Recent data have raised the intriguing possibility that sex steroids in brain modulate the pathological andclinical progression of Alzheimer's disease (AD) in men and women. The primary hypothesis of the proposedstudy is that levels of sex steroid hormones in brain regions affected by AD modify the relationship betweenindices of AD neuropathology and clinical expression of AD proximate to death. The goal of the study is toquantify brain tissue levels of sex steroid hormones and the sex steroid aromatizing enzyme cytochrome P450aromatase in men and women enrolled in the Rush Religious Orders Study and determine their relationship toAD diagnosis, scores on tests of cognitive functioning measured proximate to death and indices of ADneuropathology in postmortem brain tissue. The study will quantify levels of testosterone, estradiol,androstenedione and estrone by high sensitivity radioimmunoassay and will quantify expression and proteinlevels of cytochrome P450 aromatase using real-time RT-PCR and western immunoblotting in hippocampus,midfrontal cortex and cerebellum in men and women with and without AD. Data analyses will determine therelationship of each of the variables to clinical diagnosis of AD, to global cognitive function measuredproximate to death and to global neuropathology, amyloid load and PHFtau. The proposed study will useinnovative analyses to test the hypothesis that brain tissue levels of estradiol and aromatase modify therelationship between AD global pathology, amyloid load and PHFtau neurofibrillary tangles and diagnosis ofAD proximate to death. Similar analyses will test the hypothesis that levels of estradiol and aromatase modifythe relationship between AD global pathology, amyloid load and PHFtau neurofibrillary tangles and globalcognitive function proximate to death. A primary strength of the project is that it utilizes clinical,neuropsychological, and neuropathological data and frozen brain tissue that are available from the `ReligiousOrders Study of the Rush Alzheimer's Disease Center [NIH P30AG010161] and Risk Factors, Pathology andClinical Expression of AD [NIH R01AG15819]. The second strength is that the impact of the study is likely tobe substantial as it is highly likely to yield a large amount of data that will quickly move the scientific fieldforward in an area of research that is of great public health importance. PROJECT NARRATIVEAlzheimer's disease is a devastating health problem that may affect up to16 million older Americans by theyear 2050. One factor that may contribute is a reduction in levels of estrogen in brain tissue ofpostmenopausal women. The proposed study will measure levels of estrogen and other sex steroidhormones in brain tissue of Catholic nuns, priests and brothers enrolled in the Rush Religious Orders Study.The goal of the study will be to determine the relationship between brain tissue hormone levels andcognitive impairment prior to death and Alzheimer's disease pathology detected at the time of autopsy.
| James, Bryan D; Leurgans, Sue E; Hebert, Liesi E et al. (2014) Contribution of Alzheimer disease to mortality in the United States. Neurology 82:1045-50 |
