Association of the estrogen receptor alpha gene polymorphisms with sporadic Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial disorder determined by the int eraction of genetic, metabolic, and environmental factors. In the common la te-onset familial and sporadic forms of AD apolipoprotein E type 4 allele ( APOE-epsilon 4) is now widely accepted as a major risk factor. The associat ion of estrogen treatment with a reduction in the risk of AD together with the modulation by estrogen of the secretory metabolism of the amyloid precu rsor protein offers new possibilities for identification of other AD suscep tibility genes, as those encoding for the estrogen receptors (ERs). A total of 193 patients with sporadic late-onset AD, meeting the NINCDS-ADRDA crit eria, and a total of 202 control subjects, age and education matched, were included in this study. PvuII and XbaI ER alpha and HhaI APOE gene polymorp hisms were evaluated in genomic DNA by Polymerase Chain Reaction (PCR). The frequency of the various ER alpha genotypes by the combination of P, p and X, x was calculated for controls and AD patients stratified based on ApoE typing. When the two ER alpha gene polymorphisms were analyzed in combinati on, 7 genotypes were recognized, with a significantly increased prevalence of PPXX genotype in AD patients compared to controls (P = 0.0001). Risk of AD increased by a factor of 7.6 (CI [1.10-62.3]) in homozygous APOE-epsilon 4 individuals with PPXX ER alpha genotype. These results are consistent wi th a segregation of PPXX ER alpha genotype with a higher risk of developing late-onset sporadic AD in the Italian population. The ER alpha gene appear s to interact with the APOE-epsilon 4 genotype in determining AD susceptibi lity. (C) 1999 Academic Press.