Laboratory of Epidemiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island
Center, Columbia University College of Physicians and Surgeons, New York, USA
Correspondence: Nicole Schupf, PhD, New York State Institute for Basic Research, 1050 Forest Hill Road, Staten Island, NY 10314. Tel: 001 718 494 5301; Fax: 001 718 494 5395; e-mail: ns24{at}columbia.edu
Declaration of interest Grants IIRG-90-067 and RG3-96-077 from the Alzheimer's Association, Federal grants AG14673, HD35897, P50AG08702 and funds from New York State through its Office of Mental Retardation and Developmental Disabilities.
* Presented in part as the Blake Marsh Lecture at the Annual Meeting of the
Royal College of Psychiatrists, 6 July 2000, Edinburgh.
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ABSTRACT |
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Aims To identify factors which influence age at onset of dementia in Down's syndrome.
Method Studies of factors which influence formation of beta-amyloid (Aß) were reviewed, including atypical karyotypes, susceptibility genotypes, gender and oestrogen deficiency, and individual differences in Aß peptide levels.
Results The apolipoprotein E 4 allele, oestrogen deficiency
and high levels of Aß1-42 peptide are associated with earlier onset of
dementia, while atypical karyotypes and the apolipoprotein E
2 allele
are associated with reduced mortality and reduced risk of dementia.
Conclusions Factors which influence Aß levels, rather than overexpression of APP, may account for the differences in age at onset of dementia in Down's syndrome.
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INTRODUCTION |
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AMYLOID CASCADE HYPOTHESIS |
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Several lines of evidence suggest that deposition of Aß-42 is an important initial step in the pathogenesis of Alzheimer's disease. Aß1-42 aggregates more rapidly and is deposited earlier in Alzheimer's disease plaques than Aß1-40 (Iwatsubo et al, 1994). Mutations in the gene for APP and in presenilin (PS1/2) genes are associated with early-onset familial Alzheimer's disease and with a selective increase in Aß1-42 (Borchelt et al, 1996; Mann et al, 1996; Scheuner et al, 1996; Kosaka et al, 1997; Younkin, 1998). Brain levels of Aß1-42 increase early in the development of Alzheimer's disease and are strongly correlated with cognitive decline (Cummings & Cotman, 1995; Naslund et al, 2000), and plasma levels of Aß1-42 are higher in elderly people who subsequently develop Alzheimer's disease than in those who remain free of dementia (Mayeux et al, 1999).
Virtually all individuals with Down's syndrome have neuropathological changes consistent with a diagnosis of Alzheimer's disease by the time they reach 40 years of age, including deposition of Aß in diffuse and neuritic plaques (Wisniewski, H. et al, 1995; Mann, 1988), and most will develop dementia by the end of their seventh decade of life (Lai & Williams, 1989). Despite the nearly universal occurrence of Alzheimer's disease pathology by middle age, there is wide variation in age at onset of dementia. The prevalence of Alzheimer's disease at age 65 has ranged between 30% and 75% (Zigman et al, 1997). Most studies have shown that the average age at onset of dementia is between 50 and 55 years, with a range from 38 to 70 years (Lai & Williams, 1989; Prasher & Krishnan, 1993). Methodological problems may account for some of the variation in estimated prevalence of Alzheimer's disease in Down's syndrome. Diagnosis of Alzheimer's disease in this population requires both documentation of clinically significant decline in cognitive and adaptive competence from previously attained levels of performance and documentation of the absence of any other condition that might cause declines in performance (Aylward et al, 1997). Both these requirements are particularly difficult to address for adults with Down's syndrome, given their lifelong intellectual disability. The wide range of premorbid levels of performance associated with differences in level of intellectual disability requires specific criteria for clinically significant decline indicative of dementia for each level of function, and these are just beginning to be developed. There is, as yet, no consensus on a set of cognitive assessment tasks or on diagnostic criteria for existing cognitive assessment batteries that can differentiate adults with Down's syndrome who do and do not have dementia in its early stages. Presently, most diagnoses of Alzheimer's disease in adults with Down's syndrome are made clinically, at relatively late stages of the disease, without systematic cognitive or functional testing over time.
