Alzheimer's Disease and Down Syndrome: From Meiosis to Dementia

Experimental Neurology 158, 403–413 (1999) Article ID exnr.1999.7128, available online at http://www.idealibrary.com on

Alzheimer’s Disease and Down Syndrome: From Meiosis to Dementia Arturas Petronis1 Neurogenetics Section, Centre for Addiction and Mental Health, Clarke Division, 250 College Street, Toronto, Ontario M5T 1R8, Canada Received July 6, 1998; accepted May 8, 1999

Several molecular and clinical similarities have been detected in Alzheimer’s disease (AD) and Down syndrome (DS). The most remarkable feature is abnormal accumulation of ␤-amyloid in the brains of both individuals affected with AD and aging DS patients followed by dementia. In addition, AD patients exhibit dermatoglyphic patterns similar to those in DS, and late maternal age is a risk factor in both diseases. AD and DS could be related genetically because AD families exhibit a higher rate of DS cases and vice versa. Although numerous discoveries have been made in the elucidation of the etiopathogenic factors in AD and DS, little progress has been achieved in understanding the origin of the common features of the two diseases. This article reviews clinical and molecular similarities in DS and AD and also chromosome 21 studies in both diseases. A new hypothesis explaining the association between AD and DS is suggested, and this hypothesis is based on the poorly understood molecular phenomenon of aberrant meiotic recombination. Aberration in meiotic recombination has been consistently detected in chromosomal diseases including trisomy 21 and sex chromosomes. There are no studies dedicated to meiotic recombination in genetic diseases; however, evidence for disturbed recombination has been documented in several neurological diseases such as Huntington’s disease, myotonic dystrophy, and fragile X syndrome. Interestingly, the rate of trisomic XXY children born to mothers transmitting fragile X mutation is higher than expected. This finding suggests that AD could be associated with DS in a similar way to which fragile X syndrome is related to trisomy of sex chromosomes. Based on analogy with fragile X syndrome, it can be predicted that AD should demonstrate aberrant meiotic recombination in chromosome 21, most likely in the region D21S1/S11–D21S16 which is linked to early onset familial AD. Based on the same 1

To whom correspondence should be addressed. E-mail: [email protected]. 2 Abbreviations used: AD, Alzheimer’s disease; cM, centimorgan; FAD, familial Alzheimer’s disease; DS, Down syndrome; APP, gene for ␤-amyloid precursor protein; APP, ␤-amyloid precursor protein; PS1, gene for presenilin 1; PS2, gene for presenilin 2; ApoE, gene for apolipoprotein E4; HD, Huntington’s disease; DM, myotonic dystrophy; fraX, fragile X syndrome; SCA1, spinocerebellar ataxia 1.

rationale, different patterns of meiotic recombination in the nondisjunct chromosome 21 within DS patients grouped according to the concomitant disease are predicted. r 1999 Academic Press Key Words: Alzheimer’s disease; Down syndrome; chromosome 21; aberration of meiotic recombination; aging; genetic risk factors; epigenetics; complex genetic disease.

INTRODUCTION

Chromosomal aberrations have been of significant heuristic value in the detection of genes for human genetic diseases. Presence of a balanced translocation in an individual affected with a genetic disease suggests that illegitimate recombination between chromosomes may have disrupted the sequence of a disease gene. In the situations when this assumption is true, cloning of a disease does not require a genome scan and linkage analysis since the locus of a translocation points to the disease gene. Another group of chromosomal anomalies, the so-called chromosomal aneuploidies (numerical deviation from the diploid set of chromosomes in somatic cells or from haploid in the germline), have also been of some interest in understanding etiologies of genetic diseases. The higher rate of a genetic disease among the aneuploidic individuals in comparison to the general population suggests that a disease gene may be located on the nondiploid chromosome. Unlike translocations, however, aneuploidies do not pinpoint the location of a disease gene on a chromosome. An example of association between a chromosomal aneuploidy and a genetic disease is trisomy 21, or Down syndrome (DS),2 and Alzheimer’s disease (AD). DS and AD have demonstrated a number of common clinical and molecular features suggesting that chromosome 21 is a putative location of at least one of the genes for AD. Over the past decade numerous studies on chromosome 21 in AD and DS have been performed; however, little progress has been achieved in understanding why these two apparently different diseases have so much in common. In this article, an overview and current status of chromosome 21 studies which are relevant to the etiology of DS and AD is provided, and a

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0014-4886/99 $30.00 Copyright r 1999 by Academic Press All rights of reproduction in any form reserved.

