Abstract
CYP17
and
CYP19
are involved in the peripheral synthesis of estrogens, and polymorphisms in
CYP17
and
CYP19
have been associated with increased risk of estrogen-related disorders. Women with Down syndrome (DS) have early onset and high risk for Alzheimer’s disease (AD). We conducted a prospective community-based cohort study to examine the relationship between SNPs in
CYP17
and
CYP19
and cumulative incidence of AD, hormone levels and sex hormone binding globulin in women with DS. Two hundred and thirty-five women with DS, 31 to 67 years of age and nondemented at initial examination, were assessed for cognitive and functional abilities, behavioral/psychiatric conditions and health status at 14–20 month intervals over five assessment cycles. We genotyped these individuals for single-nucleotide polymorphisms (SNPs) in
CYP17
and
CYP19
. Four SNPs in
CYP17
were associated with a two and one half-fold increased risk of AD, independent of
APOE
genotype. Four SNPs in
CYP19
were associated with a two-fold increased risk of AD, although three were significant only in those without an
APOE
ε4 allele. Further, carrying high risk alleles in both
CYP17
and
CYP19
was associated with an almost four-fold increased risk of AD (OR=3.8, 95% CI, 1.6–9.5) and elevated sex hormone binding globulin in postmenopausal women. The main effect of the
CYP17
and
CYP19
variants was to decrease the age at onset. These findings suggest that genes contributing to estrogen bioavailability influence risk of AD in women with DS.