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1.  A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease 
The Pharmacogenomics Journal  2009;10(5):375-384.
The ɛ4 allele of the apolipoprotein E (APOE) gene is currently the strongest and most highly replicated genetic factor for risk and age of onset of late-onset Alzheimer's disease (LOAD). Using phylogenetic analysis, we have identified a polymorphic poly-T variant, rs10524523, in the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene that provides greatly increased precision in the estimation of age of LOAD onset for APOE ɛ3 carriers. In two independent clinical cohorts, longer lengths of rs10524523 are associated with a higher risk for LOAD. For APOE ɛ3/4 patients who developed LOAD after 60 years of age, individuals with long poly-T repeats linked to APOE ɛ3 develop LOAD on an average of 7 years earlier than individuals with shorter poly-T repeats linked to APOE ɛ3 (70.5±1.2 years versus 77.6±2.1 years, P=0.02, n=34). Independent mutation events at rs10524523 that occurred during Caucasian evolution have given rise to multiple categories of poly-T length variants at this locus. On replication, these results will have clinical utility for predictive risk estimates for LOAD and for enabling clinical disease prevention studies. In addition, these results show the effective use of a phylogenetic approach for analysis of haplotypes of polymorphisms, including structural polymorphisms, which contribute to complex diseases.
doi:10.1038/tpj.2009.69
PMCID: PMC2946560  PMID: 20029386
AD genetics; phylogenetic analysis; TOMM40; APOE; poly-T variants
2.  The Effect of TOMM40 Poly-T length on Gray Matter Volume and Cognition in Middle-Aged Persons with APOE ε3/ε3 Genotype 
Objective
Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late onset Alzheimer’s disease (LOAD), with APOE ε4 having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the TOMM40 gene has been shown to influence age of onset in LOAD, with very long poly-T length associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain and cognitive changes suggestive of presymptomatic LOAD may be associated with this TOMM40 polymorphism.
Methods
Among N=117 healthy APOE ε3 homozygous adults (mean age 55), we compared those homozygous for very long (VL/VL; n=35) TOMM40 poly-T lengths (who are presumably at higher risk) to those homozygous for short (S/S; n=38) poly-T lengths, as well as those with heterozygous (S/VL; n=44) poly-T length polymorphisms, on measures of learning and memory and on structural brain imaging.
Results
The VL/VL group exhibited lower performance than the S/S TOMM40 group on primacy retrieval from a verbal list learning task, a finding which is also seen in early AD. A dose-dependent increase in the VL TOMM40 polymorphism (from no VL alleles, to S/VL heterozygous, to VL/VL homozygous) was associated with decreasing gray matter volume in the ventral posterior cingulate and medial ventral precuneus, a region of the brain affected early in LOAD.
Conclusions
These findings among APOE ε3/ε3 late middle-aged adults suggest that a subgroup with very long TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes.
doi:10.1016/j.jalz.2010.11.012
PMCID: PMC3143375  PMID: 21784354
3.  Comprehensive Search for Alzheimer Disease Susceptibility Loci in the APOE Region 
Archives of neurology  2012;69(10):1270-1279.
Objective
To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523).
Design
Conditional logistic regression models and survival analysis.
Setting
Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium.
Participants
Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls.
Main Outcome Measures
Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls.
Results
In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P<.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects.
Conclusions
APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.
doi:10.1001/archneurol.2012.2052
PMCID: PMC3579659  PMID: 22869155
4.  Genetic and clinical implications of a variable poly-T repeat within the TOMM40 gene for late-onset Alzheimer's disease 
Archives of neurology  2010;67(5):536-541.
