Division of Psychological Medicine, University of Wales College of Medicine, Cardiff
Declaration of interest This study was partly funded by the Medical Research Council (grant no. 9810900).
Correspondence: Dr S. Deb, Division of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4xN. Tel: 01222 562323. Fax: 0122 555047. E-mail Deb{at}Cardiff.ac.uk
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ABSTRACT |
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Aims To assess the role of the APOE gene in the manifestation of Alzheimer's disease in adults with Down's syndrome.
Method We studied the APOE genotypes of 24 adults with dementia and 33 non-demented adults with Down's syndrome over 35 years of age, and an additional group of 164 non-learning disabled adults. We also carried out a meta-analysis of all previously published studies of association between APOE and Down's syndrome, incorporating the current data.
Results We observed a non-significant excess of APOE
4 and a reduction of
2 in adults with dementia compared with
non-demented adults with Down's syndrome in our sample. However, meta-analysis
showed a significantly higher frequency of
4 in adults with dementia
compared with non-demented adults with Down's syndrome (odds ratio=2.02, 95%
Cl 1.33-3.07, P=0.001), but no significant reduction in the frequency
of
2.
Conclusions The APOE 4 allele acts as a risk factor
for the age-specific manifestation of Alzheimer's disease in people with
Down's syndrome.
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INTRODUCTION |
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METHOD |
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The age of onset of dementia was determined by asking the carers of adults with Down's syndrome when clinical symptoms of dementia were first noticed. Diagnosis of Down's syndrome was based on the characteristic clinical features and no karyotyping was carried out. The level of intellectual disability was determined either on the basis of IQ scores or the assessment of adaptive behaviours.
We excluded adults with Down's syndrome who showed medical, psychiatric, neurological or laboratory characteristics not related to Alzheimer's disease, but which might explain their mental deterioration, in particular severe hearing loss, untreated hypothyroidism and depression (n=2). In all, 24 adults with Down's syndrome who had a diagnosis of Alzheimer's disease were included in this study. We ascertained a second group of 33 individuals, identified as the oldest adults from a list of non-demented adults with Down's syndrome. As the prevalence of dementia in adults with Down's syndrome tends to increase with age (Lai & Williams, 1989), it is anticipated that those who have lived longer without manifesting clinical dementia have least risk factors for developing dementia, and therefore provides an appropriate group for comparison. Finally, a control group of 164 non-demented adults representative of the local population and unselected for intelligence were used (54% male, mean age 38.27 years, s.d.=12.16 years).
Genotyping
Both the adults with dementia and the non-demented adults with Down's
syndrome, and the non-demented, non-learning disabled control group were
genotyped for both the APOE and PS-1 polymorphisms using
standard techniques (Wenham et
al, 1991; Wragg et
al, 1996). For a detailed description of PS-1 data
see Deb et al (1998),
but data in relation to a multivariate analysis of risk factors in relation to
Alzheimer's disease in Down's syndrome will be presented in this paper. The
study was performed with the approval of the local research ethics committee
and written, informed consent was obtained from participants or carers where
appropriate.
Statistical analysis
The 2 and Fisher's exact tests were used to test for
association between APOE and Alzheimer's disease in Down's syndrome.
Multiple logistic regression analysis was also carried out to estimate the
relative influence of risk factors such as age, gender, APOE and
PS-1 genotype on the development of Alzheimer's disease in adults
with Down's syndrome. The Woolf method
(Woolf, 1955) was used to
perform a meta-analysis of association between APOE genotype and
Alzheimer's disease in Down's syndrome. A Mann-Whitney U-test was
used to test for a relationship between APOE and the age of onset of
Alzheimer's disease in Down's syndrome. A probability of less than one in 20
(P<0.05) was regarded as significant in all statistical
analyses.
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RESULTS |
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The distribution of APOE alleles among the three study groups is
shown in Table 1, while the
distribution of APOE genotypes is presented in
Table 2. No statistically
significant differences were observed in any of the inter-group comparisons
shown in Table 1 and
Table 2. However, a higher
frequency of 4 allele (17% v. 9%;
2=1.4,
P=0.2) and a lower frequency of
2 allele (0% v. 4.5%)
(P=0.26: Fisher's exact test) were observed among adults with Down's
syndrome with dementia compared with those without (see
Table 1).
