that of non-APOE-2 carriers. Similar to our previous report, we did not find APOE associated with ALS risk. Our findings suggest that APOE may express its strongest effect through age at onset rather than on risk.R.H. Brown Jr and T. Siddique contributed equally to this project.     

The SIRT2 polymorphism rs10410544 and risk of Alzheimer’s disease in two Caucasian case–control cohorts

BackgroundHuman sirtuins are a current hotspot for research in neurodegenerative disorders, including Alzheimer’s disease (AD). This study investigated whether genetic variants in two members of the sirtuin family, SIRT2 and SIRT3, affected AD susceptibility.MethodsA genetic case–control study was performed, comprising 534 probable AD cases and 638 nondemented control subjects from the north of Italy and Canton Ticino, Switzerland (discovery population). The study was focused on SIRT2 rs10410544, SIRT3 rs4980329, and SIRT3 rs536715 single nucleotide polymorphisms (SNPs). These SNPs were genotyped by real-time polymerase chain reaction allelic discrimination assay or restriction fragment length polymorphism. The SNPs rs7412 and rs429358, mapping within the apolipoprotein E (APOE) gene, were genotyped by real-time polymerase chain reaction allelic discrimination assay too. In a replication population comprising 756 AD cases and 847 nondemented control subjects, SIRT2 rs10410544, APOE rs7412, and APOE rs429358 were genotyped as mentioned previously.ResultsIn the discovery population, we observed an association between SIRT2 rs10410544 T allele and AD (adjusted odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.02–1.50, P = .02, after correction for sex, age, and APOE ɛ4 genotype). The association between AD and SIRT2 rs10410544 T allele was only present in APOE ɛ4 noncarriers (adjusted OR = 1.29, 95% CI: 1.03–1.61, P = .03). The replication study did not confirm this evidence. However, the combined analysis on the two cohorts detected the association (adjusted OR = 1.17, 95% CI: 1.02–1.35, P = .02), and only APOE ɛ4 noncarriers were at risk (adjusted OR = 1.2, 95% CI: 1.02–1.43, P = .03).ConclusionsThe SIRT2 rs10410544 T allele deserves further investigation as a novel minor genetic risk factor for AD in the APOE ɛ4-negative Caucasian population.     

Apolipoprotein E genotype of a Portuguese control population and Alzheimer's disease patients

The present work first describes the frequency of APOE alleles and genotypes in Portuguese populations in relation to AD pathology. We genotyped a group of late onset sporadic AD cases, their pairwise controls and a larger group of randomly selected individuals, to assess the distribution pattern of APOE alleles in the Portuguese population. APOE ?4 relative frequency may significantly vary among different populations—a fact which should be taken into consideration for the correct evaluation of the cossegregation of this allele with AD pathology. We observed a frequency of 0.087 ± 0.029 of the APOE ?4 and 0.043 ± 0.021 of the APOE ?2 allele in the Portuguese random population which as expected showed a marked prevalence of the APOE ?3 form (0.870 ± 0.035). In the AD patients the APOE ?4 allele frequency was significantly higher (0.360 ± 0.081) than in the controls (χ₂ = 31.000, p < 0.00001, df = 2). Consistently APOE ?3 allele frequency (0.640 ± 0.081) was significantly lower than in the controls while APOE ?2 was absent in the studied AD population. Taken together our results demonstrate that the Portuguese population is characterized by a relatively low frequency of the APOE ?4 allele, in good agreement with previous observations of a gradient of ?4 allele frequency in Europe, decreasing from North to South. Several lines of evidence point at APOE?e4 allele as a major genetic susceptibility factor in AD. The APOE ?4 allele was significantly higher [odds ratio (OR) = 5.93, 95% CI 3.55–9.91] in the Portuguese AD patients than in the random non-demented population. The genotype analysis of the Portuguese AD patients here described reveals a marked, increased frequency of ?4 homo- and heterozygous individuals consistent with an APOE ?4 zigosity effect as a further genetic trait predisposing to AD development.     

