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. 2017 Jul 31;40(3):577–585. doi: 10.1590/1678-4685-GMB-2016-0138

Combined association of Presenilin-1 and Apolipoprotein E polymorphisms with maternal meiosis II error in Down syndrome births

Pranami Bhaumik 1, Priyanka Ghosh 1, Sujay Ghosh 2, Eleanor Feingold 3,4, Umut Ozbek 4, Biswanath Sarkar 5, Subrata Kumar Dey 1
PMCID: PMC5596362  PMID: 28767121

Abstract

Alzheimer's disease and Down syndrome often exhibit close association and predictively share common genetic risk-factors. Presenilin-1 (PSEN-1) and Apolipoprotein E (APOE) genes are associated with early and late onset of Alzheimer's disease, respectively. Presenilin −1 is involved in faithful chromosomal segregation. A higher frequency of the APOE ε4 allele has been reported among young mothers giving birth to Down syndrome children. In this study, 170 Down syndrome patients, grouped according to maternal meiotic stage of nondisjunction and maternal age at conception, and their parents were genotyped for PSEN-1 intron-8 and APOE polymorphisms. The control group consisted of 186 mothers of karyotypically normal children. The frequencies of the PSEN-1 T allele and TT genotype, in the presence of the APOE ε4 allele, were significantly higher among young mothers (< 35 years) with meiosis II nondisjunction than in young control mothers (96.43% vs. 65.91% P = 0.0002 and 92.86% vs. 45.45% P < 0.0001 respectively) but not among mothers with meiosis I nondisjunction. We infer that the co-occurrence of the PSEN-1 T allele and the APOE ε4 allele associatively increases the risk of meiotic segregation error II among young women.

Keywords: Chromosome, genetic polymorphism, karyotype, meiosis, microsatellite markers

Introduction

Alzheimer's disease (AD), a progressive neurodegenerative disorder of old age, and Down syndrome (DS), an intellectual disability due to trisomy of chromosome 21, show co-occurrence. Brain imaging and autopsy studies revealed that Alzheimer's-like neuropathological changes, such as beta amyloid plaques and neurofibrillary tangles were common in DS patients at their forties (Olson and Shaw, 1969; Glenner and Wang, 1984; Mann and Esiri, 1989; Cork, 1990; Yoshimura et al., 1990). The common molecular mechanisms bridging the two disorders include chromosomal missegregation (Potter, 1991; 2008), overproduction of amyloid precursor protein (Rumble et al., 1989), oxidative stress and mitochondrial dysfunction (Pagano and Castello, 2012), nuclear factor of activated T cells (NFAT) and tau phosphorylation pathways (Jung et al., 2011; Perluigi et al., 2014), endocytic pathway abnormality (Cataldo et al., 2000), mutation in amyloid precursor protein gene (APP) (van Leeuwen et al., 1998), presence of Apolipoprotein E epsilon 4 (APOE ε4) allele (Del Bo et al., 1997). Familial association of AD and DS has been reported (Yatham et al., 1988; Schupf et al., 2001). Interactions among environmental agents, advancing age (Tanzi and Bertram, 2001; Grant et al., 2002) and a certain genetic polymorphisms (Bertram and Tanzi, 2005) account for 95% of sporadic late-onset AD, while only 5% AD are of early-onset type and due to mutations in APP (Goate et al., 1991), presenilin-1 (PSEN-1) (Sherrington et al., 1995) and presenilin-2 (PSEN-2) (Levy-Lahad et al., 1995; Rogaev et al., 1995) genes on chromosome 21, 14 and 1, respectively. The PSEN-1 gene encodes a protein component of the gamma-secretase complex involved in the processing of the amyloid precursor protein (APP) (Karran et al., 1998). Presenilin-1 protein is engaged in many cardinal mechanisms of several molecular pathways (Duff et al., 1996; Alberici et al., 1999; Woo et al., 2009; Ho and Shen, 2011; Trushina et al., 2012), which when impaired lead to the manifestation of AD. This protein also localizes to centromeres, the nuclear envelope of dividing cells, kinetochores at interphase, and is involved in faithful chromosomal segregation (Li et al., 1997). Mutations in PSEN-1 lead to chromosomal instability and trisomy 21 mosaicism in AD patients (Geller and Potter, 1999). Another well-documented molecular marker for both the early-onset (Corder et al., 1993) and sporadic (Brouwers et al., 2008) AD is a polymorphism in the Apolipoprotein E (APOE) gene on chromosome 19. Association of the APOE ε4 allele with AD has been demonstrated in ethnically different populations (Lehtimaki et al., 1995; Shimada et al., 1997; Tang et al., 1998; Panza et al., 1999; de-Andrade et al., 2000; Kim et al., 2001; Korovaitseva et al., 2001; Chen et al., 2003). On the other hand, DS is the most common aneuploidy in live born humans. The predominant cause of DS is the presence of a supernumerary chromosome 21, owing to nondisjunction in maternal gametogenesis in the overwhelming majority of cases (Sherman et al., 2007; Allen et al., 2009; Ghosh et al., 2010). Advanced maternal age (Hassold and Chiu, 1985; Allen et al., 2009) and an altered pattern of recombination (Warren et al., 1987; Sherman et al., 1991; Oliver et al., 2008) have been identified as two major risk factors for maternal meiotic errors. Avramopoulos et al. (1996) found a higher of the APOE ε4 allele in young mothers having DS children due to chromosomal nondisjunction in the second meiotic division (meiosis II or MII) of oocytes. The association of PSEN-1 intron 8 polymorphism and late-onset AD in North American European descendants was first reported by Wragg et al. (1996) and later supported in many studies (Higuchi et al., 1996; Isoe et al., 1996; Kehoe et al., 1996; Brookes et al., 1997; Ezquerra et al., 1997; Nishiwaki et al., 1997; Tilley et al., 1999); arguments against this association were also produced (Pérez-Tur et al., 1996; Scott et al., 1996; Cai et al., 1997; Lendon et al., 1997; Singleton et al., 1997; Sorbi et al., 1997; Tysoe et al., 1997; Jiang et al., 1999; Bagli et al., 1999; Rodriguez et al., 2000; Chandak et al., 2002; Rassas et al., 2013). The study of a DS sample from Denmark revealed the association of the T allele of the PSEN-1 intronic polymorphism (rs165932) with maternal MII nondisjunction, and thus pointed to a putative role of this polymorphic allele in chromosomal segregation (Petersen et al., 2000). The aim of the present study was to investigate the possibility of a collaborative effect of PSEN-1 and APOE polymorphisms on DS birth in the Indian subcontinent.