I coauthored a recently published research paper demonstrating that a variable length, poly-T polymorphism in the TOMM40 (Translocase of the Outer Mitochondrial Membrane 40 homolog (yeast)) gene, which lies adjacent to APOE on chromosome 19, accounts for the age of onset distribution for a complex disease, late-onset Alzheimer's disease (LOAD).1 These new data explain the average age of disease onset for patients with the APOE4/4 genotype, and differentiate two forms of TOMM40 poly-T polymorphisms linked to APOE with each form associated with a different age of disease onset distribution.2 When linked to APOE3, the longer TOMM40 poly-T repeats (19–39 nucleotides) at the rs10524523 (523) locus are associated with earlier age of onset and shorter TOMM40 alleles (11–16 nucleotides) with later onset. The data suggest that the poly-T alleles are co-dominant, with the age of onset phenotype determined by both of the two inherited alleles but with variable expressivity. Additional data will further refine the relationship between the length of the poly-T alleles and age of disease onset and determine if the relationship is linear.
doi:10.1001/archneurol.2010.88
PMCID: PMC3140162  PMID: 20457951
5.  Functional Analysis of APOE Locus Genetic Variation Implicates Regional Enhancers in the Regulation of Both TOMM40 and APOE 
Journal of Human Genetics  2011;57(1):18-25.
Genetic variation within the apolipoprotein E gene (APOE) locus is associated with late-onset Alzheimer's disease risk and quantitative traits as well as apoE expression in multiple tissues. The aim of this investigation was to explore the influence of APOE locus cis-regulatory element enhancer region genetic variation on regional gene promoter activity. Luciferase reporter constructs containing haplotypes of APOE locus gene promoters; APOE, APOC1, and TOMM40, and regional putative enhancers; TOMM40 IVS2-4, TOMM40 IVS6 poly-T, as well as previously described enhancers; ME1, or BCR, were evaluated for their effects on luciferase activity in 3 human cell lines. Results of this investigation demonstrate that in SHSY5Y cells, the APOE promoter is significantly influenced by the TOMM40 IVS2-4 and ME1 and the TOMM40 promoter is significantly influenced by the TOMM40 IVS6 poly-T, ME1 and BCR. In HepG2 cells, theTOMM40 promoter is significantly influenced by all four enhancers, whereas the APOE promoter is not influenced by any of the enhancers. The main novel finding of this investigation was that multiple APOE locus cis-elements influence both APOE and TOMM40 promoter activity according to haplotype and cell type suggesting that a complex transcriptional regulatory structure modulates regional expression.
doi:10.1038/jhg.2011.123
PMCID: PMC3266441  PMID: 22089642
APOE; TOMM40; APOC1; ME1; BCR; Regulation; Enhancer; Luciferase Reporter Assay
6.  Longitudinal Modeling of Cognitive Aging and the TOMM40 Effect 
Background
TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21–29 T residues) poly-T variants within intron 6 of TOMM40 while APOE e3 can be associated with either with a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer’s disease (AD) onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline.
Methods
An APOE e4 enriched cohort of 639 cognitively normal individuals age 21–97 years of known TOMM40 genotype underwent longitudinal neuropsychological testing every two years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross sectional and longitudinal effects of age on the auditory verbal learning test long term memory score (AVLT) by APOE, TOMM40, and the interaction between the two.
Results
There were significant effects overall for both TOMM40 (p=0.04 linear effect, p=0.03 quadratic effect) and APOE (p=0.06 linear effect, p=0.008 quadratic effect) with no significant interaction (p=0.63). These differences were age-dependent: there was a significant TOMM40 effect prior to age 60 (p=0.009) characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect; and a significant APOE effect after age 60 (p=0.006) characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect.
Conclusion
Both TOMM40 and APOE significantly influence age-related memory performance, but appear to do so independently of each other.
doi:10.1016/j.jalz.2011.11.006
PMCID: PMC3483561  PMID: 23102119
TOMM40; APOE; preclinical Alzheimer’s disease; cognitive aging; age-related memory loss; mitochondria; very long term memory; test-retest effects
7.  A homopolymer polymorphism in the TOMM40 gene contributes to cognitive performance in aging 
Introduction
A highly polymorphic T-homopolymer was recently discovered to be associated with late onset Alzheimer’s disease (LOAD) risk and age of onset.
Objective
To explore the effects of the polymorphic polyT tract (rs10524523, referred as ‘523’) on cognitive performance in cognitively healthy elderly.