The neuropathological manifestations of Alzheimer's disease in Down's syndrome have been attributed to triplication and overexpression of the gene for APP located on chromosome 21 (Rumble et al, 1989) and the increased risk of dementia in Down's syndrome may be mediated by an increased substrate for cellular production of Aß peptides. Recent neuropathological studies have shown that diffuse plaques, the most prevalent Alzheimer-type lesion seen in individuals with Down's syndrome before age 50, are not associated with dementia. Diffuse plaques contain non-fibrillar amyloid, appear at younger ages than do neuritic plaques, are not associated with neuronal degeneration, and do not appear to affect the structure and function of neurons. In contrast, increases in the numbers of neuritic plaques, containing substantial amounts of fibrillised Aß peptides, are observed in adults with Down's syndrome predominantly after 50 years of age and are associated with neuronal degeneration and loss of function (Wisniewski, T. et al, 1995). Examination of the age-specific prevalence of dementia in Down's syndrome supports the hypothesis that the clinical manifestations of Alzheimer's disease in Down's syndrome are closely associated with the development of these fibrillised plaques (Lai & Williams, 1989; Visser et al, 1997; Holland et al, 1998; Lai et al, 1999) (see Fig. 1). Although prevalence studies have employed varying sampling and diagnostic methods, there is remarkable agreement across studies that risk of Alzheimer's disease increases primarily after 50 years of age. In addition, not all adults with Down's syndrome will develop dementia even if they reach ages when the presence of high densities of neuritic plaques can be presumed. Thus, while triplication of the gene for APP may serve to increase diffuse plaques in adults with Down's syndrome, factors distinct from APP triplication must account for individual differences in susceptibility to the formation of fibrillised plaques and for the wide range in age at onset of dementia. A central task of the epidemiology of dementia in Down's syndrome is to identify factors that may influence risk of Alzheimer's disease by accelerating formation of Aß. Several avenues of investigation are suggested by existing findings and I will review the role of (a) atypical karyotypes; (b) genetic susceptibility factors; (c) gender and oestrogen deficiency; and (d) individual differences in Aß peptide levels.
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ATYPICAL KARYOTYPES |
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GENETIC SUSCEPTIBILITY FACTORS |
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Polymorphisms in the gene for apolipoprotein E (APOE) have been
associated with risk for the more common late-onset Alzheimer's disease, that
is, with onset after 65 years of age. There are three common variants of the
gene for APOE, encoded for by three alleles, 2,
3 and
4. In numerous cross-sectional and casecontrol studies, patients
with Alzheimer's disease have been found to be significantly more likely than
their peers to have one or more copies of the APOE
4 allele
(Corder et al, 1993; Mayeux et al, 1993;
Saunders et al,
1993). The APOE
4 protein may act by increasing the
rate of the process which leads to Alzheimer's disease, predisposing to
greater accumulation of Aß in those with and without Alzheimer's disease
(Roses et al, 1994;
Hyman et al, 1995;
Polvikoski et al,
1995). The presence of the least common allele, APOE
2, has been associated with a delay in disease onset or even protection
by most investigators (Corder et
al, 1994; Roses et
al, 1994).
Apolipoprotein E in Down's syndrome
The relation of APOE genotype to risk of Alzheimer's disease in
Down's syndrome has been difficult to establish. All studies have consistently
found that the presence of the APOE 2 allele increases
longevity and reduces the risk of dementia but the role of the
4 allele
has been controversial (Hardy et
al, 1994; Royston et
al, 1994; Martins et
al, 1995; van Gool et
al, 1995; Cosgrave et
al, 1996; Lambert et
al, 1996; Schupf et
al, 1996; Prasher et
al, 1997; Schupf et
al, 1998; Sekijima et
al, 1998; Tyrrell et
al, 1998; Lai et
al, 1999; Rubinszstein
et al, 1999; Deb
et al, 2000). Small sample sizes and, importantly,
failure to consider differences in the age at onset of dementia among those
with and without an
4 allele may account for some of the negative
findings. Since the effect of the
4 allele is not expressed until
midlife, inclusion of sufficient numbers of adults over 50 years of age and
analysis using survival methods that can adjust for age and years of follow-up
are important methodological considerations. Our group used survival methods
for analysis and found that the presence of the
4 allele was associated
with earlier onset of dementia and greater decline in adaptive behaviour
(Schupf et al, 1996).
Compared with those with the APOE 3/3 genotype, adults with Down's
syndrome with an
4 allele were five times as likely to develop dementia
by age 65, while no one with an
2 allele developed dementia (see
Fig. 2). Among affected
individuals, mean age at onset of dementia was 53.3 years for those with the
4 allele and 58.0 years for those with the 3/3 genotype. Four other
studies found an increased frequency of the
4 allele in adults with
Down's syndrome and dementia compared with those with Down's syndrome without
dementia (Martins et al,
1995; Sekijima et al,
1998; Rubinsztein et
al, 1999; Deb et
al, 2000).
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The results of other studies of APOE genotype in adults with
Down's syndrome have been mixed. Several studies that found that the
APOE 2 allele decreased risk of dementia had sample sizes that
were too small to demonstrate a significant effect of the
4 allele
(Hardy et al, 1994;
Royston et al, 1994;
Wisniewski, T., et al,
1995). Two casecontrol studies of adults with Down's
syndrome compared allele frequencies in individuals with and without dementia
and found no significant association between APOE genotype and
Alzheimer's disease but did not adjust for age
(van Gool et al,
1995; Prasher et al,
1997). One large study examined 100 adults with Down's syndrome
(40-70 years of age) and used survival analyses to examine age at onset of
dementia by APOE genotype (Lai
et al, 1999). The cumulative incidence of dementia by age
65 was 55% for those with the APOE 2/3 genotype, 88% for those with
the APOE 3/3 genotype and 100% for those with any
4 allele. The
effect of the
4 allele was stronger at younger ages, consistent with
findings from studies in the general population that the effect of the
4
allele is to accelerate onset of Alzheimer's disease
(Corder et al, 1993;
Saunders et al, 1993;
Meyer et al, 1998).