Subjects and Methods

Subjects

This study included 178 unrelated Bengali individuals with free trisomy 21 and their parents. We recruited 186 women that gave birth to karyotypically normal children as the control group. All subjects were randomly referred from different Medical Colleges and Hospitals of Kolkata and neighbouring areas. The study was approved by the ethical committee of the Maulana Abul Kalam Azad University of Technology. Peripheral blood was collected from the DS children and their parents, as well as from control mothers and their children after taking informed consent.

Cytogenetic analysis

Classical karyotyping was performed to select only free trisomy 21 DS cases. At least 30 metaphases were analysed from each DS sample to exclude mosaicism.

Determination of parental origin of extra chromosome 21

Genomic DNA was isolated from blood using a QIAamp DNA Blood Midi Kit (Qiagen). Ten highly polymorphic STR markers, mapped from the pericentromeric region to the telomeric region of the long arm of chromosome 21were selected to determine the maternal or paternal origin of the extra chromosome 21: D21S1432 – D21S11 – D21S1437 – D21S1270 –D21S167 – D21S1412 – D21S2055 – D21S1260 – D21S1411 – D21S1446. For determining the stage of meiotic nondisjunction, i.e. MI or MII errors, four additional pericentromeric markers were genotyped: D21S369, D21S215, D21S258 and D21S120. The maternal MI error was inferred, when maternal heterozygosity for these markers was retained in the DS child. If maternal heterozygosity was reduced to homozygosity in the DS child, maternal MII error was considered.

Detection of APOE and PSEN-1 polymorphisms

Polymorphisms in APOE gene (rs429358 and rs7412) and PSEN-1 intron 8 (rs165932) were investigated by Restriction Fragment Length Polymorphism (RFLP), and direct DNA sequencing in an ABI PRISM 3700 DNA Analyzer platform (Applied Biosystems), after PCR amplification, using oligonucleotide primers previously described by Hixson and Vernier (1990) and Sherrington et al. (1995), respectively. Restriction fragment length polymorphism (RFLP) genotyping of APOE and PSEN-1 was done, as described by Hixson and Vernier (1990) and Wragg et al. (1996) respectively.

Statistical analysis

Maternal age was considered as predictor variable in all statistical analyses. For age analyses, both case and control mothers were stratified into young (< 35 years) and old (> 35 years) groups. Chi-squared tests were performed to compare genotypic and allelic frequencies between case and control mothers, as well as between MI and MII nondisjunction groups, as distinct molecular mechanisms are supposed to be responsible for these errors.

Considered the high number of statistical tests used to compare the many partitions and combinations we created from our original groups of control and DS mothers, the alpha critical level obtained by a simple Bonferroni correction was set at 0.0005. Since the partitions and rearrangements of the total samples of control and DS mothers were somewhat correlated, we reset this value at the less stringent level alpha = 0.001.

Results

STR genotyping revealed that out of the 178 DS trisomies only eight had a paternal meiotic origin, and 170 were the result of maternal nondisjunction. MI nondisjunction was demonstrated in 106 cases (53 young mothers and 53 old mothers), and MII nondisjunction in 64 cases (33 young mothers and 31 old mothers). According to the presence of the APOE ε4 allele, stage of nondisjunction and age at conception, the 170 case- mothers were stratified into eight groups : (a) ε4 positive, - MI, - Young, n = 16; (b) ε4 positive, - MI, - Old, n = 13; (c) ε4 positive, - MII, - Young, n = 14; (d) ε4 positive, - MII, - Old, n = 8; (e) ε4 negative, - MI, - Young, n = 37; (f) ε4 negative, - MI, - Old, n = 40; (g) ε4 negative, - MII, - Young, n = 19; (h) ε4 negative, - MII, - Old, n = 23. The control mothers of karyotypically normal children were also categorised as: (a) ε4 positive, - Young, n = 22; (b) ε4 positive, - Old, n = 20; (c) ε4 negative, - Young, n = 71; (d) ε4 negative, - Old, n = 73. The distribution of PSEN-1 alleles and genotypes in each group of case and control mothers are presented in Supplementary Tables S1 (229.9KB, pdf) and S2 (212.1KB, pdf) , respectively. All groups were in Hardy-Weinberg equilibrium.

PSEN-1 polymorphism and maternal age

Stratified analyses for meiotic outcome groups revealed that the TT genotype was significantly more frequent in the group of young mothers with MII nondisjunction compared to young control mothers. (P = 0.0007; Table 1).

Table 1. Comparison of PSEN-1 TT Genotypic and T allelic frequencies among different groups of mothers of DS children and control mothers of karyotypically normal children.