Methods
181 participants were recruited from local independent-living retirement communities. Informed consent was obtained and participants completed demographic questionnaires, a conventional paper and pencil neuropsychological battery, and the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB). Saliva samples were collected for determination of the TOMM40 ‘523’ (S, L, VL) and the APOE (ε2, 3, 4) genotypes. From the initial sample of 181 individuals, 127 participants were eligible for the association analysis. Participants were divided into three groups based on ‘523’ genotypes (S/S, S/L-S/VL, and L/L-L/VL-VL/VL) Generalized linear models were used to evaluate the association between the ‘523’ genotypes and neuropsychological test performance. Analyses were adjusted for age, sex, education, depression, and APOE ε4 status. A planned sub analysis was undertaken to evaluate the association between ‘523’ genotypes and test performance in a sample restricted to APOE ε3 homozygotes.
Results
The S homozygotes performed better, although not significantly, than the S/L-S/VL and the VL/L-L/VL-VL/VL genotype groups on measures associated with memory (CANTAB Paired-Associate Learning, and VRM Free Recall) and executive function (CANTAB measures of Intra-Extradimensional set shifting). Follow-up analysis of APOEε 3 homozygotes only, showed that the S/S group performed significantly better than the S/VL group on measures of episodic memory (CANTAB Paired-Associate Learning and VRM Free Recall), attention (CANTAB RVP Latency) and executive function (Digit-Symbol substitution). The S/S group performed marginally better than the VL/VL group on Intra-Extradimensional set shifting. None of the associations remained significant after applying a Bonferroni correction for multiple testing.
Conclusions
Results suggest important APOE-independent associations between the TOMM40 ‘523’ polymorphism and specific cognitive domains of memory and executive control that are preferentially affected in early stage AD.
doi:10.1016/j.jalz.2011.10.005
PMCID: PMC3438346  PMID: 22863908
TOMM40; polyT polymorphism; cognition; aging; neuropsychological tests; CANTAB; Alzheimer’s disease
8.  Alzheimer’s Disease Susceptibility Genes APOE and TOMM40, and Hippocampal Volumes in the Lothian Birth Cohort 1936  
PLoS ONE  2013;8(11):e80513.
The APOE ε and TOMM40 rs10524523 (‘523’) variable length poly-T repeat gene loci have been significantly and independently associated with Alzheimer’s disease (AD) related phenotypes such as age of clinical onset. Hippocampal atrophy has been significantly associated with memory impairment, a characteristic of AD. The current study aimed to test for independent effects of APOE ε and TOMM40 ‘523’ genotypes on hippocampal volumes as assessed by brain structural MRI in a relatively large sample of community-dwelling older adults. As part of a longitudinal study of cognitive ageing, participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE ε2/ε3/ε4 status and TOMM40 ‘523’ poly-T repeat length, and detailed structural brain MRI at a mean age of 72.7 years (standard deviation = 0.7, N range = 624 to 636). No significant effects of APOE ε or TOMM40 523 genotype were found on hippocampal volumes when analysed raw, or when adjusted for either intracranial or total brain tissue volumes. In summary, in a large community-dwelling sample of older adults, we found no effects of APOE ε or TOMM40 523 genotypes on hippocampal volumes. This is discrepant with some previous reports of significant association between APOE and left/right hippocampal volumes, and instead echoes other reports that found no association. Previous significant findings may partly reflect type 1 error. Future studies should carefully consider: 1) their specific techniques in adjusting for brain size; 2) assessing more detailed sub-divisions of the hippocampal formation; and 3) testing whether significant APOE-hippocampal associations are independent of generalised brain atrophy.
doi:10.1371/journal.pone.0080513
PMCID: PMC3829876  PMID: 24260406
9.  Comprehensive Analysis of APOE and Selected Proximate Markers for Late-onset Alzheimer Disease: Pattern of Linkage Disequilibrium and Disease/Marker Association 
Genomics  2007;89(6):655-665.