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Adults with Down's syndrome were divided up into two age groups (below 50
years, and 50 years and older), and two gender groups (male and female). This
was done because of Sekijama et al's
(1998) finding that the
frequency of 4 allele in Down's syndrome adults with Alzheimer's disease
under 50 years was significantly higher (28.6%), and Schupf et al's
(1998) finding of earlier
onset of Alzheimer's disease in men with Down's syndrome. The APOE
4 allele frequency between the adults with dementia and the non-demented
adults with Down's syndrome according to the age- and gender-groups are
presented in Table 3. None of
the inter-group comparisons in Table
3 was statistically significant.
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A multiple logistic regression analysis was carried out in the whole cohort of adults with Down's syndrome using the presence of dementia as a dependent variable and age, gender, APOE status, and PS-1 polymorphism as convariates. The presence of dementia was only significantly related to age in adults with Down's syndrome.
To assess the influence of APOE 4 on the age of onset of
dementia in adults with Down's syndrome we compared the mean age of onset
between those who had an
4 allele and those who did not. The mean age of
onset of dementia among
4 positive cases (at least one
4 allele)
was 51 years and 53 years for those who did not have an
4 allele. A
comparison of ages of onset in those with and without an
4 allele was
not statistically significant.
Meta-analysis
Prasher et al
(1997) presented a
meta-analysis of the data collected from all the known published papers in
addition to their own data in relation to APOE status in adults with
Down's syndrome with and without Alzheimer's disease. We have added data from
two other recent studies (Sekijama et
al, 1998; Tyrell et
al, 1998), and our current study to those analysed by Prasher
et al (1997) and this
is presented in Table 4.
However, we excluded Wisniewski et al's
(1995) data, which were
included in Prasher et al's
(1997) meta-analysis, because
unlike all the other studies they diagnosed Alzheimer's disease on the basis
of neuropathological findings alone in the absence of any clinical data. The
previous meta-analysis (Prasher et
al, 1997) did not show a statistically significant difference
in the distribution of APOE alleles between the adults with dementia
and Down's syndrome and the non-demented adults with Down's syndrome. However,
the meta-analysis in the current study showed a statistically significant
excess of APOE 4 in Down's syndrome cases with Alzheimer's
disease compared with those without (odds ratio=2.02, 95% CI 1.33-3.07,
2=10.83, P=0.001) with no evidence of heterogeneity
(P=0.2). We did not observe a significantly lower rate of
APOE
2 allele frequency in Down's syndrome adults with
Alzheimer's disease (odds ratio=0.69, 95% CI 0.35-1.37). The odds ratios along
with 95% CIs of those individual studies where a statistically significant
excess of APOE
4 or reduction of
2 allele frequency was
observed among adults with Down's syndrome with Alzheimer's disease are
presented at the bottom of Table
4.
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DISCUSSION |
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Meta-analysis
To increase the possibility of detecting small effect sizes, we collated
data from all known published studies of association between APOE
status in Down's syndrome and Alzheimer's disease. This was the method
employed recently by Prasher et al
(1997) that showed no evidence
to support an involvement of APOE. However, the meta-analysis
reported here, showed a statistically significant excess of the APOE
4 allele among the subjects with dementia when compared with the
non-demented group of adults with Down's syndrome. However, we did not observe
a significant reduction of APOE
2 alleles among the adults with
dementia and Down's syndrome.
Certain factors may have influenced the outcome of the meta-analysis in the current study as well as in Prasher et al's (1997) study. It is likely that the age difference in the cohorts used in the previous studies (Table 4) is a factor that may have introduced errors into the results of meta-analysis. The age range of subjects included in these studies varied, in that some used age 18 whereas others used age 35, 40 and 50 respectively as the minimum age for inclusion in the study. If APOE is responsible for earlier age of onset of Alzheimer's disease, this differential rate of age range among the different cohorts will make the interpretation of meta-analysis difficult. The lack of appropriately matched control group is another likely source of bias. Only the current study, Tyrell et al's (1998) study and van Gool et al's (1995) study matched the dementia group with the non-dementia group. Prasher et al's (1997) study while not originally matched demonstrated no statistically significant difference between the two groups in the age and the gender distribution. The cohort size is also a likely source of error. Apart from the current study, only two other studies (see Table 4) included 20 or more adults with dementia in their cohort. Another source of error is the use of different diagnostic criteria for defining dementia in different studies. Some used formal tools like the DMR scale (Evenhuis, 1992) and Adaptive Behaviour Scale (Nihira et al, 1974), whereas others made their diagnosis on the basis of clinical findings alone.