Further examination of the candidate genes in chromosome 12p13 locus for late-onset Alzheimer disease

A broad region on chromosome 12p13 has been intensely investigated for novel genetic variants associated with Alzheimer disease (AD). We examined this region with 23 microsatellite markers using 124 North European (NE) families and 209 Caribbean Hispanic families with late-onset AD (FAD). Significant evidence for linkage was present in a 5-cM interval near 20 cM in both the NE FAD (LOD = 3.5) and the Caribbean Hispanic FAD (LOD = 2.2) datasets. We further investigated these families and an independent NE case–control dataset using 14 single nucleotide polymorphisms (SNPs). The initial screening of the region at ∼20 cM in the NE case–control dataset revealed significant association between AD and seven SNPs in several genes, with the strongest result for rs2532500 in TAPBPL (p = 0.006). For rs3741916 in GAPDH, the C allele, rather than the G allele as was observed by Li et al. (Proc Natl Acad Sci U S A 101(44):15688–15693, 2004), was the risk allele. When the two family datasets were examined, none of the SNPs were significant in NE families, but two SNPs were associated with AD in Caribbean Hispanics: rs740850 in NCAPD2 (p = 0.0097) and rs1060620 in GAPDH (p = 0.042). In a separate analysis combining the Caribbean Hispanic families and NE cases and controls, rs740850 was significant after correcting for multiple testing (empirical p = 0.0048). Subsequent haplotype analyses revealed that two haplotype sets—haplotype C-A at SNPs 6–7 within NCAPD2 in Caribbean Hispanics, and haplotypes containing C-A-T at SNPs 8–10 within GAPDH in Caribbean Hispanic family and NE case–control datasets—were associated with AD. Taken together, these SNPs may be in linkage disequilibrium with a pathogenic variant(s) on or near NCAPD2 and GAPDH. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Apolipoprotein E genotype,dementia, and mortality in the oldest old: The 90+ Study

BackgroundAlthough the apolipoprotein E (APOE) ɛ4 allele is a major genetic risk factor for Alzheimer’s disease (AD), it is not clear whether this relationship persists among the oldest old. Several European studies suggest that the effect of the APOE ɛ4 allele on dementia and mortality disappears in very old age. We describe the APOE allele and genotype frequencies and examine whether the presence of the APOE ɛ4 or APOE ɛ2 alleles is related to prevalent dementia, incident dementia, and mortality in a population-based cohort of oldest-old participants in the United States.MethodsWe studied 904 participants aged 90 years and older from The 90+ Study. Eight hundred two (89%) participants were genotyped and included in the prevalent dementia and mortality analyses. The 520 initially nondemented participants were included in the incident dementia analyses and were evaluated for dementia every 6 months.ResultsThe APOE ɛ4 allele was significantly associated with prevalent dementia (odds ratio = 2.06) and AD (odds ratio = 2.37) in women but not in men. The APOE ɛ2 allele was not related to prevalent dementia in either sex. After an average follow-up of 2.4 years, 188 incident dementia cases were identified. Neither the APOE ɛ4 nor the APOE ɛ2 allele was related to incident dementia or AD. Five hundred ten (64%) participants died after an average follow-up of 2.3 years, and their mortality was not related to the presence of either the APOE ɛ2 or APOE ɛ4 allele.ConclusionsOur findings suggest that the associations between APOE ɛ4, dementia, and mortality are age dependent, and that APOE ɛ4 no longer plays a role in dementia and mortality at very old ages.     

BACE1 Polymorphisms Do Not Influence Platelet Membrane β-secretase Activity or Genetic Susceptibility for Alzheimer’s Disease in the Northern Irish Population

β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a biological and positional candidate gene for Alzheimer’s disease (AD). BACE1 is a protease that catalyses APP cleavage at the β-secretase site. We evaluated all common and putatively functional polymorphisms in the genomic region encompassing BACE1 for an association with AD, and for functional effects on platelet β-secretase activity. Tag SNPs (n = 10) derived from phase II of the International HapMap Project, and a nonsynonymous variant, were successfully genotyped in 901 Caucasian individuals from Northern Ireland using Sequenom iPLEX and TaqMan technologies. APOE genotyping was performed by PCR-RFLP. Platelet membrane β-secretase activity was assayed in a subset of individuals (n = 311). Hardy–Weinberg equilibrium was observed for all variants. Evidence for an association with AD was observed with multi-marker haplotype analyses (P = 0.01), and with rs676134 when stratified for APOE genotype (P = 0.02), however adjusting for multiple testing negated the evidence for association of this variant with AD. χ² analysis of genotype and allele frequencies in cases versus controls for individual SNPs revealed no evidence for association (5% level). No genetic factors were observed that significantly influenced platelet membrane β-secretase activity. We have selected an appropriate subset of variants suitable for comprehensive genetic investigation of the BACE1 gene. Our results suggest that common BACE1 polymorphisms and putatively functional variants have no significant influence on genetic susceptibility to AD, or platelet β-secretase activity, in this Caucasian Northern Irish population.     