The ε4 allele of APOE confers a two- to four-fold increased risk for late-onset Alzheimer’s disease (LOAD), but LOAD pathology does not all fit neatly around APOE. It is conceivable that genetic variation proximate to APOE contributes to LOAD risk. Therefore, we investigated the degree of linkage disequilibrium (LD) for a comprehensive set of 50 SNPs in and surrounding the APOE using a substantial Caucasian sample of 1100 chromosomes. SNPs in APOE were further molecular haplotyped to determine their phases. One set of SNPs in TOMM40, roughly 15 Kb upstream of APOE, showed intriguing LD with the ε4 allele, and were strongly associated with the risk for developing AD. However, when all the SNPs were entered into a logit model, only the effect of APOE ε4 remained significant. These observations diminish the possibility that loci in the TOMM40 may have a major effect on the risk of LOAD in Caucasians.
doi:10.1016/j.ygeno.2007.02.002
PMCID: PMC1978251  PMID: 17434289
molecular haplotyping; apolipoprotein E; selection; linkage disequilibrium; genetic association; Alzheimer’s disease
10.  TOMM40 poly-T repeat lengths, age of onset and psychosis risk in Alzheimer disease 
Neurobiology of aging  2011;32(12):2328.e1-2328.e9.
Apolipoprotein E (APOE) ε4 alleles increase the risk for late-onset Alzheimer disease (LOAD) and decrease the age of onset. Recently, sequencing the APOE region in a small sample of LOAD subjects identified a variable length poly-T repeat sequence in the nearby gene, TOMM40, which may affect age of onset. We genotyped the TOMM40 poly-T repeat using a novel statistical approach to refine the identification of allele length in 892 LOAD subjects and evaluated its effects on age of onset. Because psychosis in LOAD is a heritable phenotype which has shown conflicting associations with APOE genotype, we also evaluated the association of poly-T repeat length with psychosis. Poly-T repeat lengths had a trimodal distribution which differed between APOE genotype groups. After accounting for APOE ε4 there was no association of poly-T repeat length with age of onset. Neither APOE ε4 nor poly-T repeat length was associated with psychosis. Our findings do not support the association of poly-T repeat length with age of onset in LOAD. The clinical implications of this repeat length polymorphism remain to be elucidated.
doi:10.1016/j.neurobiolaging.2011.06.016
PMCID: PMC3192304  PMID: 21820212
Apolipoprotein E (APOE) ε4; late-onset Alzheimer disease (LOAD); psychosis; TOMM40; variable length poly-T repeat sequence
11.  Promising Genetic Biomarkers of Preclinical Alzheimer's Disease: The Influence of APOE and TOMM40 on Brain Integrity 
Finding biomarkers constitutes a crucial step for early detection of Alzheimer's disease (AD). Brain imaging techniques have revealed structural alterations in the brain that may be phenotypic in preclinical AD. The most prominent polymorphism that has been associated with AD and related neural changes is the Apolipoprotein E (APOE) ε4. The translocase of outer mitochondrial membrane 40 (TOMM40), which is in linkage disequilibrium with APOE, has received increasing attention as a promising gene in AD. TOMM40 also impacts brain areas vulnerable in AD, by downstream apoptotic processes that forego extracellular amyloid beta aggregation. The present paper aims to extend on the mitochondrial influence in AD pathogenesis and we propose a TOMM40-induced disconnection of the medial temporal lobe. Finally, we discuss the possibility of mitochondrial dysfunction being the earliest pathophysiological event in AD, which indeed is supported by recent findings.
doi:10.1155/2012/421452
PMCID: PMC3328927  PMID: 22550605
12.  Genetic variation at a single locus and age of onset for Alzheimer’s Disease 
This perspective article is an opportunity to explain a new genetic finding for late-onset Alzheimer s disease (LOAD). This invited perspective is specifically writtenfor physicians and scientists who are interested in LOAD, but it may be relevant to those interested in identifying susceptibility variants for other complex diseases. The significant finding discussed here is that a variable–length, deoxythymidine homopolymer (poly-T) within intron 6 of the TOMM40 gene is associated with the age of onset of LOAD [3]. This result was obtained with a phylogenetic study of the genetic polymorphisms that reside within the linkage disequilibrium [LD] block that contains TOMM40, APOE, and APOC1 genes on each chromosome from patients with LOAD and age-matched subjects without disease. While the data will have diagnostic, prognostic and therapeutic strategy implications, this perspective is meant to place the inheritance pattern for this complex human disease into context, and to highlight the potential utility of applying phylogenetic tools to the study of the genetics of complex diseases.
