The effect of the C488&A Polymorphism of the CYP1A1 Gene on Cognitive Function

“The effect of the C488&A Polymorphism of the CYP1A1 Gene on Cognitive Function”
PI: R. Villareal MD

Project Overview
Alzheimer’s Disease (AD) is a devastating illness for which there is no cure possible at present. Although prevention seems to be the best strategy, the approach to preventing AD is not clear as the underlying mechanisms of the disease remain poorly understood. Several genetic factors have been linked to AD. However, despite the plethora of association studies, not one of these candidate genes has emerged as a single critical determinant of cognition, certainly not to the extent that would allow its use as a diagnostic tool, thus, the disease is still considered polygenic. One of the factors considered important in the preservation of cognitive function is estrogen sufficiency. This is inferred from observations of an increase in the prevalence of AD among postmenopausal women. On the other hand, not everyone develops AD and those who do, don’t develop AD at a particular time after menopause, suggesting that the rates of cognitive decline vary.

Estrogen is metabolized into metabolites of variable estrogenic activity, but for the most part into metabolites that have inferior estrogenic activity than the parent compound, estradiol. It is metabolized by enzymes belonging to the CYP450 enzyme system namely: CYP1A1, CYP1A2, CYP1B1 and CYP3A4. We believe that polymorphisms in any of these enzymes may result in differences in enzymatic activity among the variants resulting in variable accumulation of metabolites with different estrogenic activity and, thus, may account for varying rates of bone loss in the postmenopausal period. In fact, we have found that the C4887A polymorphism of the CYP1A1 gene, which results in an amino acid change from threonine to asparagine, is associated with an increase in estrogen catabolism and lower circulating free estradiol in those carrying the A allele, present in 19% of the population (1). This is associated with a lower bone mineral density (BMD) in those carrying the A allele, understandably so, as bone is a hormone-dependent tissue. Since cognition is also dependent on adequate levels of circulating estrogen and women with the A allele have accelerated estrogen catabolism, we speculate that these women are at an increased risk for accelerated cognitive deterioration from a relative hypoestrogenic state. The main aim of this pilot project is to evaluate the effect of the C4887A polymorphism on cognitive function as evaluated by psychometric methods. We anticipate that women with the A allele will have poor age-adjusted cognitive test scores compared to those without the A allele. Understanding the role of estrogen metabolism in cognition, as it is in bone health, will lead to early identification of women at risk for both AD and osteoporosis. The data generated from this project will be used to develop a full-scale proposal and test the long-term hypothesis that CYP gene polymorphism is a critical determinant of cognitive development, maintenance, and loss. This proposal is directly related to the mission of Longer Life Foundation as it focuses on studying factors (i.e. genetic determinants of cognitive function) that predict morbidity and mortality (i.e. development of AD) in the rapidly growing elderly population. If our hypothesis is proven that CYP gene polymorphism can identify a specific group of women at increased risk for development of AD (as we have observed with the risk for osteoporosis) it could lead to future interventions at preventing this common and devastating illness that currently has no cure.