<Emphasis Type="Italic">PEMT</Emphasis> G523A (V175M) Is Associated with Sporadic Alzheimer's Disease in a Chinese Population

There is evidence that increased concentrations of circulating homocysteine are associated with Alzheimer's disease (AD). Phosphatidylethanolamine N-methyltransferase (PEMT) is an important catalyst involved in the production of homocysteine. We investigated the association of a functional single nucleotide polymorphism (rs7946) in PEMT with sporadic AD risk in a Han Chinese population that included 386 AD patients and 366 controls. PEMT G523A was genotyped by either sequencing or PCR-restriction fragment length polymorphism analysis. The plasma homocysteine concentrations of 210 subjects were determined by high-performance liquid chromatography. Significant higher frequency of the A allele was detected in AD cases than in controls (A vs. G, p = 0.007, OR = 1.482, 95% CI 1.114–1.972). After adjusting for gender, age/age at onset, and APOE ε4 status, logistic analysis showed rs7946 was associated with AD in a dominant model (AA + GA vs. GG, p = 0.007, OR = 1.596, 95% CI 1.138–2.240). When stratified by APOE ε4 status or gender, the significant difference was only observed in the APOE ε4 non-carriers and in the female subjects, respectively. We did not find a relationship of this polymorphism with plasma homocysteine levels. These results suggested that PEMT G523A is associated with AD and that the A allele is an APOE ε4-independent risk factor for AD among Han Chinese women.     

Modulation by DLST of the genetic risk of Alzheimer's disease in a very elderly population

The mitochondrial α-ketoglutarate dehydrogenase complex (KGDHC) is deficient in Alzheimer's disease (AD). The DLST gene encodes the core, dihydrolipoyl succinyltransferase (DLST) component of KGDHC, and recent reports indicate an association between polymorphisms of DLST and AD in both white and Japanese patients. We therefore examined the relationship between AD and the DLST and apolipoprotein E (APOE) genes in elderly (89 ± 7 years) AD patients, in whom the ε4 allele of APOE (APOE4) is a weak risk factor for AD. Polymorphisms of DLST (A19,117G and T19,183C), shown to be of interest in previous studies, were analyzed by restriction fragment length polymorphism analysis after polymerase chain reaction amplification. In a series of 429 white subjects from two Jewish nursing homes, an association of APOE4 with AD was found only in patients homozygous for the G,C allele of DLST. Similar relationships occurred in the “very elderly” (≥85 years, n = 302) subgroup of this series, and also in an autopsy series (n = 225) that included white subjects from the Jewish nursing homes as well as other white subjects. These findings suggest a relationship between APOE4 and a DLST locus in the pathogenesis of AD in very elderly subjects. Ann Neurol 1999;45:48–53     

Apolipoproteins E and C1 and brain morphology in memory impaired elders

Previous research has shown that polymorphisms of the apolipoproteins E (APOE) and APOC1 represent genetic risk factors for dementia and for cognitive impairment in the elderly. The brain mechanisms by which these genetic variations affect behavior or clinical severity are poorly understood. We studied the effect of APOE and APOC1 genes on magnetic resonance imaging measures in a sample of 50 subjects with age-associated memory impairment. The APOE E4 allele was associated with reduced left hippocampal volumes and APOE*E3 status was associated with greater frontal lobe white matter volumes. However, no APOE effects were observed when analyses accounted for other potential confounding variables. The effects of APOC1 on hippocampal volumes appeared to be more robust than those of the APOE polymorphism. However, no modulatory effects on brain morphology outside the medial temporal lobe region were observed when demographic variables, clinical status, and other anatomical brain measurements were taken into consideration. Our results suggest that the role of the APOC1 polymorphism in brain morphology of the cognitively impaired elderly should be examined in further studies. Electronic Publication     

Association between apolipoprotein E genotypes and Parkinson’s disease

Previous studies on the association between apolipoprotein E (APOE) alleles and Parkinson’s disease (PD) have shown contradictory results. A recent study showed that APOE is involved in a molecular pathway of α-synuclein-induced neurodegeneration. We therefore conducted the first Thai study on APOE genotypes in patients with PD. We analysed the frequencies of APOE genotypes in our case-control study of 155 patients with sporadic PD and 158 control participants. We identified a higher frequency of the APOE-ε2 allele among patients with PD than among controls (odds ratio = 2.309, 95% confidence interval = 1.111–4.799). Genetic association is a powerful tool for detecting disease susceptibility alleles, but there are many pitfalls to consider before claiming any association. The discrepancy among the results of the genetic association studies of APOE genotypes as a risk of susceptibility to PD emphasises that this association merits clarification by the study of a single large homogeneous population.     