Comparisons TT genotypic frequency P value of Chi–squared test T allelic frequency P value of Chi–squared test
Case Control Case Control
Case mothers (N = 170) vs. 55.29% 48.92% 0.36 72.35% 68.55% 0.65
Control mothers (N = 186)
MI case mothers (N = 106) vs. 49.06% 48.92% 0.98 68.39% 68.55% 0.98
Control mothers (N = 186)
MII case mothers (N = 64) vs. 65.63% 48.92% 0.02 78.91% 68.55% 0.21
Control mothers (N = 186)
MII case mothers (N = 64) vs. 65.63% 49.06% 0.02 78.91% 68.39% 0.20
MI case mothers (N = 106)
Young case mothers (N = 86) vs. 55.81% 44.09% 0.08 73.26% 63.98% 0.25
Young control mothers (N = 93)
Old case mothers (N = 84) vs. 54.76% 53.76% 0.89 71.43% 73.12% 0.84
Old control mothers (N = 93)
MI - young case mothers (N = 53) vs. 49.06% 44.09% 0.45 68.87% 63.98% 0.54
Young control mothers (N = 93)
MI - old case mothers (N = 53) vs. 49.06% 53.76% 0.52 67.92% 73.12% 0.54
Old control mothers (N = 93)
MII - young case mothers (N = 33) vs. Young control mothers (N = 93) 66.67% 44.09% 0.0007 80.3% 63.98% 0.04
MII - old case mothers (N = 31) vs. 64.52% 53.76% 0.14 77.42% 73.12% 0.62
Old control mothers (N = 93)
APOE ε4 positive - young case mothers (N = 30) vs. APOE ε4 positive - young control mothers (N = 22) 66.67% 45.45% 0.002 80% 65.91% 0.08
APOE ε4 positive - old case mothers 52.38% 55% 0.72 69.05% 72.5% 0.69
(N = 21) vs. APOE ε4 positive - old control mothers (N = 20)
APOE ε4 negative - young case mothers (N = 56) vs. APOE ε4 negative - young control mothers (N = 71) 50% 43.66% 0.34 69.64% 63.38% 0.43
APOE ε4 negative - old case mothers 55.56% 53.42% 0.77 72.22% 73.29% 0.90
(N = 63) vs. APOE ε4 negative - old control mothers (N = 73)
APOE ε4 positive - MI - young case mothers (N = 16) vs. APOE ε4 positive - young control mothers (N = 22) 43.75% 45.45% 0.80 65.62% 65.91% 0.97
APOE ε4 positive - MI - old case mothers (N = 13) vs. APOE ε4 positive - old control mothers (N = 20) 46.15% 55% 0.23 65.38% 72.5% 0.40
APOE ε4 negative - MI - young case mothers (N = 37) vs. APOE ε4 negative - young control mothers (N = 71) 51.35% 43.66% 0.24 70.27% 63.38% 0.39
APOE ε4 negative - MI - old case mothers (N = 40) vs. APOE ε4 negative - old control mothers (N = 73) 50% 53.42% 0.64 68.75% 73.29% 0.59
APOE ε4 positive - MII - young case mothers (N = 14) vs. APOE ε4 positive - young control mothers (N = 22) 92.86% 45.45% <0.0001 96.43% 65.91% 0.0002
APOE ε4 positive - MII - old case mothers (N = 8) vs. APOE ε4 positive - old control mothers (N = 20) 62.5% 55% 0.31 75% 72.5% 0.77
APOE ε4 negative - MII - young case mothers (N = 19) vs. APOE ε4 negative - young control mothers (N = 71) 47.37% 43.66% 0.57 68.42% 63.38% 0.53
APOE ε4 negative - MII - old case mothers (N = 23) vs. APOE ε4 negative - old control mothers (N = 73) 65.22% 53.42% 0.11 78.26% 73.29% 0.56
APOE ε4 positive - MII case mothers 81.82% 44.83% <0.0001 88.64% 65.52% 0.004
(N = 22) vs. APOE ε4 positive - MI case mothers (N = 29)
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Young mothers, < 35 yrs of age; Old mothers, < 35 yrs of age

MI, nondisjunction at meiotic division I; MII, nondisjunction at meiotic division II

APOE ε4 allele and nondisjunction

The detailed genotypes and alleles of APOE gene polymorphism in DS mothers and controls, according to age and meiotic nondisjunction stage are given in the Supplementary Table S3 (227KB, pdf) .

In young case mothers, the presence of ε4/- genotypes (i.e. ε4/ε4, ε3/ε4 or ε2/ε4) increased the risk for DS 1.73 times (Table 2). Both the allelic (ε4) and genotypic (ε4/ε4 + ε3/ε4 + ε2/ε4) frequencies were significantly increased in the MII nondisjunction young group when compared with young controls and with MI nondisjunction old group (P < 0.001, for genotypic and allelic frequencies). In the group of MII nondisjunction young mothers, the risk of nondisjunction was increased 2.48 times in the presence of the ε4 allele when compared with the group of MI nondisjunction old mothers (OR = 2.48, 95% CI = 1.11 – 5.53; Table 2) and 2.23 times when compared with young control mothers (OR = 2.23, 95% CI = 1.12 – 4.47; Table 2).

Table 2. Comparative analysis of APOE ε4/- genotypic and ε4 allelic frequencies in mothers of DS children and control mothers of karyotypically normal children.

APOE ε4 positive genotypic frequency
(ε4/ ε4 + ε3/ ε4 + ε2/ ε4)		 APOE ε4 allelic frequency
Comparisons Chi square P value of Chi - squared test OR 95 % CI Chi square P value of Chi - squared test OR 95 % CI
Case mothers (N= 170) vs. control mothers(N= 186) 2.44 0.12 1.47 0.91 -2.36 1.8 0.18 1.46 0.96 - 2.23
Young case mothers (N= 86) vs. Young control mothers (N= 93) 5.33 0.02 1.73 0.90 – 3.32 2.98 0.08 1.59 0.90 - 2.79
Old case mothers (N= 84) vs. Old control mothers (N= 93) 0.57 0.45 1.22 0.60 - 2.45 0.8 0.37 1.32 0.69 - 2.50
MI - young case mothers (N= 53) vs. Young control mothers (N= 93) 1.8 0.18 1.4 0.65 - 2.97 0.5 0.48 1.23 0.63 - 2.40
MI - old case mothers (N= 53) vs. Old control mothers (N= 93) 0.43 0.51 1.19 0.53 - 2.63 0.21 0.64 1.16 0.55 - 2.44
MII - young case mothers (N= 33) vs. Young control mothers (N= 93) 14.89 0.0001 2.38 1.03 - 5.51 11.29 0.0008 2.23 1.12 – 4.47
MII - old case mothers (N= 31) vs. Old control mothers (N= 93) 0.86 0.35 1.27 0.49 - 3.26 2.69 0.1 1.6 0.70 - 3.63
MII - Young case mothers (N= 33) vs. MI - old case mothers (N= 53) 13.06 0.0003 2.27 0.89 - 5.76 14.85 0.0001 2.48 1.11 - 5.53
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Young mothers, < 35 yrs of age; Old mothers, > 35 yrs of age

MI, nondisjunction at meiotic division I; MII, nondisjunction at meiotic division II

Combined effect of the PSEN-1 T allele and the APOE ε4 allele and maternal aging on non disjunction

We found a significant increase in both TT genotypic and T allelic frequencies in APOE ε4 positive, - MII nondisjunction,- young case mothers upon comparison with APOE ε4 positive, - young control mothers (P < 0.00001 and 0.0002, respectively; Table 1).

