The role of estrogens in Alzheimer's disease (AD) is controversial. We investigated the association between well-recognized, and potentially functional, polymorphisms in the estrogen receptor (ER) alpha gene and the risk of AD in a prospective study of 6056 Caucasian older men and women aged 55 years and over. In a subset of 468 participants, we assessed volumes of the hippocampus and amygdala, which have a high density of ERalpha, with brain magnetic resonance imaging (MRI) (1.5 T MR unit). During a total of 35405 person-years of follow-up (mean per persons 5.8 years), 312 new cases of dementia were detected, of whom 230 were diagnosed with AD. Neither the Pvull nor the Xbal polymorphism or haplotypes thereof were associated with the risk of all-cause dementia or AD. In contrast, we found that nondemented women who carried the Pvull p allele or haplotype 'px' had smaller amygdalar volumes on MRI in an allele-dose-dependent fashion. Total amygdalar volume was 4.50 (SE 0.10) in PP genotype, 4.45 (SE 0.06) in Pp genotype, and 4.18 ml (SE 0.08) in pp genotype (P trend = 0.008). Further studies are required to investigate whether this smaller amygdalar volume has functional significance.
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