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new interpretation which may lead to integration of clinical, pathological, and molecular similarities in DS and AD is suggested. EVIDENCE FOR CLINICAL AND GENETIC RELATIONSHIP BETWEEN ALZHEIMER’S DISEASE AND DOWN SYNDROME

The brain in AD has many structural and biochemical alterations, but the pathognomic neuropathological features are neurofibrillary tangles and senile plaques (16, 57). Neurofibrillary tangles are composed of paired helical filaments and degenerating neurites. The main component of senile plaques is ␤-amyloid (23, 24) which originates from a larger protein, amyloid precursor protein (APP) (40). Deposits of ␤-amyloid are thought to accumulate when the amount of ␤-amyloid is increased in the brain parenchyma as a result of either overexpression or altered processing of the APP. Very similar pathological findings including neurofibrillary tangles and senile plaques composed of abnormal neurites surrounding a core of ␤-amyloid have been detected in postmortem brains of trisomy 21 patients who live beyond the age of 40 years (11, 55, 60). This similarity of brain lesions suggested that pathogenic pathways of AD and DS may have some features in common and/or are even caused by the same predisposing gene or genes (60). A number of epidemiological studies supported the idea of shared etiopathogenic factors of dementia in DS and AD. Several groups have shown statistically significant excess of DS cases in AD families in comparison to control families. When compared with both a control group and the general population, there was an excess of DS among the relatives of AD patients (P ⫽ 0.002) (32). In another study, a threefold increase in the frequency of DS was observed among relatives of early age at onset (⬍70 years) AD probands (35). A large international EURODEM study has also shown an association between AD and DS, which was strongest in the patients with familial AD (P ⫽ 0.012) (98). In the follow-up of the EURODEM study, it was confirmed that for AD patients with a positive family history of dementia, the odds ratio for DS cases among the relatives was fourfold higher in comparison to sporadic cases of AD (99). Evidence for association between AD and DS was also detected in an Australian sample of AD patients and controls matched for age and sex (5). In several other studies a trend toward higher rate of DS in the families of AD was detected although it did not reach statistical significance (56, 72). Absence of a positive association could be explained by several reasons. In the Mendez et al. (56) study, the number of controls was rather small (n ⫽ 50), while the rate of DS in the control group was surprisingly high (2%), 12-fold higher than the generally accepted rate of 0.16% (84).

Other negative studies (1, 48, 58, 82) could be explained by a lack of power since the number of investigated individuals was small (see discussion in Ref. 67). Evidence for shared genetic susceptibility to DS and AD has also come from the opposite design where the risk for AD was investigated among the mothers of DS probands in comparison to mothers of control individuals (75). An increased risk of AD-type dementia among mothers of DS probands compared with control mothers was identified (risk ratio 2.6), and this finding supports the hypothesis of common genetic factors in DS and AD (75). In a study performed by Yatham et al. (110), 12 cases of Alzheimer’s dementia among the first and second degree relatives of 67 families of DS probands were found which was significantly higher than expected. A study by Berr et al. (2) did not detect an excess of dementia of AD type among the relatives of DS probands. This could have been due to fact that the risk for AD was investigated in the second and third degree relatives (grandparents and great grandparents) instead of parents (75) or other first plus second degree relatives (110). Further, older maternal age at the birth of a proband is known to be a significant risk factor in DS (17, 111) and is also likely to predispose to AD (69). The multinational EURODEM study showed that maternal age of 40 years and over is associated with a higher risk of AD (relative risk 1.7) (69). Although several limitations in the collection of data regarding maternal age were acknowledged, the collaborative study suggested that late maternal age should be further investigated as a possible risk factor for AD. In addition, three of the four EURODEM studies also suggested an increased risk for very young maternal age at index birth between 15 and 19 years (relative risk 1.5). It is interesting to note that evidence for a similar effect of very young mothers has been detected in DS. The risk of having a DS child for mothers of ages 15 years and less is significantly higher than in the maternal age group 20 to 25 years, approaching those for mothers of ages 30 up to 35 years (21). A series of studies have provided evidence that common genetic factors influence developmental processes in both DS and AD. The fingerprint dermatoglyphic patterns observed in AD patients correspond remarkably with the patterns observed in DS patients. The formation of epidermal ridge patterns occurs during fetal development, and once formed, the patterns do not change during life. Factors influencing the formation of dermal patterns are not clear although there is a strong genetic influence. It was demonstrated that AD patients, in a similar way to DS individuals, have an increased frequency of ulnar loops on the fingertips, Simian creases on the palms, palmar hypothenar patterns, and large distal loops in the hallucal region (107, 108). Other studies have also provided evidence support-