These results suggest that the PSEN-1 T allele and the APOE ε4 allele may collaboratively increase the risk of MII nondisjunction among young mothers.

Discussion

The aim of the present work was to explore the notion that the etiology of DS birth and AD is somehow related at the molecular level. The result of our analyses suggested that polymorphisms of PSEN-1 might explain the co-occurrence of DS and AD in one same family.

The result of our case control study showed that the ‘T allele’ of PSEN-1 intronic polymorphism (rs165932) was associated with MII nondisjunction, but not with MI nondisjunction. It is not clear at this point how this polymorphism impacts the chromosome segregation, but two hypotheses have been put forward to explain its molecular role. According to the first hypothesis, the PSEN-1 intron 8 T allele may be in linkage disequilibrium with a coding segment in the gene itself or in other gene(s) (Hutton and Hardy, 1997); and the second hypothesis postulates that this polymorphic site may affect the pre-mRNA splicing and give rise to a different isoform of the protein, which may affect chromosome segregation (Meshorer and Soreq, 2002). Abnormality in cell cycle regulation is apparent in both familial and sporadic AD cases (Potter, 1991, 2005, 2008; Arendt et al., 1996; Geller and Potter, 1999; Yang et al., 2001, 2006; Nagy, 2005; Yang and Herrup, 2007; Varvel et al., 2008).

The significant increase in T allelic and TT genotypic frequencies in ε4 positive young mothers with MII nondisjunction would imply a collaborative effect of both alleles in increasing the risk of MII nondisjunction at young age. Avramopoulos et al. (1996) found higher APOE ε4 allele frequencies in young mothers giving birth to DS child due to meiotic II nondisjunction error. This would be explained by compromised microcirculation due to the high plasma cholesterol deposition in APOE ε4 allele carriers causing atherosclerosis in microvasculature surrounding ovarian follicles. This would imply reduced blood flow and oxygen supply, and increased anaerobic products such as lactic acid accumulation in the follicular cell and as a consequence the size of the spindle, could become reduced due to high pH inside the follicle, resulting in nondisjunction (Gaulden, 1992). Another explanation is that isoform-specific binding of ApoE to microtubule-associated protein would affect microtubule stability and function and, thus, hamper meiotic chromosomal segregation (Strittmatter et al., 1993, 1994; Hansen et al., 1998). Support to this prediction has been provided by Nagy et al. (2000), who showed that trisomy 13 and trisomy 21 conceptuses have a higher APOE ε4 allele frequency.

A recent study has shown that APOE regulates telomere dynamics, and the females who carry APOE ε4 allele experience a six-times higher rate of telomere shortening than non-carriers (Jacobs et al., 2013). Greater erosion of telomere length in Alzheimer's patients with APOE ε4 allele is also evident (Takata et al., 2012). Interestingly, the study of Ghosh et al. (2010) revealed higher degree of telomere loss in mothers of DS patients resulting from MII nondisjunction than in MI nondisjunction cases and controls. But it is difficult at this point to explain how these data fit together.

Taking all the above into account, we may conclude that the T allele and TT genotype of PSEN-1 polymorphism is associated with MII nondisjunction in younger women giving birth to DS children. Petersen et al. (2000) reported similar findings in Denmark. This result is somewhat interesting as we (Ghosh et al., 2009) and others (Oliver et al., 2008) have found that MII nondisjunction is frequent among older mothers, and represents a maternal age dependent phenomenon. The present set of results suggests that MII nondisjunction can be a maternal age independent phenomenon, when mothers carry the APOE ε4 and PSEN-1 T alleles. The gradual increase in the association of the three factors - PSEN-1 T allele, APOE ε4 allele and young age with MII nondisjunction but not with MI nondisjunction, suggests that these two errors are mutually exclusive and involve different molecular mechanisms. Considering the findings of previous studies (Oliver et al., 2008; Ghosh et al., 2009) and the present data together, we could infer predictively that APOE ε4 allele and PSEN-1 rs165932 T allele create a microenvironment in the younger oocyte, which mimics the subcellular condition of chronologically older ovum and causes MII nondisjunction, a possibility warranting confirmation through elaborate molecular study. Nevertheless, our study provides the first independent confirmation of PSEN-1 as the prospective molecular candidate that relates AD with DS. The association of the T allele of PSEN-1 intronic polymorphism (rs165932) and the APOE ε4 allele would be the collaborative risk factor for both AD and DS, reciprocally exacerbating the risk of MII nondisjunction. Moreover, for the very first time we have clearly demonstrated that the distribution of risk alleles is statistically similar among controls and MI nondisjunction groups. These results being in accordance with those of Peterson et al. (2000) suggest that the molecular risk factor underlying the association of AD and DS is independent of ethnicity. Our findings represent a step towards the understanding of the genetic basis of DS birth and AD occurance within one same family.

Acknowledgments

We would like to thank the families participated in the study and professionals who helped us in collection of blood samples. We are thankful to the Director, Anthropological Survey of India, Kolkata, for providing laboratory facilities for some experimental work and Mr. Biswaroop Mookherjee, for his kind help regarding data analysis. The project was funded by Indian Council of Medical Research (ICMR) [grant sanction no. 54/10/2012-HUM-BMS, 31.03.2013].

Supplementary material

The following online material is available for this article:

Table S1. - PSEN-1 genotypic and allelic frequencies in mothers of DS children.
Click here for additional data file. (229.9KB, pdf)
Table S2. - PSEN-1 genotypic and allelic frequencies in control mothers.
Click here for additional data file. (212.1KB, pdf)
Table S3. - APOE genotypic and allelic frequencies in mothers of DS children and control mothers.
Click here for additional data file. (227KB, pdf)