Cumulative incidence to age 55 was 0.71 among those with an
4 allele and
0.40 among those with the APOE 3/3 genotype. The authors suggested
that the
4 effect in their study may have been attenuated by the high
rates of dementia at more advanced ages. They concluded that the effect of the
4 allele may be dependent on the age of the study sample.
These findings are consistent with reduced Aß deposition
(Polvikoski et al,
1995) and less plaque formation
(Benjamin et al, 1994; Lippa et al, 1994) in those with an 2 allele, and with
acceleration of Aß pathology in those with an
4 allele (Hymen
et al, 1995; Polvikoski et
al, 1995). The size of the
4 effect, the relation of
the presence of an
4 allele to early mortality and the interaction of
APOE genotype with other risk factors for dementia in Down's syndrome
such as gender and level of learning disability remain to be resolved. This
will require larger and older samples and analytic procedures which can
provide better adjustment for age and other potential confounders.
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GENDER AND OESTROGEN DEFICIENCY |
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In human studies, some, but not all, data show higher age-specific rates of Alzheimer's disease in women compared with men (Bachman et al, 1993) and approximately half the risk of Alzheimer's disease in women who have received oestrogen replacement therapy (Barrett-Conner & Kritz-Silverstein, 1993; Brenner et al, 1994; Henderson et al, 1994; Paganini-Hill & Henderson, 1994; Mortel & Meyer, 1995; Tang et al, 1996). Such findings support the hypothesis that oestrogen deficiency contributes to the aetiology of Alzheimer's disease. In contrast, randomised controlled clinical trials of oestrogen replacement therapy in women with moderate to severe Alzheimer's disease have failed to show cognitive improvement, suggesting that the major effect of oestrogen is to delay onset rather than reverse cognitive and functional decline (Henderson et al, 2000; Mulnard et al, 2000).
Gender differences and the effects of oestrogen in Down's syndrome have not
been systematically investigated and more work is needed to clarify how
hormonal risk factors may influence onset of dementia. Few studies have
presented results separately for men and women. Studies that have compared
women with men have found conflicting results, with different studies showing
earlier onset (Raghaven et al, 1994;
Lai et al, 1999),
later onset (Farrer et al,
1997; Schupf et al,
1998) or no difference in age at onset
(Visser et al, 1997;
Lai & Williams, 1989) by
gender. Two studies employed survival methods to examine age at onset
distributions by gender, adjusting for both age and level of learning
disability, and found conflicting results. My colleagues and I found that men
with Down's syndrome were three times as likely as women to develop
Alzheimer's disease by age 65 (see Fig.
3a); the effect of gender was observed in all age groups
over 50 years (Schupf et al,
1998). Both men and women with Down's syndrome show elevations of
follicle stimulating hormone (FSH) and luteinising hormone at puberty
indicative of primary gonadal dysfunction, which appear to progress with age
and be more frequent in men than in women
(Hasen et al, 1980; Campbell et al, 1982;
Hsiang et al, 1987;
Hestnes et al, 1991). Thus, older men may not benefit from the relative preservation of oestrogen
proposed to account for lower risk of Alzheimer's disease in men in the
general population. In contrast, another study found that women with Down's
syndrome were approximately twice as likely to develop dementia as men
(Lai et al, 1999)
(see Fig. 3b). In that
study, the effect of gender was seen primarily at younger ages. In both
studies, gender differences were largest in those with the APOE 3/3
genotype, suggesting that the high risk associated with the presence of the
APOE 4 allele can mask gender effects. The basis for the
different results in studies of gender differences is not clear.
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Only one published study has examined the influence of oestrogen deficiency on age at onset of dementia in women with Down's syndrome (Cosgrave et al, 1999). Menstrual profiles and risk of dementia in 143 women with Down's syndrome were studied. Twelve women were postmenopausal and diagnosed with dementia. There was a significant relationship between age at menopause and age at onset of dementia in this subsample (r=0.57). Although the sample size is small, the results are consistent with the hypothesis that higher endogenous oestrogen levels can lower risk of dementia by decreasing Aß peptide levels and maintaining cholinergic function in critical neuronal populations. If the association between age at menopause and onset of dementia can be confirmed and supporting hormonal data provided, oestrogen replacement therapy might prove to be an important intervention to delay onset of dementia.
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INDIVIDUAL DIFFERENCES IN Aß PEPTIDE LEVELS |
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DISCUSSION |
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication January 5, 2001. Revision received June 8, 2001. Accepted for publication June 13, 2001.