No association between the HLA-A2 allele and Alzheimer disease

The apolipoprotein E (APOE)-4 allele is a major risk factor for late-onset Alzheimer disease (AD), but it does not account for all the genetic variation in late-onset AD; thus, other genetic markers must be examined. Previous studies suggest an HLA-A2 allele association with risk and earlier onset age of AD. Because these effects may be additive to those of APOE-4, we studied HLA-A2 and APOE-4 frequencies in AD patients and cognitively intact controls. A total of 712 unrelated Caucasian subjects included 479 patients with AD (435 sporadic, 44 familial) and 233 controls. Patients (mean±SD age 73.9±7.9 years, range 42–93 years) had probable AD, according to standard diagnostic criteria; controls (mean±SD age 70.4±8.5 years, range 37–92 years) were cognitively intact. APOE and HLA-A2 typing used polymerase chain reaction to indicate the number of APOE-4 alleles present as well as the presence (A1/A2, A2/A2 genotypes) or absence (A1/A1 genotype) of HLA-A2. A two-way analysis of variance was used to assess the effect of the HLA-A2 allele on age at onset of dementia. No association between HLA-A2 and APOE-4 was found, and the presence of HLA-A2 allele did not increase AD risk. There was also no evidence for an association between HLA-A2 and earlier onset age of AD. Examination age, sex, family history of AD, and recruitment site had no influence on these results. In conclusion, the HLA-A2 allele did not influence AD risk or onset age in this study population. A2 heterozygosity, and population differences, including stratification sub-structures, and other undetermined factors could contribute to discrepant findings among studies. Received: October 30, 1998 / Accepted: January 23, 1999 / Published online: June 22, 1999     

Association of alpha 2-macroglobulin polymorphisms and Alzheimer disease in Mainland Han Chinese

This study used case-control method to investigate roles of two α2-macroglobulin (A2M) polymorphisms, a 5-bp insertion/deletion (A2M-I/D) and an A→G substitution (A2M-A/G), in the development of sporadic Alzheimer disease (AD) in Mainland Han Chinese. Our results showed a trend of lower D-carrying genotype frequency in APOE-ε4 carrying AD patients than in corresponding control subjects (χ²=3.67, p=0.055). The ID/AA genotype frequency was lower in AD patients comparing with controls (χ²=4.04, p=0.044). In AD patients, the G-carrying genotype frequency was significantly higher in APOE-ε4 carrier subgroup than in APOE-ε4 non-carriers (χ²=7.38, OR=2.99, 95% CI: 1.33-6.71, p=0.007). These results indicated that A2M-D allele was probably a weak AD protective factor, and there was a possible interaction of APOE-ε4 and A2M-G alleles to increase AD risk in Mainland Han Chinese.     

No Association of <Emphasis Type="Italic">VEGF</Emphasis> Polymorphims with Alzheimer’s Disease

The vascular hypothesis of Alzheimer’s disease (AD) has brought the vascular endothelial growth factor (VEGF) into focus. The genomic region including the VEGF gene has been linked to AD and single nucleotide polymorphisms (SNPs) of the VEGF have in previous studies been associated with AD risk. To further evaluate these findings, we genotyped two SNPs in the VEGF gene (rs699947 [−2578]) and rs1570360 [−1154]) by TaqMan Allelic Discrimination in a study sample including AD patients (n = 801) and controls (n = 286). In a subgroup of the population these SNPs were analyzed in relation to APOE ε4 genotype, to cerebrospinal fluid biomarkers (T-tau, P-tau, and β₄₂-Amyloid) as well as to neuropathological markers for AD (neurofibrillary tangles and senile plaques). No significant associations with risk for AD or any of the studied biomarkers could be found in this study, thus not supporting VEGF as being a major risk gene for AD.     