Footnotes

Associate Editor: Angela M. Vianna-Morgante

References

  1. Alberici A, Moratto D, Benussi L, Gasparini L, Ghidoni R, Gatta LB, Finazzi D, Frisoni GB, Trabucchi M, Growdon JH, et al. Presenilin 1 protein directly interacts with Bcl-2. J Biol Chem. 1999;274:30764–30769. doi: 10.1074/jbc.274.43.30764. [DOI] [PubMed] [Google Scholar]
  2. Allen EG, Freeman SB, Druschel C, Hobbs CA, O’Leary LA, Romitti PA, Royle MH, Torfs CP, Sherman SL. Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: A report from the Atlanta and National Down Syndrome Projects. Hum Genet. 2009;125:41–52. doi: 10.1007/s00439-008-0603-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arendt T, Rodel L, Gartner U, Holzer M. Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer's disease. Neuroreports. 1996;7:3047–3049. doi: 10.1097/00001756-199611250-00050. [DOI] [PubMed] [Google Scholar]
  4. Avramopoulos D, Mikkelsen M, Vassilopoulos D, Grigoriadou M, Petersen MB. Apolipoprotein E allele distribution in parents of Down's syndrome children. Lancet. 1996;347:862–865. doi: 10.1016/s0140-6736(96)91346-x. [DOI] [PubMed] [Google Scholar]
  5. Bagli M, Papassotiropoulos A, Schwab SG, Jessen F, Rao ML, Maier W, Heun R. No association between an intronic polymorphism in the presenilin-1 gene and Alzheimer disease in a German population. J Neurol Sci. 1999;167:34–36. doi: 10.1016/s0022-510x(99)00131-8. [DOI] [PubMed] [Google Scholar]
  6. Bertram L, Tanzi RE. Alzheimer's disease: One disorder, too many genes? Hum Mol Genet. 2005;13:R135–R141. doi: 10.1093/hmg/ddh077. [DOI] [PubMed] [Google Scholar]
  7. Brookes AJ, Howell WM, Woodburn K, Johnstone EC, Carothers A. Presenilin-I, presenilin-II, and VLDL-R associations in early onset Alzheimer's disease. Lancet. 1997;350:336–337. doi: 10.1016/S0140-6736(05)63387-9. [DOI] [PubMed] [Google Scholar]
  8. Brouwers N, Sleegers K, Van Broeckhoven C. Molecular genetics of Alzheimer's disease: An update. Ann Med. 2008;18:1–22. doi: 10.1080/07853890802186905. [DOI] [PubMed] [Google Scholar]
  9. Cai X, Stanton J, Fallin D, Hoyne J, Duara R, Gold M, Sevush S, Scibelli P, Crawford F, Mullan M. No association between the intronic presenilin polymorphism and Alzheimer's disease in clinic and population-based samples. Am J Med Genet. 1997;74:202–203. [PubMed] [Google Scholar]
  10. Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA. Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: Differential effects of APOE genotype and presenilin mutations. Am J Pathol. 2000;157:277–286. doi: 10.1016/s0002-9440(10)64538-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chandak GR, Sridevi MU, Vas CJ, Panikker DM, Singh L. Apolipoprotein E and presenilin-1 allelic variation and Alzheimer's disease in India. Hum Biol. 2002;74:683–693. doi: 10.1353/hub.2002.0051. [DOI] [PubMed] [Google Scholar]
  12. Chen D, Zhang JW, Zhang ZX, Zhao HL, Li XQ, Wu YN, Qu QM. Apolipoprotein E gene polymorphisms and Alzheimer disease. Yi Chellan Xue Bao. 2003;30:1167–1170. [PubMed] [Google Scholar]
  13. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type e4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921–923. doi: 10.1126/science.8346443. [DOI] [PubMed] [Google Scholar]
  14. Cork LC. Neuropathology of Down syndrome and Alzheimer disease. Am J Med Genet Suppl. 1990;7:282–286. doi: 10.1002/ajmg.1320370756. [DOI] [PubMed] [Google Scholar]
  15. de-Andrade FM, Larrandaburu M, Callegari-Jacques SM, Gastaldo G, Hutz MH. Association of apolipoprotein E polymorphism with plasma lipids and Alzheimer'sdisease in a Southern Brazilian population. Braz J Med Biol Res. 2000;33:529–537. doi: 10.1590/s0100-879x2000000500007. [DOI] [PubMed] [Google Scholar]
  16. Del Bo R, Comi GP, Bresolin N, Castelli E, Conti E, Degiuli A, Ausenda CD, Scarlato G. The apolipoprotein E epsilon4 allele causes a faster decline of cognitive performances in Down's syndrome subjects. J Neurol Sci. 1997;145:87–91. doi: 10.1016/s0022-510x(96)00249-3. [DOI] [PubMed] [Google Scholar]
  17. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, et al. Increased amyloid-beta 42 (43) in brains of mice expressing mutant presenilin 1. Nature. 1996;383:710–713. doi: 10.1038/383710a0. [DOI] [PubMed] [Google Scholar]
  18. Ezquerra M, Blesa R, Tolosa E, Lopez Pousa S, Aguilar M, Peña J, Van Broeckhoven C, Ballesta F, Oliva R. The genotype 2/2 of the presenilin-1 polymorphism is decreased in Spanish early-onset Alzheimer's disease. Neurosci Lett. 1997;227:201–204. doi: 10.1016/s0304-3940(97)00328-5. [DOI] [PubMed] [Google Scholar]
  19. Gaulden ME. Maternal age effect: The enigma of Down syndrome and other trisomic conditions. Mutat Res. 1992;296:69–88. doi: 10.1016/0165-1110(92)90033-6. [DOI] [PubMed] [Google Scholar]
  20. Geller LN, Potter H. Chromosome missegregation and trisomy 21 mosaicism in Alzheimer's disease. Neurobiol Dis. 1999;6:167–179. doi: 10.1006/nbdi.1999.0236. [DOI] [PubMed] [Google Scholar]
  21. Ghosh S, Feingold E, Dey SK. Etiology of Down syndrome: Evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations. Am J Med Genet A. 2009;149A:1415–1420. doi: 10.1002/ajmg.a.32932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ghosh S, Bhaumik P, Ghosh P, Dey SK. Chromosome 21 nondisjunction and Down syndrome birth in an Indian cohort: Analysis of incidence and aetiology from family linkage data. Genet Res (Camb) 2010;92:189–197. doi: 10.1017/S0016672310000224. [DOI] [PubMed] [Google Scholar]