doi:10.1016/j.jalz.2010.01.011
PMCID: PMC2874876  PMID: 20298972
13.  APOE mRNA and Protein Expression in Postmortem Brain are Modulated by an extended Haplotype Structure 
Currently the ε4 allele of the apolipoprotein E gene (APOE) is the strongest genetic risk factor for late onset Alzheimer's disease (AD). However, inheritance of the APOE ε 4 allele is not necessary or sufficient for the development of AD. Genetic evidence suggests that multiple loci in a 70 kb region surrounding APOE are associated with AD risk. Even though these loci could represent surrogate markers in linkage disequilibrium with APOE ε4 allele, they could also contribute biological effects independent of the APOE ε4 allele. Our previous study identified multiple SNPs upstream from APOE that are associated with cerebrospinal fluid apoE levels, suggesting that a haplotype structure proximal to APOE can influence apoE expression. In this study, we examined apoE expression in human post-mortem brain (PMB), and constructed chromosome-phase-separated haplotypes of the APOE proximal region to evaluate their effect on PMB apoE expression. ApoE protein expression was found to differ among AD brain regions and to differ between AD and control hippocampus. In addition, an extended APOE proximal haplotype structure, spanning from the TOMM40 gene to the APOE promoter, may modulate apoE expression in a brain region-specific manner and may influence AD disease status. In conclusion, this haplotype-phenotype analysis of apoE expression in PMB suggests that either; (1) the cis-regulation of APOE expression levels extends far upstream of the APOE promoter or (2) an APOE ε4 allele independent mechanism involving the TOMM40 gene plays a role in the risk of AD.
doi:10.1002/ajmg.b.30993
PMCID: PMC2829359  PMID: 19554612
Alzheimer's disease; APOE; post-mortem brain; TOMM40
14.  Cerebrospinal fluid cortisol concentrations in healthy elderly are affected by both APOE and TOMM40 variants 
Psychoneuroendocrinology  2011;37(3):366-371.
Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis have been reported in subjects with Alzheimer’s disease (AD) and may include increased cerebrospinal fluid (CSF) cortisol concentrations. Moreover, presence of the APOE ε4 allele, which is an established risk factor for the development of AD, has been shown to associate with higher CSF cortisol levels, especially in AD sufferers. In this study, we examined whether TOMM40 variants, which have been reported to influence age of onset of AD, also had an effect on CSF cortisol levels, in healthy, cognitively intact individuals with or without APOE ε4. In our results, the increase in CSF cortisol associated with the presence of the APOE ε4 allele was only detected when a short TOMM40 poly-T variant, shown to associate with later age of onset of AD in ε4 carriers, was not when present. These results are consistent with previous reports (e.g., Roses et al. 2009) suggesting that TOMM40 poly-T variants influence the effects of APOE alleles.
doi:10.1016/j.psyneuen.2011.07.006
PMCID: PMC3207029  PMID: 21803501
TOMM40 poly-T; APOE; cerebrospinal fluid; cortisol; Alzheimer’s disease; hippocampus
15.  Characterization of the Poly-T Variant in the TOMM40 Gene in Diverse Populations 
PLoS ONE  2012;7(2):e30994.