ALZHEIMER’S DISEASE AND DOWN SYNDROME: FROM MEIOSIS TO DEMENTIA

ing dermatoglyphic similarities between DS and AD, with a higher rate of bilateral Sydney lines in AD and DS patients in comparison to unaffected controls (59). Dermatoglyphic analyses have also suggested that only those with early onset AD had significantly more similarities to dermatoglyphic patterns in DS patients (3, 78) or that DS dermatoglyphic pattern is more common among AD females in comparison to males (52). In conclusion, a number of epidemiological and clinical findings have suggested that etiologies of DS and AD are related. These findings warrant the search for common genetic factor(s) for the two diseases. CHROMOSOME 21 STUDIES IN ALZHEIMER’S DISEASE AND DOWN SYNDROME

Alzheimer’s disease. Pathological similarities in the aging brain in AD and DS suggested that one of genetic risk factors for AD could be located on chromosome 21 (13). The saga of molecular genetic studies of AD started more than 10 years ago when linkage of familial AD (FAD) with D21S1/S11 and D21S16 was detected in four AD multiple families with a maximal lod score of ⫹4.25 (85). Approximately at the same time it was detected that the gene for ␤-amyloid precursor protein (APP) maps to 21q (28, 40, 94), and there was a good reason to believe that APP was one of the genes for AD. However, the studies of chromosome 21 in AD turned out to be far more complicated. The original finding of AD linkage to chromosome 21 was followed by quite controversial results. At least one study did detect evidence for AD linkage to chromosome 21 markers (25), although other studies were negative (62, 73, 96). In order to resolve the conflicting findings, the FAD collaborative study group undertook a study of 5 polymorphic chromosome 21 markers in a large unselected series of pedigrees with FAD (86). The results showed that early-onset (ⱕ65 years) AD families were linked to chromosome 21, whereas the late-onset (⬎65 years) AD has other causes. In the group of early onset AD families, the multipoint linkage analysis generated a maximal lod score of ⫹5.03 (affected pedigree member (APM) method, P ⬍ 0.0001), while linkage in late-onset families to chromosome 21 markers was excluded (APM, P ⫽ 0.34). Although age at onset-based division of AD families was of significant heuristic value, this rule is not universal. Not all early-onset AD families were linked to chromosome 21 (74, 86), as well as not all late onset were unlinked to chromosome 21 (33, 41). In addition to evidence for genetic locus heterogeneity, another confounding finding in linkage studies was the obligate recombinants between APP and the chromosome 21 AD locus in some of the putatively linked families. Presence of recombination events signifi-