  23. Glenner GG, Wang CW. Alzheimer's disease and Down's syndrome: Sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984;122:1131–1135. doi: 10.1016/0006-291x(84)91209-9. [DOI] [PubMed] [Google Scholar]
  24. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991;349:704–706. doi: 10.1038/349704a0. [DOI] [PubMed] [Google Scholar]
  25. Grant WB, Campbell A, Itzhaki RF, Savory J. The significance of environmental factors in the etiology of Alzheimer's disease. J Alzheimers Dis. 2002;4:179–189. doi: 10.3233/jad-2002-4308. [DOI] [PubMed] [Google Scholar]
  26. Hansen C, Bugge M, Brandt CA, Hertz JM, Tranebjaerg L, Mikkelsen M, Petersen MB. Apolipoprotein E alleles in mothers of trisomy 18 conceptuses. Clin Genet. 1998;53:321–322. doi: 10.1111/j.1399-0004.1998.tb02707.x. [DOI] [PubMed] [Google Scholar]
  27. Hassold T, Chiu D. Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy. Hum Genet. 1985;70:11–17. doi: 10.1007/BF00389450. [DOI] [PubMed] [Google Scholar]
  28. Higuchi S, Muramatsu T, Matsushita S, Arai H, Sasaki H. Presenilin-1 polymorphism and Alzheimer's disease. Lancet. 1996;347:1186–1186. [PubMed] [Google Scholar]
  29. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31:545–548. [PubMed] [Google Scholar]
  30. Ho A, Shen J. Presenilins in synaptic function and disease. Trends Mol Med. 2011;17:617–624. doi: 10.1016/j.molmed.2011.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hutton M, Hardy J. The presenilins and Alzheimer's disease. Hum Mol Genet. 1997;6:1639–1646. doi: 10.1093/hmg/6.10.1639. [DOI] [PubMed] [Google Scholar]
  32. Isoe K, Urakami K, Ji Y, Adachi Y, Nakashima K. Presenilin polymorphism in patients with Alzheimer's disease, vascular dementiaand alcohol- associated dementia in Japanese population. Acta Neurol Scand. 1996;94:326–328. doi: 10.1111/j.1600-0404.1996.tb07074.x. [DOI] [PubMed] [Google Scholar]
  33. Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH, Rasgon NL. Accelerated cell aging in female APOE-ε4 carriers: Implications for hormone therapy use. PLoS One. 2013;8:e54713. doi: 10.1371/journal.pone.0054713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Jiang S, Lin S, Tang G, Feng G, Qian Y, Wang D, Ren D, Gu N. No association between the intronicpresenilin 1 polymorphism and Alzheimer's disease in the Chinese population. Am J Med Genet. 1999;88:1–3. [PubMed] [Google Scholar]
  35. Jung MS, Park JH, Ryu YS, Choi SH, Yoon SH, Kwen MY, Oh JY, Song WJ, Chung SH. Regulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation. J Biol Chem. 2011;286:40401–40412. doi: 10.1074/jbc.M111.253971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Karran EH, Allsop D, Christie G, Davis J, Gray C, Mansfield F, Ward RV. Presenilins in search of functionality. Biochem Soc Trans. 1998;26:491–496. doi: 10.1042/bst0260491. [DOI] [PubMed] [Google Scholar]
  37. Kehoe P, Williams J, Holmans P, Liddell M, Lovestone S, Holmes C, Powell J, Neal J, Wilcock G, Owen MJ. Association between a PS 1 intronic polymorphism and late onset Alzheimer's disease. Neuroreport. 1996;7:2155–2158. doi: 10.1097/00001756-199609020-00019. [DOI] [PubMed] [Google Scholar]
  38. Kim HC, Kim DK, Choi IJ, Kang KH, Yi SD, Park J, Park YN. Relation of apolipoprotein E polymorphism to clinically diagnosed Alzheimer's disease in the Korean population. Psychiatry Clin Neurosci. 2001;55:115–120. doi: 10.1046/j.1440-1819.2001.00797.x. [DOI] [PubMed] [Google Scholar]
  39. Korovaitseva GI, Shcherbatykh TV, Selezneva NV, Gavrilova SI, Golimbet VE, Voskresenskaia NI, Rogaev EI. Genetic association between the apolipoprotein E(ApoE) gene alleles and various forms of Alzheimer's disease. Genetika. 2001;37:529–535. [PubMed] [Google Scholar]
  40. Lehtimäki T, Pirttilä T, Mehta PD, Wisniewski HM, Frey H, Nikkari T. Apolipoprotein E polymorphism and its influence on apoE concentrations in the cerebrospinal fluid in Finnish patients with Alzheimer's disease. Hum Genet. 1995;95:39–42. doi: 10.1007/BF00225071. [DOI] [PubMed] [Google Scholar]
  41. Lendon CL, Myers A, Cumming A, Goate AM, St Clair D. A polymorphism in the presenilin 1 gene does not modify risk for Alzheimer's disease in a cohort with sporadic early onset. Neurosci Lett. 1997;228:212–214. doi: 10.1016/s0304-3940(97)00393-5. [DOI] [PubMed] [Google Scholar]
  42. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro, PD, Schmidt SD, Wang K, et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995;269:973–977. doi: 10.1126/science.7638622. [DOI] [PubMed] [Google Scholar]
  43. Li J, Xu M, Zhou H, Ma J, Potter H. Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest role in chromosome segregation. Cell. 1997;90:917–927. doi: 10.1016/s0092-8674(00)80356-6. [DOI] [PubMed] [Google Scholar]
  44. Mann DM, Esiri MM. The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. J Neurol Sci. 1989;89:169–179. doi: 10.1016/0022-510x(89)90019-1. [DOI] [PubMed] [Google Scholar]
  45. Meshorer E, Soreq H. Pre-mRNA splicing modulations in senescence. Aging Cell. 2002;1:10–16. doi: 10.1046/j.1474-9728.2002.00005.x. [DOI] [PubMed] [Google Scholar]
  46. Nagy B, Bán Z, Tóth-Pál E, Papp C, Fintor L, Papp Z. Apolipoprotein E allele distribution in trisomy 13, 18,and 21 conceptuses in Hungarian population. Am J Clin Pathol. 2000;113:535–538. doi: 10.1309/WXA4-YBRT-D2AG-EV67. [DOI] [PubMed] [Google Scholar]