We previously discovered that a polymorphic, deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6 of the TOMM40 gene is associated with age-of-onset of Alzheimer's disease and with cognitive performance in elderly. Three allele groups were defined for rs10524523, hereafter ‘523’, based on the number of ‘T’-residues: ‘Short’ (S, T≤19), ‘Long’ (L, 20≤T≤29) and ‘Very Long’ (VL, T≥30). Homopolymers, particularly long homopolymers like ‘523’, are difficult to genotype because ‘slippage’ occurs during PCR-amplification. We initially genotyped this locus by PCR-amplification followed by Sanger-sequencing. However, we recognized the need to develop a higher-throughput genotyping method that is also accurate and reliable. Here we describe a new ‘523’ genotyping assay that is simple and inexpensive to perform in a standard molecular genetics laboratory. The assay is based on the detection of differences in PCR-fragment length using capillary electrophoresis. We discuss technical problems, solutions, and the steps taken for validation. We employed the novel assay to investigate the ‘523’ allele frequencies in different ethnicities. Whites and Hispanics have similar frequencies of S/L/VL alleles (0.45/0.11/0.44 and 0.43/0.09/0.48, respectively). In African-Americans, the frequency of the L-allele (0.10) is similar to Whites and Hispanics; however, the S-allele is more prevalent (0.65) and the VL-allele is concomitantly less frequent (0.25). The allele frequencies determined using the new methodology are compared to previous reports for Ghanaian, Japanese, Korean and Han Chinese cohorts. Finally, we studied the linkage pattern between TOMM40-‘523’ and APOE alleles. In Whites and Hispanics, consistent with previous reports, the L is primarily linked to ε4, while the majority of the VL and S are linked to ε3. Interestingly, in African-Americans, Ghanaians and Japanese, there is an increased frequency of the ‘523’S-APOEε4 haplotype. These data may be used as references for ‘523’ allele and ‘523’-APOE haplotype frequencies in diverse populations for the design of research studies and clinical trials.
doi:10.1371/journal.pone.0030994
PMCID: PMC3281049  PMID: 22359560
16.  Alzheimer’s disease: diagnostics, prognostics and the road to prevention 
The Epma Journal  2010;1(2):293-303.
Alzheimer’s disease (AD) presents one of the leading healthcare challenges of the 21st century, with a projected worldwide prevalence of >107 million cases by 2025. While biomarkers have been identified, which may correlate with disease progression or subtype for the purpose of disease monitoring or differential diagnosis, a biomarker for reliable prediction of late onset disease risk has not been available until now. This deficiency in reliable predictive biomarkers, coupled with the devastating nature of the disease, places AD at a high priority for focus by predictive, preventive and personalized medicine. Recent data, discovered using phylogenetic analysis, suggest that a variable length poly-T sequence polymorphism in the TOMM40 gene, adjacent to the APOE gene, is predictive of risk of AD age-of-onset when coupled with a subject’s current age. This finding offers hope for reliable assignment of disease risk within a 5-7 year window, and is expected to guide enrichment of clinical trials in order to speed development of preventative medicines.
doi:10.1007/s13167-010-0024-3
PMCID: PMC2987528  PMID: 21124753
Alzheimer’s disease; Personalized medicine; Phylogenetic analysis; Translocase of outer mitochondrial membrane (TOMM40); Apolipoprotein E; Poly-T variant
17.  Multiple SNPs Within and Surrounding the Apolipoprotein E Gene Influence Cerebrospinal Fluid Apolipoprotein E Protein Levels 
The ε4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer’s disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21–87 years of age (n = 134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE ε4 and correlation between SNPs (linkage disequilibrium). APOE ε4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.
PMCID: PMC3192652  PMID: 18430993
Apolipoprotein E gene; apolipoprotein E protein; cerebroshinal fluid; enhancer; promoter; SNP
18.  No effect of the α1-antichymotrypsin A allele in Alzheimer's disease 
The apolipoprotein E (ApoE)-ε4 allele is associated in a dose dependent manner to an increased risk for Alzheimer's disease. However, the ApoE-ε4 allele effect does not account for all patients with Alzheimer's disease, and the existence of other genetic risk factors has been postulated. Kamboh et al reported an association between Alzheimer's disease and the A allele of α1-antichymotrypsin (Aact) gene, which was not confirmed in a larger series more recently analysed. The ApoE and Aact genotypes were analysed in 314 patients with Alzheimer's disease and 173 healthy controls, confirming the dose dependent effect of the ApoE-ε4 allele. Nevertheless, even using odds ratios adjusted for age and sex, there was no significant effect of the Aact genotype on Alzheimer's disease or on the ApoE-ε4 allele associated risk for Alzheimer's disease.


