Project Overview:
Alzheimer’s disease (AD) is a devastating illness for which there is no cure 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.
Final Report:
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, 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 CYP450 group of enzymes namely: CYP1A1, CYP1A2, CYP1B1 and CYP3A4. A polymorphism of the CYP1A1 gene (i.e. the C4887A) has been found to be associated with increase estrogen catabolism in those carrying the A allele (found in 19%v of the population) resulting in lower bone mineral density in these individuals. Since, cognition is also dependent on adequate levels of circulating estrogen, we hypothesize carriers of the A allele will have poor age-adjusted cognitive test scores because of accelerated rate of estrogen catabolism and resulting relative hypoestrogenism. The main aim of this pilot project was to evaluate the effect of the C4887A polymorphism on cognitive function. Secondarily, we also evaluated if there is a correlation between bone mineral density (BMD) and cognitive test scores, both health issues being dependent on adequate circulating estrogen levels. Because of gender difference in the incidence of AD (i.e. the risk for women is higher than in men), this study was conducted in both sexes.
We enrolled 164 subjects, (114 postmenopausal women and 50 men > 50 years old) to undergo cognitive, bone mineral density and genetic testing. We found a positive correlation between the minimental status exam (MMSE) and BMD of the spine and femoral intertrochanter. A positive correlation was also found between test of verbal fluency and BMD of the spine, and total femur. Analyzing women separately from men showed a stronger correlation between BMD of the different skeletal sites and the MMSE and fluency among women than in men. Comparing cognitive test scores between the genotypes for the CYP1A1 C4887A polymorphism showed that women carriers of the A allele took a longer time to finish the task for Trail making test A compared to those without the A allele (CC=39.5±1.4 vs. CA+AA=46.97±3.6, p=0.05). There were no differences in the other cognitive test scores (such as MMSE, verbal fluency and Trail making test B) between the genotypes. There were also no differences in cognitive test scores between the genotypes among men.
In a small population sample, we found a correlation between BMD and tests of cognitive function, i.e., women with low BMD have poor cognitive performance and vice-versa. We also found that women carrying the A allele for the C4887A polymorphism performed poorly in one test of cognitive function suggesting that these women may not only be at risk for osteoporosis but for AD as well because of accelerated rate of estrogen catabolism. This association is weak and deserves further investigation in a larger sample size.