Age of onset of Alzheimer's disease
In the current study, a regression analysis unequivocally showed an
influence of ageing on the occurrence of Alzheimer's disease in adults with
Down's syndrome. Age is a well-known risk factor for the development of
Alzheimer's disease in both the general population and in the adults with
Down's syndrome. This effect seems more pronounced among the adults with
Down's syndrome. Some have suggested that age of death among adults with
Down's syndrome is influenced by the APOE status. In Hardy et
al's (1994) autopsy study,
the Down's syndrome cases showing Alzheimer's disease neuropathology and who
had an APOE 4 (n=10) allele, tended to die at a
younger age (age of death ranged between 48 and 60 years, mean 54, s.d.=6)
than those who had an
2 allele (n=2) (age of death 69 and 76
years respectively). A similar trend was also reported by both Royston et
al (1994) and Mann et
al (1995) based on their
small cohort studies. Some suggested that APOE status also influences
the age of onset of Alzheimer's disease in the general population
(Corder et al, 1993).
However, the findings of the current study do not suggest such trend among
cases of Down's syndrome. Considering the small cohort size included for the
analysis of age of onset data in the current study, a Type II error is likely
to influence the out-come. As early symptoms of Alzheimer's disease could be
difficult to detect in adults with Down's syndrome, it is difficult to be
precise about the exact age of onset of Alzheimer's disease in this
cohort.
The frequency of APOE 4 allele distribution among the adults
with dementia and Down's syndrome in different studies mentioned in
Table 4 varied between 12.5%
and 33.4%, apart from Prasher et al's
(1997) study, which showed a
much lower (5.9%) frequency than that expected in the general population. In
contrast, the frequency of APOE
2 alleles varied widely between
0% in the current study, and that of Schupf et al's
(1996) and Tyrell et
al's (1998), to the 11.8%
observed in Prasher et al's
(1997) study, which is higher
than expected even for the general population. The frequency of
2 allele
among the non-demented subjects with Down's syndrome was on average much
higher than that expected in the general population, with a wide range between
2.3% in Sekijima et al's
(1998) study and 50% in
Royston et al's
(1994) study. Overall these
data are indicative of APOE
4 being a risk factor for the
manifestation of Alzheimer's disease in adults with Down's syndrome.
APOE 4 and Alzheimer's disease neuropathology in
Down's syndrome
The findings of autopsy studies of patients with Down's syndrome, however,
show a somewhat unclear relationship between APOE 4 and
Alzheimer's disease neuropathology in this population. For example, in
Wisniewski et al's
(1995) autopsy study of brains
of 40 subjects with Down's syndrome (of whom 15 showed Alzheimer's disease
neuropathology), only one 21-year-old subject had an APOE
4
allele (
3
4 genotype) and his brain did not show the Alzheimer's
disease neuropathology. In Mann et al's
(1995) study of 20 brains of
subjects with Down's syndrome, all of whom showed Alzheimer's disease
neuropathology, only 35% (n=7) had APOE
4 allele (one
with
2
4 and six with
3
4). Similarly, in Hardy et
al's (1994) series of 22
autopsy brains of subjects with Down's syndrome, all of whom showed
Alzheimer's disease neuropathology, 45% (n=10) had APOE
4 (all with
3
4 allele). Further research is needed to
clarify this apparent discrepancy perhaps by using immunoneuropathological
techniques. It is also important to explore the exact mechanism by which
APOE
4 may influence the clinical manifestation of Alzheimer's
disease in Down's syndrome subjects. However, it is well known that despite
the increased risk associated with the
4 allele, the presence of
4
is neither necessary nor sufficient for the development of Alzheimer's disease
(Blacker & Tanzi,
1998).
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Blacker, D. & Tanzi, R. E. (1998) The
genetics of Alzheimer's disease. Archives of
Neurology, 55,
294-296.
Corder, E. H., Saunders, A. M., Strittmater, W. J., et al (1993) Gene dose of apolipoprotein E-type 4 allele and the risk of Alzheimer's disease in late onset families. Science, 261, 921-92.[Medline]
Deb, S., de Silva, P. N., Gemmell, H. G., et al (1992) Alzheimer's disease in adults with Down's syndrome: the relationship between regional cerebral blood flow deficits and dementia. Acta Psychiatrica Scandinavica, 86, 340-345.[Medline]
Deb, S., Braganza, J., Owen, M., et al (1998) No significant association between a PS-I intronic polymorphism and dementia in Down's syndrome. Alzheimer's Report, 1, 365-368.
Deb, S., & Braganza, J. (1999) Comparison of rating scales for the diagnosis of dementia in adults with Down's syndrome. Journal of Intellectual Disability Research, 43, 400-407.[CrossRef][Medline]
Evenhuis, H. M. (1992) Evaluation of a screening instrument for dementia in aging mentally retarded persons. Journal of Intellectual Disability Research, 36, 337-347.[Medline]
Gedye, A. (1995) Dementia Scale for Down Syndrome Manual. Vancouver: Gedye Research and Consulting.