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cantly reduced the probability that APP was an etiological gene for AD in these families (63, 91, 96, 97). Later, sequencing of APP exons in individuals affected with AD showed that mutations in APP were very rare (50, 90, 93), explaining only 1–3% familial AD cases (30). Finally, interest in chromosome 21 decreased significantly after linkage to chromosome 14 was detected in the families that initially seemed to be linked to chromosome 21 (87). Later two genes for early-onset familial AD, presenilin 1 (PS1) on chromosome 14 (81) and presenilin 2 (PS2) on chromosome 1 (47), were cloned. Despite the evidence for involvement of other genes in FAD, it is unlikely that the role of chromosome 21 in the etiology of AD is limited to several rare mutations in APP. The discrepancy arises from the rarity of mutations on the one hand and relatively strong evidence for linkage on the other. A meta-analysis of 94 FAD pedigrees consisting of more than 2000 individuals was performed for chromosome 19 and 21 markers using parametric and nonparametric linkage methods (22). Although FAD linkage results varied significantly depending on linkage parameters such as marker allele frequency and disease gene penetrance, evidence for linkage to chromosome 21 across studies was very similar to that for chromosome 19 (reviewed in Ref. 109). Now it is well known that chromosome 19 contains a gene for the apolipoprotein E4, an allele of which, ApoE ⑀4, is a common susceptibility allele for late-onset AD (71). The input of ApoE ⑀4 varies depending on numerous factors including family history of AD, ethnic background, sex, and age of the investigated population (18). A genetic risk factor to AD similar to ApoE ⑀4 may be located on chromosome 21. Down syndrome. Over the past decade much effort has been paid to the understanding of the causes of developing dementia in DS. The most straightforward explanation for dementia in DS is the presence of three instead of two copies of APP in DS individuals. This idea was supported by experimental findings of APP overexpression detected in various (4, 29, 61) although not in all (8) tissues from DS individuals. On the other hand, a number of findings remain unclear. Substantial variability in the ␤-amyloid deposition within the same age groups in DS patients was detected suggesting that other factors, besides trisomy 21, may be contributing to the timing and severity of ␤-amyloid deposition (46). In addition, although the presence of amyloid deposition is an absolute attribute of the senescent brain in DS, not all elderly trisomy 21 individuals develop AD-type dementia (20, 34, 39, 112) or develop it at a very old age for DS (⬎70 years) (100). According to other authors, clinical dementia in DS individuals is almost inevitable, with the average age of onset between 51 and 54 years (range ⬃39–69 years), although

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AD-type neuropathology is universally detectable in the brains of DS patients by age 35 years (36). These findings suggest that simple accumulation of ␤-amyloid is not enough to develop AD-type dementia. Studies on experimental animals have also confirmed that the presence of abundant amounts of amyloid in the brain is not sufficient to cause dementia. In transgenic models, despite the massive amyloidization of the brain and the formation of neuritic and diffuse plaques, neurons do not die (38). It is most likely that in addition to the higher degree of APP expression there are some other genetic or environmental factors that predispose to dementia in DS. At least one hereditary factor could be located on chromosome 21. In the study of 41 elderly DS patients (mean age 48.1 ⫾ 1.1 years), alleles at D21S11 demonstrated genetic association with cognitive decline in DS (19). No association was detected between dementia in DS and APOE and APP alleles. These findings are complementary with chromosome 21 linkage studies in AD as D21S11 but not APP demonstrated linkage in some early onset AD families (see above). Other molecular analyses of chromosome 21 in DS led to the finding of an aberrant pattern of meiotic recombination in DS patients. A significant overall reduction in meiotic recombination of the nondisjunct chromosome 21 was detected in a series of studies (45, 79, 80, 103). The total genetic length of the nondisjunct chromosome 21 female map, based on the meiosis I trisomy cases, was approximately one-half the length of the normal female map, varying between 30 and 40 cM, according to different studies, vs 72 cM, respectively (P ⬍ 0.001) (42, 80). The highest degree of recombination suppression was detected in the group of older (⬎31 years) mothers (on average 26 cM) in comparison to younger mothers (⬍31 years; 45 cM) (80). Although there was an overall suppression of meiotic recombination in meiosis I trisomy 21, according to some (80) but not all (42) studies, the telomeric region, D21S212 to D21S171, exhibited a sixfold increase in recombination in comparison to the reference genetic map (P ⫽ 0.05). In contrast to meiosis I, the map based on meiosis II trisomy was larger (88 cM in Ref. 80 and 105 cM in ref. 45) in comparison to the reference map. The increase in recombination was most notable in the pericentromeric part of chromosome 21, with a higher rate of recombination in the group of ‘‘older’’ mothers (⬎31 years at proband’s birth) in comparison to the group of ‘‘younger’’ mothers (⬍31 years at proband’s birth). Evidence for aberrant recombination has been detected in other trisomies as well. Trisomies of 16, 18, and the sex chromosomes have consistently shown reduced levels of meiotic recombination in the nondisjoined bivalent (reviewed in Ref. 42). The role of aberrant meiotic recombination in the origin of chromosomal aneuploidies is not clear. It has been hypoth-

