Genetic and host factors for dementia in Down's syndrome

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 (Abeta) were reviewed, including atypical karyotypes, susceptibility genotypes, gender and oestrogen deficiency, and individual differences in Abeta peptide levels. Results The apolipoprotein E epsilon4 allele, oestrogen deficiency and high levels of AbetaI-42 peptide are associated with earlier onset of dementia, while atypical karyotypes and the apolipoprotein E epsilon2 allele are associated with reduced mortality and reduced risk of dementia. Conclusions Factors which influence Abeta levels, rather than overexpression of APP, may account for the differences in age at onset of dementia in Down's syndrome, 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 Off ice of Mental Retardation and Developmental Disabilities.