Genetics of Down's syndrome and Alzheimer's disease

S. Shamas-Ud-Din

Arundel House, Smithdown Health Park, Merseycare NHS Trust, Smithdown Road, Liverpool L15 2LF, UK

In an extremely interesting article which touched upon early-onset dementia I feel that Dr Holmes (2002) failed to mention Down's syndrome as being a particular risk factor for the development of early-onset Alzheimer's disease because of triplication of the amyloid precursor gene. It is well known that almost all adults over the age of 40 years with Down's syndrome display Alzheimer's neuropathology (Mann, 1988) and the prevalence of dementia in people with Down's syndrome is 0-4% under the age of 30 years rising to 29-75% at 60-65 years of age, which falls under the category of early-onset Alzheimer's disease (Zigman et al, 1997). Studies have shown that the prevalence of Alzheimer's disease in those with learning disability, especially Down's syndrome, is higher than in those with no learning disability (Patel et al, 1993).

The occurrence of Alzheimer-like neuropathology in Down's syndrome suggests that the genetic defect for familial Alzheimer's disease might reside on chromosome 21, which was, therefore, the first of the 22 autosomes to be tested using a genetic linkage strategy (McGuffin et al, 1994).

Dr Holmes's article was published among papers with the overall topic of old age psychiatry; early-onset Alzheimer's disease tends to fall within the remit of old age psychiatry except in those with Down's syndrome, who remain within learning disability services. From all the information I have gathered on Alzheimer's disease I have assumed that the clearest evidence for a genetic contribution to the aetiology of Alzheimer's disease is its association with Down's syndrome, which surely deserves a mention when discussing this specific area.

EDITED BY KHALIDA ISMAIL

REFERENCES

Holmes, C. (2002) Genotype and phenotype in Alzheimer's disease. British Journal of Psychiatry, 180, 131-134.[Abstract/Free Full Text]

Mann, D. M. A. (1988) Alzheimer's disease and Down's syndrome. Histopathology, 13, 125-127.[Medline]

McGuffin, P., Owen, M. J., O'Donovan, M. C., et al (1994) Dementia. In Seminars in Psychiatric Genetics, pp. 192-206. London: Gaskell.

Patel, P., Goldberg, D. & Moss, S. (1993) Psychiatric morbidity in older people with moderate and severe learning disability. II: The prevalence study. British Journal of Psychiatry, 163, 481-491.[Abstract]

Zigman, W., Schupf, N., Haveman, M., et al (1997) The epidemiology of Alzheimer's disease in mental retardation: results and recommendations from an international conference. Journal of Intellectual Disability Research, 41, 76-80.[Medline]


 

Authors' reply

C. Holmes

Memory Assessment and Research Centre, West Hampshire NHS Trust, Moorgreen Hospital, Botley Road, West End, Southampton SO 30 3JB, UK

EDITED BY KHALIDA ISMAIL

I thank Dr Shamas-Ud-Din for showing interest in my paper and would have to concur with the general criticism that Down's syndrome should have been mentioned. I would like to say, in my defence, that the article was written within the remit of ‘advances in old age psychiatry’. A large number of old age psychiatric services see patients with Alzheimer's disease regardless of their age of onset and hence there was a need to cover some of the aspects of the genetics of early-onset Alzheimer's disease. However, I am unaware of any old age psychiatric service within the UK that routinely sees patients with Down's syndrome and Alzheimer's disease. This defence does not, however, excuse a restricted view that is damaging both to patient management and basic research.

Clearly, no patient should be excluded from expert dementia services because of their learning disability. In addition, there is much to learn about the genetic influences on the development of Alzheimer's disease in patients with Down's syndrome and on its clinical phenotype. Thus, as well as the effects of triplication of the amyloid precursor gene, the presence of the APOE{epsilon}4 allele also appears to be associated with an increased risk of developing Alzheimer's disease (Deb et al, 2000). The effect of the presence of the APOE{epsilon}4 allele on age of onset is still unclear but, unlike in those with no learning disability, the presence of APOE{epsilon}4 appears to be associated with an earlier age of death (Hardy et al, 1994). At post-mortem the brain lesions and cholinergic losses seen in individuals with Down's syndrome are the same as those seen in both early- and late-onset Alzheimer's disease. However, despite these neuropathological findings, the evidence for the beneficial effects of cholinesterase inhibitors in patients with Down's syndrome and Alzheimer's disease is still largely anecdotal (Kishani et al, 1999). It is clear that the two specialities, old age psychiatry and learning disabilities, have much to learn from each other.

REFERENCES

Deb, S., Braganza, J., Norton, N., et al (2000) APOE{epsilon}4 influences the manifestations of Alzheimer's disease in adults with Down's syndrome. British Journal of Psychiatry, 176, 468-472.[Abstract/Free Full Text]

Hardy, J., Crook, R., Perry, R., et al (1994) Apo E genotype and Down's syndrome. Lancet, 343, 979-980.[Medline]

Kishani, P., Sullivan, J., Walter, B., et al (1999) Cholinergic therapy for Down's syndrome (letter). Lancet, 353, 1064-1065.[CrossRef][Medline]





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