esized that the position of a meiotic recombination event may predispose to nondisjunction of chromosomes (45). Specifically, maternal proximal chiasma configurations in chromosome 21 predispose to meiosis II nondisjunction, while distal exchanges increase the chance for meiosis I nondisjunction. THEORIES EXPLAINING THE ASSOCIATION BETWEEN DOWN SYNDROME AND ALZHEIMER’S DISEASE

Several theories have been suggested to explain the association between DS and AD. The majority of the models emphasize putative dysregulation of APP and/or hyperproduction of ␤-amyloid. This may occur under two main conditions: (i) germline or somatic increase of the number of genes for APP and (ii) influence of genetic and nongenetic factors on APP expression and processing of amyloid precursor protein. It is expected that both groups of factors lead to accumulation of ␤-amyloid in the brain. One of the first models suggested that trisomy of chromosome 21 results in both DS and dementia of AD type, while duplication of a small segment of chromosome 21 undetectable by cytogenetic methods leads to only AD (76). This hypothesis received some experimental support as three copies of APP in leukocyte DNA in each of three patients with sporadic AD were detected (14). However, numerous other attempts to replicate this finding failed with no evidence for duplication of chromosome 21 genes, including APP, detected in AD patients (65, 88, 92, 104). These findings suggest that small sized duplications of chromosome 21 in AD are very rare. Another disadvantage of this hypothesis is that the duplication model, although having the potential to explain neuropathological features observed in both DS and AD, cannot explain the genetic relationship between AD and DS, i.e., the excess of DS cases among the relatives of AD proband and vice versa. In another ‘‘gene dosage’’ model, it has been hypothesized that AD is caused by mitotic nondisjunction events that result in somatic cells being mosaic with normal and trisomic 21 cells (67). AD would occur by the same mechanism as in DS, and age of onset of dementia would be determined by how many cells in the brain were having trisomy 21. Additional support for this theory may come from the finding that presenilins are colocalized with kinetochores on the nucleoplasmic surface of the inner nuclear membrane (49). This observation suggests that presenilins may play a role in chromosome segregation, and mutant forms of presenilin may lead to chromosome missegregation during mitosis which results in trisomy 21 mosaicism. Although this is an interesting hypothesis, several technical and methodological difficulties may be envisaged. As neurons are thought to be mitotically inactive after birth, which tissue and cells should be responsible for

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accumulation of ␤-amyloid in AD and therefore investigated for AD-related aneuploidy in vivo? It also remains unclear why ␤-amyloid is mainly deposited in the brain in AD although it is produced in other tissues as well (77). If the effect of presenilins on chromosomal nondisjunction is proven, why is there no association between AD and other trisomies, e.g., chromosome 18 or 16? How can the selective action of presenilins on disjunction of chromosome 21 be explained? The second group of theories is based on the finding that AD-causing factors influence the processing of the amyloid precursor protein. Cell biology studies have shown that mutations in PS1 and PS2 as well as the ApoE ⑀4 allele are associated with increased ␤-amyloid load in AD brains by favoring the production of ‘‘long’’ ␤-amyloid, a form of the peptide with 42 rather than 40 residues, which are more prone to aggregate and form ␤-amyloid deposits in the brain (reviewed in Refs. 31, 77). These findings provide a clue in explaining common pathogenesis but not common genesis of DS and AD. A new hypothetical model for the common molecular mechanism leading to DS and AD has recently arisen from the observation that aberration of meiotic recombination is not limited to chromosomal trisomies but could be a feature of human genetic diseases. Evidence for such a local aberration of meiotic recombination in genetic disease is briefly reviewed in the next section, and the rationale to relate these findings to AD and DS is provided. ABERRATION OF MEIOTIC RECOMBINATION IN GENETIC DISEASES