PMCID: PMC2169624  PMID: 9221977
19.  Screening and Evaluation of Deleterious SNPs in APOE Gene of Alzheimer's Disease 
Introduction. Apolipoprotein E (APOE) is an important risk factor for Alzheimer's disease (AD) and is present in 30–50% of patients who develop late-onset AD. Several single-nucleotide polymorphisms (SNPs) are present in APOE gene which act as the biomarkers for exploring the genetic basis of this disease. The objective of this study is to identify deleterious nsSNPs associated with APOE gene. Methods. The SNPs were retrieved from dbSNP. Using I-Mutant, protein stability change was calculated. The potentially functional nonsynonymous (ns) SNPs and their effect on protein was predicted by PolyPhen and SIFT, respectively. FASTSNP was used for functional analysis and estimation of risk score. The functional impact on the APOE protein was evaluated by using Swiss PDB viewer and NOMAD-Ref server. Results. Six nsSNPs were found to be least stable by I-Mutant 2.0 with DDG value of >−1.0. Four nsSNPs showed a highly deleterious tolerance index score of 0.00. Nine nsSNPs were found to be probably damaging with position-specific independent counts (PSICs) score of ≥2.0. Seven nsSNPs were found to be highly polymorphic with a risk score of 3-4. The total energies and root-mean-square deviation (RMSD) values were higher for three mutant-type structures compared to the native modeled structure. Conclusion. We concluded that three nsSNPs, namely, rs11542041, rs11542040, and rs11542034, to be potentially functional polymorphic.
doi:10.1155/2012/480609
PMCID: PMC3317072  PMID: 22530123
20.  Interaction between the α-T catenin gene (VR22) and APOE in Alzheimer's disease 
Journal of Medical Genetics  2005;42(10):787-792.
Background: APOE is the only gene that has been consistently replicated as a risk factor for late onset Alzheimer's disease. Several recent studies have identified linkage to chromosome 10 for both risk and age of onset, suggesting that this region harbours genes that influence the development of the disease. A recent study reported association between single nucleotide polymorphisms (SNPs) in the VR22 gene (CTNNA3) on chromosome 10 and plasma levels of Aß42, an endophenotype related to Alzheimer's disease.
Objective: To assess whether polymorphisms in the VR22 gene are associated with Alzheimer's disease in a large sample of Alzheimer's disease families and an independent set of unrelated cases and controls.
Results: Several SNPs showed association in either the family based or case–control analyses (p<0.05). The most consistent findings were with SNP6, for which there was significant evidence of association in both the families and the unrelated cases and controls. Furthermore, there was evidence of significant interaction between APOE-4 and two of the VR22 SNPs, with the strongest evidence of association being concentrated in individuals carrying APOE-4.
Conclusions: This study suggests that VR22 or a nearby gene influences susceptibility to Alzheimer's disease, and the effect is dependent on APOE status.
doi:10.1136/jmg.2004.029553
PMCID: PMC1735932  PMID: 16199552
21.  GAB2 Alleles Modify Alzheimer’s Risk in APOE ε4 Carriers 
Neuron  2007;54(5):713-720.
SUMMARY
The apolipoprotein E (APOE) ε4 allele is the best established genetic risk factor for late-onset Alzheimer’s disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In ε4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 × 10−11) was associated with an odds ratio of 4.06 (confidence interval 2.81–14.69), which interacts with APOE ε4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE ε4 carriers and influences Alzheimer’s neuropathology.
doi:10.1016/j.neuron.2007.05.022
PMCID: PMC2587162  PMID: 17553421
22.  The Association between Sporadic Alzheimer’s Disease and the Human ABCA1 and APOE Gene Polymorphisms in Iranian Population 
Background
Apolipoprotein E (APOE), which its ε4 allele has been reported as a risk factor in late onset Alzheimer’s disease (AD), is the main cholesterol carrier in the brain. ATP-binding cassette transporter A1 (ABCA1) gene on chromosome 9, which has been known by genome-wide AD linkage study, has an important role in cellular cholesterol efflux. This study determines the association between sporadic AD and the human ABCA1 and APOE gene polymorphisms in Iranian population.
Methods
154 AD cases and 162 control subjects from Iranian population were genotyped for APOE genotypes and ABCA1 polymorphism (R219K).
Results
The frequency of ε2ε3 genotype was higher in control subjects comparing AD patients but was not significant (13% versus 5.8%) and ε3ε4 genotype frequency was significantly higher in AD cases comparing with control subjects. APOE-ε2 allele frequency in cases was lower than control subjects but this difference was not significant (4.5% versus 8%). Individuals carrying ε4 allele, developed AD 6.5 times more than non-carriers (OR=6.52, 95%CI=2.63-16.17). There was no significant association between ABCA1 polymorphism and AD.
