A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families

Context Genetic determinants of Alzheimer disease (AD) have not been compre hensively examined in Caribbean Hispanics, a population in the United State s in whom the frequency of AD is higher compared with non-Hispanic whites. Objective: Ta identify variant alleles in genes related to familial early-o nset AD among Caribbean Hispanics. Design and Setting Family-based case series conducted in 1998-2001 at an AD research center in New York, NY, and clinics in the Dominican Republic. Patients Among 206 Caribbean Hispanic families with 2 or more living member s with AD who were identified, 19 (9.2%) had at least 1 individual with ons et of AD before the age of 55 years. Main Outcome Measure The entire coding region of the presenilin 1 gene and exons 16 and 17 of the amyloid precursor protein gene were sequenced in pro bands from the 19 families and their living relatives. Results A G-to-C nucleotide change resulting in a glycine-alanine amino aci d substitution at codon 206 (Gly206Ala) in exon 7 of presenilin 1 was obser ved in 23 individuals from 8 (42%) of the 19 families. A Caribbean Hispanic individual with the Gly206Ala mutation and early-onset familial disease wa s also found by sequencing the corresponding genes of 319 unrelated individ uals in New York City. The Gly206Ala mutation was not found in public genet ic databases but was reported in 5 individuals from 4 Hispanic: families, w ith AD referred for genetic testing. None of the members of these families were related to one another, yet all carriers of the Gly206Ala mutation tes ted shared a variant allele at 2 nearby microsatellite polymorphisms, indic ating a common ancestor. No mutations were found in the amyloid precursor p rotein gene. Conclusions The Gly206Ala mutation was found in 8 of 19 unrelated Caribbean Hispanic families with early-onset familial AD. This genetic change may be a prevalent cause of early-onset familial AD in the Caribbean Hispanic pop ulation.