Apolipoprotein E ε4 modulates functional brain connectome in Alzheimer's disease

The apolipoprotein E (APOE) ?4 allele is a well‐established genetic risk factor for Alzheimer's disease (AD). Recent research has demonstrated an APOE ?4‐mediated modulation of intrinsic functional brain networks in cognitively normal individuals. However, it remains largely unknown whether and how APOE ?4 affects the brain's functional network architecture in patients with AD. Using resting‐state functional MRI and graph‐theory approaches, we systematically investigated the topological organization of whole‐brain functional networks in 16 APOE ?4 carriers and 26 matched noncarriers with AD at three levels: global whole‐brain, intermediate module, and regional node/connection. Neuropsychological analysis showed that the APOE ?4 carriers performed worse on delayed memory but better on a late item generation of a verbal fluency task (associated with executive function) than noncarriers. Whole‐brain graph analyses revealed that APOE ?4 significantly disrupted whole‐brain topological organization as characterized by (i) reduced parallel information transformation efficiency; (ii) decreased intramodular connectivity within the posterior default mode network (pDMN) and intermodular connectivity of the pDMN and executive control network (ECN) with other neuroanatomical systems; and (iii) impaired functional hubs and their rich‐club connectivities that primarily involve the pDMN, ECN, and sensorimotor systems. Further simulation analysis indicated that these altered connectivity profiles of the pDMN and ECN largely accounted for the abnormal global network topology. Finally, the changes in network topology exhibited significant correlations with the patients' cognitive performances. Together, our findings suggest that the APOE genotype modulates large‐scale brain networks in AD and shed new light on the gene‐connectome interaction in this disease. Hum Brain Mapp 36:1828–1846, 2015. © 2015 Wiley Periodicals, Inc .     

Local ancestry at APOE modifies Alzheimer's disease risk in Caribbean Hispanics

IntroductionAlthough the relationship between APOE and Alzheimer's disease (AD) is well established in populations of European descent, the effects of APOE and ancestry on AD risk in diverse populations is not well understood.MethodsLogistic mixed model regression and survival analyses were performed in a sample of 3067 Caribbean Hispanics and 3028 individuals of European descent to assess the effects of APOE genotype, local ancestry, and genome-wide ancestry on AD risk and age at onset.ResultsAmong the Caribbean Hispanics, individuals with African-derived ancestry at APOE had 39% lower odds of AD than individuals with European-derived APOE, after adjusting for APOE genotype, age, and genome-wide ancestry. While APOE E2 and E4 effects on AD risk and age at onset were significant in the Caribbean Hispanics, they were substantially attenuated compared with those in European ancestry individuals.DiscussionThese results suggest that additional genetic variation in the APOE region influences AD risk beyond APOE E2/E3/E4.     

Study of estrogen receptor-α and receptor-β gene polymorphisms on Alzheimer's disease

Estrogen treatment can modulate the risk for developing dementia in women. Therefore, single nucleotide polymorphisms (SNPs) in the estrogen receptor genes may constitute genetic susceptibility factors to Alzheimer's disease (AD). Thus, we investigated the impact of the genetic variability of the estrogen receptor α 1 (ESR1) and estrogen receptor α 2 (ESR2) genes on late onset AD risk. We analyzed 39 SNPs in ESR1 and 5 SNPs in ESR2 in a French case-control study of sporadic AD (1007 cases/647 controls). Individuals carrying the minor allele of rs7450824 had a lower risk of AD than homozygous subjects for the major allele (age, gender, and APOE ε4 allele adjusted odds ratio = 0.71 [0.57-0.89], p = 0.003). However, this association did not resist Bonferroni correction for multiple testing (p-threshold < 0.001). Consistently, no significant association could be detected when considering age of onset. We also tested for possible interactions between the ESR SNPs and APOE status (ε4 allele) or gender but no significant interaction could be observed. Even after stratifying the sample on APOE status or gender, no significant association with AD risk could be detected. Finally, we searched for potential gene-gene interactions between ESR1 and ESR2 SNPs but no significant interaction could be detected. Our results reinforce the notion that SNPs in the ESR1 or ESR2 genes do not seem to play a major role in the genetic susceptibility of AD.     

Association of the RAGE G82S polymorphism with Alzheimer’s disease

The receptor for advanced glycation end-products (RAGE) has been implicated in several pathophysiological processes relevant to Alzheimer’s disease (AD), including transport and synaptotoxicity of AD-associated amyloid β (Aβ) peptides. A recent Chinese study (Li et al. in J Neural Transm 117:97–104, 2010) suggested an association between the 82S allele of the functional single nucleotide polymorphism (SNP) G82S (rs2070600) in the RAGE-encoding gene AGER and risk of AD. The present study aimed to investigate associations between AGER, AD diagnosis, cognitive scores and cerebrospinal fluid AD biomarkers in a European cohort of 316 neurochemically verified AD cases and 579 controls. Aside from G82S, three additional tag SNPs were analyzed to cover the common genetic variation in AGER. The 82S allele was associated with increased risk of AD (P _c = 0.04, OR = 2.0, 95% CI 1.2–3.4). There was no genetic interaction between AGER 82S and APOE ε4 in producing increased risk of AD (P = 0.4), and none of the AGER SNPs showed association with Aβ₄₂, T-tau, P-tau₁₈₁ or mini-mental state examination scores. The data speak for a weak, but significant effect of AGER on risk of AD.