Modification of estrogen's association with Alzheimer's disease risk by genetic polymorphisms

Contrasting effects of estrogen treatment on cognitive function and Alzheimer's disease (AD) risk have been reported. It may be that genetic factors modify these relations. In the present study, 696 participants from the Oxford Project to Investigate Memory and Ageing were included (355 AD cases, 341 controls). Those individuals with other types of dementia and those using hormone treatment had been excluded. Analyses controlled for body mass index, age at blood sampling, and education. Analyses of variance revealed main effects, but not an interaction, for apolipoprotein E (APOE) and Catechol-O-methyl transferase (COMT) genotypes on estradiol (E2) levels in men (p = 0.003 and p = 0.10, respectively), but not in women (p = 0.82 and p = 0.49, respectively). Men carrying the APOE ε4 allele had lower E2 levels, while those carrying the COMT Val/Val alleles had higher E2 levels compared to Met/Val (p < 0.05) allele carriers. Higher estrone (E1) levels and carrying the APOE ε4 allele (but not COMT alone, or in combination with the APOE genotype) were independent risk factors for AD. Similar to earlier studies, the heterozygous COMT genotype (Met/Val) showed a synergistic effect with the APOE ε4 allele being non-significantly associated with lower cognitive function. In conclusion, the present study suggests that elevated E1 levels significantly increase AD risk in both men and women. However, interactions between APOE ε4 and genetic polymorphisms related to sex steroid metabolism and AD risk need to be further investigated.

Research Highlights
► High estrone is a risk factor for AD in both men and women.
► Estradiol interacted with the APOE ε4 allele on cognitive performance which was positive in men but negative in women.
► COMT Val/Met heterozygotes who also carry an APOE ε4 allele may also be at risk for AD, but this needs further investigation.