Conclusion
Unlike other studies, R219K polymorphism was not dependent on gender and APOE-ε4 allele and there was no association between APOE and ABCA1 in AD patients compared to controls.
PMCID: PMC3371965  PMID: 22737475
Alzheimer’s disease; Genetic association; Apolipoprotein E; Polymorphism; ATP-binding cassette transporter A1; Iran
23.  The complex interaction between APOE promoter and AD: an Italian case–control study 
The single nucleotide polymorphisms (SNPs) rs449647, rs769446 and rs405509 in the promoter region of the APOE gene have been variously suggested to be ɛ4-independent risk factors for Alzheimer's disease (AD). A previous Italian study found that the rs449647 was significantly associated with late-onset AD. The aim of this study was to verify whether these APOE promoter SNPs are genetic risk factors for AD and to investigate their interaction with the common APOE polymorphism. A total of 169 clinically diagnosed AD patients and 99 cognitively intact age-matched controls were included in the study. Significant associations with AD independent from sex, age and APOE/ɛ4 status were found for rs449647 A/A and rs405509 G/G genotypes (positive), and rs449647 A/T and rs405509 T/T genotypes (negative). Haplotype frequency estimation at the APOE locus showed significant associations for the ATG4, ATT4 and ACG3 (positive) and ATT2, ATT3 and TCG3 (negative) haplotypes. Therefore this study confirms the role of the rs449647 A/A genotype as risk factor for AD in Italy and suggests that promoter genotypes and APOE haplotypes might have a complex function in AD-associated genetic risk factors.
doi:10.1038/ejhg.2008.263
PMCID: PMC2986491  PMID: 19172988
APOE promoter; haplotypes; Alzheimer's disease; genetic risk factors
24.  Mass Spectrometry Quantification Revealed Accumulation of C-Terminal Fragment of Apolipoprotein E in the Alzheimer's Frontal Cortex 
PLoS ONE  2013;8(4):e61498.
Polymorphic variation in the apolipoprotein E (apoE) gene is the major genetic susceptibility factor for late-onset Alzheimer's disease (AD) and likely contributes to neuropathology through various pathways. It is also recognized that apoE undergoes proteolytic cleavage in the brain and the resultant apoE fragments likely have a variety of bioactive properties that regulate neuronal signaling and may promote neurodegeneration. ApoE fragmentation in the human brain has been intensively studied using different immunochemical methods, but has never been analyzed in a quantitative manner to establish preferably accumulated fragments. Here we report quantification using multiple reaction monitoring mass spectrometry (MRM MS) with 15N-labeled full-length apoE4 as an internal standard. Measurements were performed on frontal cortex from control and severe AD donors. Our data point to a preferable accumulation of C-terminal apoE fragment in the insoluble fraction of tissue homogenate in the severe AD group versus the control group. Further insight into the biological consequences of this accumulation may lead to a better understanding of the basic mechanism of AD pathology.
doi:10.1371/journal.pone.0061498
PMCID: PMC3623866  PMID: 23593485
25.  Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer’s disease 
Current Opinion in Neurobiology  2011;21(6):920-928.
The largest genetic risk for late-onset Alzheimer’s disease (AD) resides at the apolipoprotein E gene (APOE) locus, which has three common alleles (ε2, ε3, ε4) that encode three isoforms (apoE2, apoE3, apoE4). The very strong association of the APOE ε4 allele with AD risk and its role in the accumulation of amyloid β and animal models solidify the biological relevance of apoE isoforms but do not provide mechanistic insight. The innate immune response is consistently observed in AD and is a likely contributor to neuronal injury and response to injury. Here we review emerging data showing that apoE isoform regulation of multiple facets of the innate immune response in the brain may alter AD not only through amyloid β-dependent mechanisms, but also through other, amyloid β-independent mechanisms.
doi:10.1016/j.conb.2011.08.002
PMCID: PMC3237894  PMID: 21907569

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