In several diseases caused by trinucleotide repeat expansion, such as Huntington’s disease (HD) and myotonic dystrophy (DM), evidence for aberration of meiotic recombination at the disease locus was detected (64). For HD, three genetic maps for 4p16.3 markers have been evaluated, and these include: (i) the CEPH reference; (ii) non-HD meioses in the Venezuelan HD kindred; and (iii) HD meioses in the Venezuelan HD kindred (9, 53). The HD-based genetic map was consistently shorter for the markers around the HD locus in comparison to the CEPH and Venezuelan non-HD maps. The sex-averaged genetic distance between the HD gene flanking markers D4S10 and D4S90 is 5.9, 6, and 3 cM, for CEPH, non-HD, and HD maps, respectively, and the difference between the HD and non-HD genetic map was statistically significant (P ⬍ 0.005) (9). Evidence of aberrant meiotic recombination was also detected at the DM locus on 19q. According to CEPH reference family linkage data, female meioses exhibited a higher recombination fraction between the DM gene and the proximal marker ApoC2 when compared to male meioses (1.5 and 0.5 cM) (106). At least two

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independent DM multipoint linkage studies have shown recombination rate in DM males exceeds that in DM females: the distance ApoC2-DM was 0.1 and 2.2 cM (7), and the distance CKM-DM was 0.1 and 1.8 cM (44), for female and male meioses, respectively. Although support intervals for sex-specific recombination fractions were not specified, lod scores of around 20 in the pairwise linkage analyses for these markers were quite high, thus providing evidence that male/female recombination inversion is unlikely to occur by chance. In our recent yet unpublished reanalysis of Canadian DM families, a design used in the HD study was applied. Recombination rates at the DM gene (DM-PK) locus in DM meioses and non-DM meioses were investigated separately, and the proportion of recombinant to nonrecombinant meioses was counted in each group. Despite a relatively small number of informative meioses (245 meioses in the group of individuals affected with DM and 215 meioses in the group of unaffected individuals), it was detected that the rate of meiotic recombination is significantly lower in DM group in comparison to the non-DM group (P ⫽ 0.049). These findings are consistent with meiotic recombination study in HD. Deviation in meiotic recombination patterns may be suspected in other unstable DNA diseases as well, although it is difficult to make an unequivocal conclusion because no studies dedicated specifically to meiotic recombination around the disease loci have been performed. In a large data set of fragile X syndrome families, evidence for recombination heterogeneity at the fragile X locus was detected: some fragile X families showed significantly shorter genetic distance between F9 and the fragile X gene, while a subgroup of other fragile X families demonstrated evidence of increased recombination between F9 and the fragile X locus (6, reviewed in 83). In spinocerebellar ataxia 1 (SCA1), the genetic distance between the flanking markers, D6S88 and D6S89, was shorter in comparison to the CEPH families (reviewed in 64). Although support intervals for genetic distances in SCA1 chromosomes make the data compatible with those in the CEPH data set, there is a clear trend toward recombination suppression in SCA1 chromosomes. The studies of HD, DM, and other unstable DNA diseases suggest that aberration of meiotic recombination is not an exclusive attribute of chromosomal aneuploidies but may be present in human genetic diseases. At least two molecular factors can account for disturbed meiotic recombination in the unstable DNA diseases. It has been demonstrated that trinucleotide repeats have an effect on nucleosome formation and therefore chromatin conformation (26, 102) which may influence meiotic recombination. In addition, it has been shown that epigenetic DNA methylation of the trinucleotide repeats contributes to the functional organization of chromatin as well (26, 101). The two factors—trinucleotide repeat expansion and

