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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 ER alpha, with brain magnetic resonance imaging (MRI) (1.5 T MR unit). During a total of 35 405 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 PvuII nor the XbaI 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 PvuII 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.

Original publication




Journal article


Molecular psychiatry

Publication Date





1129 - 1135


Department of Epidemiology & Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.


Amygdala, Hippocampus, Humans, Dementia, Alzheimer Disease, Genetic Predisposition to Disease, Apolipoproteins E, Estrogen Receptor alpha, Magnetic Resonance Imaging, Organ Size, Risk Factors, Prospective Studies, Sex Factors, Polymorphism, Genetic, Aged, Middle Aged, European Continental Ancestry Group, Female, Male