Hardy, J., Crook, R., Perry, R., et al (1994) Apo E genotype and Down's syndrome. Lancet, 343, 979-980.[Medline]
Kehoe, P., Williams, J., Holmans, P., et al (1996) Association between a PS-I intronic polymorphism and late onset Alzheimer's disease. Neuroreport, 7, 2155-2158.[Medline]
Lai, F. & Williams, R. S. (1989) A prospective study of Alzheimer's disease in Down syndrome. Archives of Neurology, 46, 849-853.[Abstract]
Lambert, J. C., Perez-Tur, J., Dupire, M. J., et al (1996) Analysis of APOE alleles impact in Down's syndrome. Neuroscience Letters, 200, 57-60.[CrossRef]
Mann, D. M. A. (1988) Alzheimer's disease and Down's syndrome. Histopathology, 13, 125-137.[Medline]
Mann, D. M. A., Pickering-Brown, S. M., Siddons, M. A., et al (1995) The extent of amyloid deposition in brain in patients with Down's syndrome does not depend upon the apolipoprotein E genotype. Neuroscience Letters, 196, 105-108.[CrossRef][Medline]
Martins, R. N., Clarnette, R., Fisher, C., et al (1995) ApoE genotypes in Australia: Roles in early and late onset Alzheimer's disease and Down's syndrome. Neuroreport, 6, 1513-1516.[Medline]
Nihira, K., Foster, R., Shellhaas, M., et al (1974) Adaptive Behavior Scale. Washington, DC: American Association on Mental Retardation.
Prasher, V. P., Chowdhury, T. A., Rowe, B. R., et al (1997) APOE genotype and Alzheimer's disease in adults with down syndrome: meta-analysis. American Journal on Mental Retardation, 102, 103-110.[Medline]
Royston, M. C., Mann, D., Pickering-Brown, S. M., et al
(1994) Apolipoprotein in E 2 allele promotes longevity
and protects patients with Down syndrome from dementia.
Neuroreport, 5,
2583-2585.[Medline]
Saunders, A. M., Strittmater, W. J., Schmechel, D., et
al (1993) Association of apolipoprotein E allele 4
with late-onset familial and sporadic Alzheimer's disease.
Neurology, 43,
1467-1472.[Abstract]
Sekijima, Y., Ideda, S., Tokuda, T., et al (1998) Prevalence of dementia of Alzheimer type and apolipoprotein E phenotypes in aged patients with Down's syndrome. European Neurology, 39, 234-237.[Medline]
Schupf, N., Kapell, D., Lee, J. E., et al
(1996) Onset of dementia is associated with apolipoprotein E
4. Archives of Neurology,
40,
799-801.
Schupf, N., Kapell, D., Nightingale, B., et al (1998) Earlier onset of Alzheimer's disease in men with Down syndrome. Neurology, 50, 991-995.[Abstract]
Tyrell, J., Cosgrave, M., Hawi, Z., et al
(1998) A protective effect of apolipoprotein E 2 allele
on dementia in Down's syndrome. Biological Psychiatry,
43,
397-400.[CrossRef][Medline]
van Gool, W. A., Evenhuis, H. M. & van Duijin, C. M. (1995) A case-controlled study of apolipoprotein E genotypes in Alzheimer's disease associated with Down's syndrome. Annals of Neurology, 38, 225-230.[Medline]
Wenham, P. R., Price, W. H. & Blundell, G. (1991) Apolipoprotein E genotyping by one-stage PCR. Lancet, 337, 1158-1159.[Medline]
Wisniewski, T., Morelli, L., Wegiel, J., et al (1995) The influence of apolipoprotein E isotopes on Alzheimer's disease pathology in 40 cases of Down's syndrome. Annals of Neurology, 37, 136-138.
Woolf, B. (1955) On estimating the relation between blood group and disease. Annals of Human Genetics, 19, 251-253.
World Health Organization (1992) The Tenth Revision of the International Classification of Diseases and Related Disorders (ICD-10). Geneva: WHO.
Wragg, M., Hutton, M. & Talbot, C. (1996) Genetic association between intronic polymorphism in presenilin-I gene and late-onset Alzheimer's disease. Lancet, 347, 509-512.[Medline]
Received for publication June 15, 1999. Revision received September 29, 1999. Accepted for publication October 1, 1999.