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DNA methylation—may act on the recombination rate synergistically. Studies of V(D)J recombination in lymphocytes have shown that DNA methylation can affect recombination rates in the absence of trinucleotide repeat expansion (reviewed in Ref. 64). The idea to link genetic diseases with chromosomal trisomies, and specifically AD and DS, through the aberration in meiotic recombination came about from the observation that mothers—obligatory heterozygotes for the fragile X mutation—deliver children with trisomies of sex chromosomes more frequently than the rate in general population. Eight XXY children born to fragile X carrier mothers were identified, and this number is too high to be by chance assuming that the rate of XXY male in population is less than 1 in 1000 and the number of investigated fragile X pedigrees was about several hundred (83). In a similar way to trisomy 21, aberrant meiotic recombination was detected in nondisjunct X chromosome in female meioses, and the genetic length of X chromosome MI nondisjunction was 98.2 cM instead of 181.4 cM in the reference genetic map (54). This observation may become of critical importance to the further understanding of the origin of common features in AD and DS, as the association of fragile X and trisomy of sex chromosomes is very similar to that of AD and DS. As described above, AD families demonstrate a higher rate of trisomy 21 cases. If both carriers of the mutant gene for fragile X and carriers of nondisjunct chromosome X exhibit evidence for perturbed meiotic recombination (51, 54, 64), it could be expected that AD patients have a defect of meiotic recombination on chromosome 21 similar to that in DS patients. HYPOTHESIS 1: ABERRANT MEIOTIC RECOMBINATION IN CHROMOSOME 21 IN ALZHEIMER’S DISEASE AND OTHER DISEASES THAT COSEGREGATE WITH DOWN SYNDROME

Based on the rationale provided above, it can be hypothesized that meiotic recombination is aberrant in chromosome 21 in the patients affected with AD. Distortion of meiotic recombination is expected at D21S1/S11– D21S16, the region that showed evidence for linkage to familial AD (see Fig. 1). According to the linkage results, the strongest evidence for distortion of meiotic recombination is expected in the early-onset AD families. Analysis of families with sporadic cases of AD would be of significant interest because progress in understanding genetic predisposition to sporadic AD has been relatively slow. In addition to AD, the idea of aberrant meiotic recombination can be applied to numerous other complex genetic diseases which are associated with DS, such as congenital heart disease, anomalies of gastrointestinal tract, acute leukemia (43), depression (10,

FIG. 1. A hypothetical local suppression of meiotic recombination in AD at D21S16–D21S11. Normal female genetic map and meiosis I nondisjunction map in DS reproduced from Koehler et al. (42). Dark color represents the regions of aberrant meiotic recombination. Numbers on the left side of the reference chromosome indicate genetic length in centimorgans. APP is the gene for amyloid precursor protein. The lines connecting chromosomes correspond to the position of genetic markers.

105), and seizures (68, 70). In a similar way to AD linkage studies on chromosome 21, for some of these diseases evidence for genetic risk factors on chromosome 21 has been shown. 21q22.3 markers demonstrated linkage to bipolar affective disease (15, 89). Evidence for association between COL6A1 and congenital heart disease was detected when genotypes of DS patients with the disease were compared to those in DS patients without heart defects (12). Like in AD, the regions demonstrating evidence for linkage and/or association to a specific genetic disease may also demonstrate aberration of meiotic recombination in the meioses of affected individuals or obligate carriers. HYPOTHESIS 2: HETEROGENEITY FOR RATES OF MEIOTIC RECOMBINATION IN CHROMOSOME 21 IN THE SUBGROUPS OF DOWN SYNDROME

Consistent with the idea of disease-related variation of meiotic recombination, comparative analysis of DS patients with atrioventricular septal defect versus DS patients without such a defect showed that there is a difference between the groups for the rate of meiotic recombination in chromosome 21 (113). The DS group with atrioventricular defect exhibited a statistically significant decrease in the rate of meiotic recombination on chromosome 21 in comparison to the DS group