  47. Nagy Z. The last neuronal division: A unifying hypothesis for the pathogenesis of Alzheimer's disease. J Cell Mol Med. 2005;9:531–541. doi: 10.1111/j.1582-4934.2005.tb00485.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Nishiwaki Y, Kamino K, Yoshiiwa A, Sato N, Tateishi K, Takeda M, Kobayashi T, Yamamoto H, Nonomura Y, Yoneda H, et al. T/G polymorphism at intron 9 of presenilin 1 gene is associated with, but not responsible for sporadic late-onset Alzheimer's disease in Japanese population. Neurosci Lett. 1997;227:123–126. doi: 10.1016/s0304-3940(97)00317-0. [DOI] [PubMed] [Google Scholar]
  49. Oliver TR, Feingold E, Yu K, Cheung V, Tinker S, Yadav-Shah M, Masse N, Sherman SL. New insight into human nondisjunction of chromosome 21 in oocyte. PloS Genet. 2008;4:e1000033. doi: 10.1371/journal.pgen.1000033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Olson MI, Shaw CM. Presenile dementia and Alzheimer's disease in mongolism. Brain. 1969;92:147–156. doi: 10.1093/brain/92.1.147. [DOI] [PubMed] [Google Scholar]
  51. Pagano G, Castello G. Oxidative stress and mitochondrial dysfunction in Down syndrome. Adv Exp Med Biol. 2012;724:291–299. doi: 10.1007/978-1-4614-0653-2_22. [DOI] [PubMed] [Google Scholar]
  52. Panza F, Solfrizzi V, Torres F, Mastroianni F, Del Parigi A, Colacicco AM, Basile AM, Capurso C, Noya R, Capurso A. Decreased frequency of apolipoprotein E epsilon4 allele from Northern to Southern Europe in Alzheimer's disease patients and centenarians. Neurosci Lett. 1999;277:53–56. doi: 10.1016/s0304-3940(99)00860-5. [DOI] [PubMed] [Google Scholar]
  53. Pérez-Tur J, Wavrant-De Vrieze F, Lambert JC, Chartier-Harlin MC. Presenilin-1 polymorphism and Alzheimer's disease. The Alzheimer's Study Group. Lancet. 1996;347:1560–1561. [PubMed] [Google Scholar]
  54. Perluigi M, Pupo G, Tramutola A, Cini C, Coccia R, Barone E, Head E, Butterfield DA, Di Domenico F. Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain. Biochim Biophys Acta. 2014;1842:1144–1153. doi: 10.1016/j.bbadis.2014.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Petersen MB, Karadima G, Samaritaki M, Avramopoulos D, Vassilopoulos D, Mikkelsen M. Association between presenilin-1 polymorphism and maternal meiosis II errors in Down syndrome. Am J Med Genet. 2000;93:366–372. doi: 10.1002/1096-8628(20000828)93:5<366::aid-ajmg5>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  56. Potter H. Review and hypothesis: Alzheimer disease and Down syndrome chromosome 21 nondisjunction may underlie both disorders. Am J Hum Genet. 1991;48:1192–1200. [PMC free article] [PubMed] [Google Scholar]
  57. Potter H. Cell cycle and chromosome segregation defects in Alzheimer's disease. In: Copani A, Nicoletti F, editors. Cell Cycle Mechanisms and Neuronal Cell Death. Landes Bioscience; Austin: 2005. pp. 55–78. [Google Scholar]
  58. Potter H. Down syndrome and Alzheimer's disease: Two sides of the same coin. Fut Neurol. 2008;3:29–37. [Google Scholar]
  59. Rassas AA, Fredj SH, Khiari HM, Sahnoun S, Bibi A, Siala H, Mrabet A, Messaoud T. No association between an intronic polymorphism in the presenilin-1 gene and Alzheimer disease in a Tunisian population. J Neural Transm. 2013;120:1355–1358. doi: 10.1007/s00702-013-0985-1. [DOI] [PubMed] [Google Scholar]
  60. Rodriguez MT, Calella AM, Silva S, Munna E, Modena P, Chiesa R, Terrevazzi S, Ruggieri RM, Palermo R, Piccoli F, et al. Apolipoprotein E and intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in Alzheimer's disease and vascular dementia. Dement Geriatr Cogn Disord. 2000;11:239–244. doi: 10.1159/000017245. [DOI] [PubMed] [Google Scholar]
  61. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995;376:775–778. doi: 10.1038/376775a0. [DOI] [PubMed] [Google Scholar]
  62. Rumble B, Retallack R, Hilbich C, Simms G, Multhaup G, Martins R, Hockey A, Montgomery P, Beyreuther K, Masters CL. Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. N Engl J Med. 1989;320:1446–1452. doi: 10.1056/NEJM198906013202203. [DOI] [PubMed] [Google Scholar]
  63. Schupf N, Kapell D, Nightingale B, Lee JH, Mohlenhoff J, Bewley S, Ottman R, Mayeux R. Specificity of the fivefold increase in AD in mothers of adults with Down syndrome. Neurology. 2001;57:979–984. doi: 10.1212/wnl.57.6.979. [DOI] [PubMed] [Google Scholar]
  64. Scott WK, Growdon JH, Roses AD, Haines JL, Pericak-Vance MA. Presenilin-1 polymorphism and Alzheimer's disease. Lancet. 1996;347:1186–1187. [PubMed] [Google Scholar]
  65. Sherman SL, Takaesu N, Freeman SB, Grantham M, Phillips C, Blackstone RD, Jacobs PA, Cockwell AE, Freeman V, Uchida I, et al. Trisomy 21: Association between reduced recombination and nondisjunction. Am J Hum Genet. 1991;49:608–620. [PMC free article] [PubMed] [Google Scholar]
  66. Sherman SL, Allen EG, Bean L, Freeman SB. Epidemiology of Down syndrome. Ment Retard Dev Disab Res Rev. 2007;13:221–227. doi: 10.1002/mrdd.20157. [DOI] [PubMed] [Google Scholar]
  67. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995;375:754–760. doi: 10.1038/375754a0. [DOI] [PubMed] [Google Scholar]
  68. Shimada K, Yasuda M, Maeda K. Apolipoprotein E genotype as a risk factor in Japanese patients with early onset and late onset Alzheimer's disease. Seishin Shinkeigaku Zasshi. 1997;99:575–587. [PubMed] [Google Scholar]
  69. Singleton AB, Lamb H, Leake A, McKeith IG, Perry RH, Morris CM. No association between an intronic polymorphism in the presenilin-1 gene and Alzheimer's disease. Neurosci Lett. 1997;234:19–22. doi: 10.1016/s0304-3940(97)00653-8. [DOI] [PubMed] [Google Scholar]
