Recent data have raised the intriguing possibility that sex steroids in brain modulate the pathological and clinical progression of Alzheimer's disease (AD) in men and women. The primary hypothesis of the proposed study is that levels of sex steroid hormones in brain regions affected by AD modify the relationship between indices of AD neuropathology and clinical expression of AD proximate to death. The goal of the study is to quantify brain tissue levels of sex steroid hormones and the sex steroid aromatizing enzyme cytochrome P450 aromatase in men and women enrolled in the Rush Religious Orders Study and determine their relationship to AD diagnosis, scores on tests of cognitive functioning measured proximate to death and indices of AD neuropathology in postmortem brain tissue. The study will quantify levels of testosterone, estradiol, androstenedione and estrone by high sensitivity radioimmunoassay and will quantify expression of cytochrome P450 aromatase using real-time RT-PCR in hippocampus, midfrontal cortex and cerebellum in men and women with and without AD. Data analyses will determine the relationship of each of the variables to clinical diagnosis of AD, to global cognitive function measured proximate to death and to global neuropathology, amyloid load and PHFtau. The proposed study will use innovative analyses to test the hypothesis that brain tissue levels of estradiol and aromatase modify the relationship between AD global pathology, amyloid load and PHF tau neurofibrillary tangles and diagnosis of AD proximate to death. Similar analyses will test the hypothesis that levels of estradiol and aromatase modify the relationship between AD global pathology, amyloid load and PHFtau neurofibrillary tangles and global cognitive 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 "Religious Orders Study of the Rush Alzheimer's Disease Center" [NIH P30AG010161] and "Risk Factors, Pathology and Clinical Expression of AD" [NIH R01AG15819]. The second strength is that the impact of the study is likely to be substantial as it is highly likely to yield a large amount of data that will quickly move the scientific field forward in an area of research that is of great public health importance. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a devastating health problem that may affect up to16 million older Americans by the year 2050. The goal of the study will be to determine the relationships between sex steroid hormone levels in the brain, cognitive impairment prior to death and Alzheimer's disease neuropathology in the Religious Orders Study of The Rush Alzheimer's Disease Center.