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Correspondence |
Department of Psychiatry, University of Birmingham, Queen Elizabeth Psychiatric Hospital, Mindelsohn Way, Birmingham B15 2QZ
Research & Development Unit, South Birmingham Mental Health Trust, Birmingham
We read with interest the article by Deb et al (2000) apparently demonstrating findings contrary to our own (Prasher et al, 1997). Overall, we agree with the findings by Deb et al, although clarification on several important points is required.
The principle reason why we did not find a statistically significant
association (at the 5% significance level) between apolipo-protein E (ApoE)
4 and Alzheimer's disease in adults with Down's syndrome was because at
that time there was a much smaller sample size of adults with Down's syndrome
and dementia available for meta-analysis (102 subjects previously included
compared to 158 in Deb et al's report). The three additional reports
included in Deb et al's metaanalysis are of significantly la ger
samples. However, even with this greater number of subjects available for
meta-analysis the power remains at 76%. Given the proportions of 4 in
the groups with and without dementia in the Deb et al paper, for a
power of 90%, a minimum of 224 adults with Down's syndrome and dementia are
required to demonstrate statistical significance at the 5% level. Furthermore,
the 4 allele frequency in the different studies varies from 5.9% to
33.4% in subjects with dementia (Deb et
al, 2000) and therefore future studies are still required if
an association between ApoE 4 genotype and Alzheimer's disease in adults
with Down's syndrome is to be established.
Deb et al are incorrect to exclude the study by Wisniewski et
al (1995) because
"they diagnosed Alzheimer's disease on the basis of neuropathological
findings alone". Wisniewski et al
(1995) made a diagnosis of
dementia (not Alzheimer's disease) by a clinical assessment alone "as
judged by the physician following the patient". However, the inclusion
of this study in the present meta-analysis makes little difference to the
findings by Deb et al
(2000) as only one person with
an 4 allele was present.
The increase in risk of developing dementia in adults with Down's syndrome
(odds ratio 2.02) appears to be less than that in populations with no learning
disability where it can be increased by as much as 30 times for people with
two copies of the 4 allele (Swartz
et al, 1999). From the allele frequency given by Deb
et al (2000) the
diagnostic accuracy of ApoE 4 for adults with Down's syndrome and
dementia is of some clinical value. The sensitivity is 18% (95% CI 13.5-22%)
and specificity 90% (95% CI 88-92%). The absence of an 4 allele strongly
suggests the absence of Alzheimer's disease. ApoE genotyping in the Down's
syndrome population may possibly be used to screen for dementia.
We conclude, as previously (Prasher
et al, 1997), that the presence of an 4 allele is
neither sufficient nor necessary to cause Alzheimer's disease but ApoE 4
genotype does have a role to play in the presentation of Alzheimer's disease
in adults with Down's syndrome. The effect is, however,
‘overwhelmed’ by the excessive amyloidosis due to the triplication
of the amyloid precursor gene.
REFERENCES
Deb, S., Braganza, J., Norton, N., et al
(2000) APOE 4 influences the manifestation of
Alzheimer's disease in adults with Down's syndrome. British Journal
of Psychiatry, 17,
468-472.
Prasher, V. P., Chowdhury, T. A., Rowe, B. R., et al (1997) ApoE genotype and Alzheimer's disease in adults with Down's syndrome: meta-analysis. American Journal on Mental Retardation, 102, 103-110.
Swartz, R. H., Black, S. E., St George-Hyslop, P. (1999) Apolipoprotein E and Alzheimer's disease: a genetic molecular and neuroimaging review. Canadian Journal of Neurological Sciences, 26, 77-88.[Medline]
Wisniewski, T., Morelli, L., Wegiel, J., et al (1995) The influence of Apolipoprotein E isotypes on Alzheimer's disease pathology in 40 cases of Down's syndrome. Annals of Neurology, 37, 136-138.
Division of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN
We thank Drs Prasher & Haque for their interest in our paper and are pleased that they agree with our conclusions. It is quite obvious that the difference in findings in the meta-analysis between our study and Prasher et al's study was due to the inclusion of data in our study that were not available at the time of Prasher et al's study. According to our calculation, our meta-analysis has 92% power (95% CI 88-96%) at the 5% level. However, traditional power calculation is not applicable in this case because instead of simply adding allele frequencies among all studies, we have used the computerised version of the Woolf (1995) method of meta-analysis that takes account of each study individually. Also, because of the varied nature of studies included in the meta-analysis we did not feel it appropriate to calculate specificity and sensitivity in the traditional way.
It was not stated in Prasher et al's (1997) paper which 31
patients (15 with and 16 without dementia) out of 40 patients with Down's
syndrome, presented in Wisniewski et al's (1995) study, were included
in their meta-analysis. The age of death of patients reported in Wisniewski
et al's study ranged widely between 15 and 69 years. They mentioned
at the bottom of their table that "The presence of dementia is defined
as a deterioration of competence, as judged by the physician following the
patient". No detail about diagnosis was mentioned in the text and no
patient over age 30 had an 4 allele. For these reasons we chose not to
include this study in our meta-analysis. However, as Prasher & Haque point
out inclusion of this study would have made little difference to our
findings.
Whereas Prasher & Haque rightly suggest that further research is needed
to clarify the role of ApoE 4 in Alzheimer's disease in people with
Down's syndrome, we were surprised to see that they have recommended ApoE
genotyping as a possible screening test for dementia in this population. This
will be totally inappropriate at this stage considering the uncertain
relationship between Alzheimer's neuropathology and ApoE genotype in people
with Down's syndrome, as we mentioned in the last paragraph of the Discussion
in our paper.
We agree with Prasher & Haque that the presence of 4 allele is
neither necessary nor sufficient for the development of Alzheimer's
disease.
REFERENCES
Woolf, B. (1995) On estimating the relation between blood group and disease. Analysis of Human Genetics, 19, 251-253.
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