DESCRIPTION (provided by applicant): This is the first resubmission of renewal application to address new fundamental questions regarding the complex web of causes of cognitive decline. The Baltimore Memory Study is a multilevel longitudinal cohort study of the causes of cognitive decline in persons aged 50 to 70 years at enrollment. During Phase I we enrolled 1,140 subjects with diversity by sex, race/ethnicity, and SES and followed 943 (82.7%) of them to the third study visit an average (SD) of 2.5 (0.2) years later. Study subjects completed an extensive cognitive test battery at each of three study visits, and completed other health assessments and an extensive interview. We have a very broad set of measures of risk factors and potential causes, including lead in blood, patella, and tibia, blood mercury, serum PCBs, serum lipids and homocysteine, salivary cortisols across the study visit, detailed SES assessment, health-related habits (i.e., tobacco, alcohol, diet, physical activity), social networks, social support, and 10 genetic polymorphisms in 8 genes relevant to neurotoxicants, brain function, or stress. Finally, we developed a rigorous metric for assessment of the social environment in neighborhoods, termed the Neighborhood Psychosocial Hazards (NPH) scale, to evaluate how the neighborhood conditions can interact with other causes to impact cognitive function. In the first five years we have made a number of novel observations. These include that cumulative lead dose was associated with decrements in cognitive function and with amnestic mild cognitive impairment; NPH was associated with decrements in cognitive function; cortisol metrics that summarized four salivary cortisol measures across the study visit were associated with decrements in cognitive function (and this effect was worse among those with the APOE-e4 allele); NPH was associated with the cortisol metrics; and NPH modified relations of tibia lead with cognitive test scores. We now want to follow 800 subjects into Phase II, for two additional study visits over 32 months and new measures of vascular health (CRP, sICAM-1) and the HPA axis (six salivary cortisol measures). This will allow us to determine if the Phase I effects are persistent or progressive, and to examine relations among cognitive function, neurotoxicant exposures, the social environment, the HPA axis and "stress," vascular health, and aging, knowledge that will contribute to understanding etiology and mechanism and thus lead to public health and clinical interventions in the future.