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without such a defect (P ⬍ 0.001) (113). Interestingly, when DS patients with various types of congenital heart disease (atrioventricular septal defect, tetralogy Fallot, isolated ventricular and atrial defects, mitral valve dysfunction) were not differentiated into subgroups and analyzed all together, no formal deviation from the normal recombination rate on chromosome 21 was detected (37). Taken together the two studies suggest that at least some of congenital heart diseases which are not atrioventricular septal defects may exhibit increased rate of meiotic recombination in chromosome 21 in DS. The above findings favor the idea that there could be some degree of molecular heterogeneity within DS which is reflected in various patterns of meiotic recombination of the nondisjunct chromosome 21 (see Fig. 2). Rates of crossovers and their distribution in nondisjunct 21 may be different in the group of DS with AD dementia in comparison to DS with acute leukemia or in comparison to DS with congenital heart disease. In a similar way, it can be predicted that DS patients with early AD (e.g., onset of dementia ⬍50 years) should exhibit a higher degree of aberration of meiotic recombination at D21S1/S11–D21S16 in comparison to late

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onset (⬎50 years) AD. With the exception of a few association studies in DS (12, 19), there has been no testable molecular explanation of why the clinical phenotypes of DS patients with full trisomy 21 are so different in terms of concomitant symptoms and syndromes. Analysis of patterns of meiotic recombination of nondisjoined chromosome 21 in various clinical subgroups of DS patients may help to dissect the complex clinical phenotype of DS. FINAL NOTES

An important advantage of the meiotic recombinationbased hypothesis of AD and DS is that it is relatively easy to test or, in Popper’s (66) terms, to falsify. For generation of genetic maps, DNA samples of AD and DS families and a set of microsatellite markers for chromosome 21 are required. At this stage of the project development it would be premature to guess about the exact molecular mechanism of how meiotic recombination is related to etiology of DS and AD. As a methodological note, however, it is the author’s belief that meiotic recombination is not causally involved in the etiology or pathogenesis of neither DS, nor AD, nor any of the above-discussed diseases. Meiotic recombination serves only as a reporter of the genetic and epigenetic status of a specific chromosomal region. The real culprit is a genetic or epigenetic defect, or a combination of the two, in a specific chromosomal locus that affects the process of meiotic recombination. If deviation from normal meiotic recombination is demonstrated in AD and other DS concomitant diseases as well as various subgroups of DS, the next experimental goal will be to identify the molecular substrate that disturbs meiotic recombination. It is expected that this molecular defect also (i) increases the risk to chromosomal nondisjunction and (ii) leads to dysfunction of some specific genes which play an etiological role in AD or other genetic diseases of the DS spectrum. Maternal age-dependent changes in meiotic recombination rates in chromosome 21 in both DS (80) and control meioses (95) suggest that the underlying molecular factor may vary in oocytes ovulated at a different maternal age. ACKNOWLEDGMENTS

FIG. 2. Putative heterogeneity of various DS subphenotypes: DS-AV, Down syndrome with atrioventricular defect; DS-AD, DS with early onset dementia; DS-D, DS with depression; DS-X, -Y, and -Z, other nonspecified concomitant conditions. Dark color indicates regions demonstrating aberration of meiotic recombination in comparison to the reference map. As in Fig.1, the reference (normal) female chromosome 21 map and Down syndrome chromosome 21 map (MI non-disjunction) was taken from Koehler et al. (42). Numbers 0–70 on the left side of reference chromosome 21 indicate genetic length in centimorgans.

I thank Drs. David Westaway and Peter St. George-Hyslop (University of Toronto, Ontario, Canada), Dr. Andrew Paterson (Centre for Addiction and Mental Health, Toronto, Ontario, Canada), and Dr. Andrew Collins (University of Southampton, United Kingdom) for their valuable comments and suggestions. This work was supported by the Ontario Mental Health Foundation and the National Alliance for Research in Schizophrenia and Depression.

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