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Genetic and host factors for dementia in Down's syndrome^*

Laboratory of Epidemiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island

Gertrude H. Sergievsky

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.

Background The high risk for dementia in adults with Down's syndrome has been attributed to triplication and overexpression of the gene for amyloid precursor protein (APP). But the wide variation in age at onset must be due to other risk factors.

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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