  70. Sorbi S, Nacmias B, Tedde A, Forleo P, Piacentini S, Latorraca S, Amaducci L. Presenilin-1 gene intronic polymorphism in sporadic and familial Alzheimer'sdisease. Neurosci Lett. 1997;222:132–134. doi: 10.1016/s0304-3940(97)13345-6. [DOI] [PubMed] [Google Scholar]
  71. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:1977–1981. doi: 10.1073/pnas.90.5.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KH, Dong LM, Jakes R, Huang DY, Pericak-Vance M, Schmechel D, Roses AD. Isoform specific interaction of apolipoprotein E with microtubule associated protein tau: Implications for Alzheimer disease. Proc Natl Acad Sci U S A. 1994;91:11183–11186. doi: 10.1073/pnas.91.23.11183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Takata Y, Kikukawa M, Hanyu H, Koyama S, Shimizu S, Umahara T, Sakurai H, Iwamoto T, Ohyashiki K, Ohyashiki JH. Association between ApoE phenotypes and telomere erosion in Alzheimer's disease. J Gerontol A Biol Sci Med Sci. 2012;67:330–335. doi: 10.1093/gerona/glr185. [DOI] [PubMed] [Google Scholar]
  74. Tang MX, Stern Y, Marder K, Bell K, Gurland B, Lantigua R, Andrews H, Feng L, Tycko B, Mayeux R. The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans,Whites and Hispanics. JAMA. 1998;279:751–755. doi: 10.1001/jama.279.10.751. [DOI] [PubMed] [Google Scholar]
  75. Tanzi RE, Bertram L. New frontiers in Alzheimer's disease genetics. Neuron. 2001;32:181–184. doi: 10.1016/s0896-6273(01)00476-7. [DOI] [PubMed] [Google Scholar]
  76. Tilley L, Morgan K, Grainger J, Marsters P, Morgan L, Lowe J, Xuereb J, Wischik C, Harrington C, Kalsheker N. Evaluation of polymorphisms in the presenilin-1 gene and the butyrylcholinesterase gene as risk factors in sporadic Alzheimer's disease. Eur J Hum Genet. 1999;7:659–663. doi: 10.1038/sj.ejhg.5200351. [DOI] [PubMed] [Google Scholar]
  77. Trushina E, Nemutlu E, Zhang S, Christensen T, Camp J, Mesa J, Siddiqui A, Tamura Y, Sesaki H, Wengenack TM, et al. Defects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer's disease. PLoS One. 2012;7:e32737. doi: 10.1371/journal.pone.0032737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Tysoe C, Whittaker J, Cairns NJ, Atkinson PF, Harrington CR, Xuereb J, Wilcock G, Rubinsztein DC. Presenilin-1 intron 8 polymorphism is not associated with autopsy-confirmed late-onset Alzheimer's disease. Neurosci Lett. 1997;222:68–69. doi: 10.1016/s0304-3940(97)13339-0. [DOI] [PubMed] [Google Scholar]
  79. van Leeuwen FW, de Kleijn DP, van den Hurk HH, Neubauer A, Sonnemans MA, Sluijs JA, Köycü S, Ramdjielal RD, Salehi A, Martens GJ, et al. Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science. 1998;279:242–247. doi: 10.1126/science.279.5348.242. [DOI] [PubMed] [Google Scholar]
  80. Varvel NH, Bhaskar K, Patil AR, Pimplikar SW, Herrup K, Lamb BT. Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease. J Neurosci. 2008;28:10786–10793. doi: 10.1523/JNEUROSCI.2441-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Warren AC, Chakravarti A, Wong C, Slaugenhaupt SA, Halloran SL, Watkins PC, Metaxotou C, Antonarakis SE. Evidence for reduced recombination on the nondisjoined chromosomes 21 in Down syndrome. Science. 1987;237:652–654. doi: 10.1126/science.2955519. [DOI] [PubMed] [Google Scholar]
  82. Woo HN, Park JS, Gwon AR, Arumugam TV, Jo DG. Alzheimer's disease and Notch signaling. Biochem Biophys Res Commun. 2009;390:1093–1097. doi: 10.1016/j.bbrc.2009.10.093. [DOI] [PubMed] [Google Scholar]
  83. Wragg M, Hutton M, Talbot C. Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer's disease. Alzheimer's Disease Collaborative Group. Lancet. 1996;347:509–512. doi: 10.1016/s0140-6736(96)91140-x. [DOI] [PubMed] [Google Scholar]
  84. Yang Y, Geldmacher DS, Herrup K. DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci. 2001;21:2661–2668. doi: 10.1523/JNEUROSCI.21-08-02661.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Yang Y, Varvel NH, Lamb BT, Herrup K. Ectopic cell cycle events link human Alzheimer's disease and amyloid precursor protein transgenic mouse models. J Neurosci. 2006;26:775–784. doi: 10.1523/JNEUROSCI.3707-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Yang Y, Herrup K. Cell division in the CNS: Protective response or lethal event in post-mitotic neurons? Biochim Biophys Acta. 2007;1772:457–466. doi: 10.1016/j.bbadis.2006.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Yatham LN, McHale PA, Kinsella A. Down syndrome and its association with Alzheimer's disease. Acta Psychiatr Scand. 1988;77:38–41. doi: 10.1111/j.1600-0447.1988.tb05074.x. [DOI] [PubMed] [Google Scholar]
  88. Yoshimura N, Kubota S, Fukushima Y, Kudo H, Ishigaki H, Yoshida Y. Down's syndrome in middle age. Topographical distribution and immunoreactivity of brain lesions in an autopsied patient. Acta Pathol Jpn. 1990;40:735–743. [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1. - PSEN-1 genotypic and allelic frequencies in mothers of DS children.
Click here for additional data file. (229.9KB, pdf)
Table S2. - PSEN-1 genotypic and allelic frequencies in control mothers.
Click here for additional data file. (212.1KB, pdf)
Table S3. - APOE genotypic and allelic frequencies in mothers of DS children and control mothers.
Click here for additional data file. (227KB, pdf)

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