Summary of work: The neuroanatomic and neurophysiologic underpinnings of age-associated cognitive and memory change remain unclear, as there are a limited number of studies of longitudinal brain changes in individuals without dementia. We are performing serial magnetic resonance imaging (MRI), positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change and cognitive impairment. These evaluations allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's Disease (AD). An understanding of these associations and early detection of brain changes will be critical in identifying individuals likely to benefit from new interventions. Since 2005, we also have acquired 11-C-PIB PET imaging studies of amyloid distribution in the brain to enhance the identification of preclinical AD. In addition, we are using neuroimaging tools to investigate modulators of cognitive and brain changes, including sex differences in brain aging, genetic risk factors and the effects of sex steroid and other hormones. We continue to perform serial MRI and PET scans for neuroimaging study participants of the Baltimore Longitudinal Study of Aging. Our longitudinal MRI investigations have demonstrated widespread tissue loss in non-demented older adults and accelerated tissue loss in specific brain regions in individuals with mild cognitive impairment (MCI). Using the 11-C-PIB PET scan data, we confirmed the experience at other centers that 20-30% of cognitively normal older adults have PIB positive scans, i.e., deposition of brain amyloid. Over the last year, we have shown that higher PiB retention is associated with longitudinal decline in mental status and verbal episodic memory in non-demented elderly but amyloid deposition is not associated with longitudinal change in brain volume measures after accounting for age effects. Recent findings from our group also have shown longitudinal increases in PiB retention in individuals with higher PiB retention at initial PiB assessment and both concordance and discordance between in vivo amyloid patterns and pathological ratings of amyloid plaques according to the CERAD classification for pathological diagnosis of AD. In addition to our findings on amyloid deposition, the BLSA Neuroimaging study has also reported different patterns of longitudinal change in regional cerebral blood flow in Apolipoprotein E e4 carriers;associations between clusterin and mesial temporal PiB binding;differences in frontal atrophy in relation to history of elevated depressive symptoms;and sex differences in the neural correlates of Opennesss to Experience. Approximately half of the neuroimaging study participants are enrolled in the BLSA autopsy program, and the integration of autopsy and imaging findings remains an active area of investigation to gain a better understanding of factors that promote cognitive resilience in individuals who have amyloid pathology but do not show memory impairment. BLSA studies have shown that individuals with AD pathology at autopsy but without antemortem cognitive impairment (Asymptomatic AD) have larger nuclei and nucleoli of the anterior and posterior cingulate and the hippocampus, suggesting either a compensatory or inflammatory process. Ongoing studies investigate the cellular basis of neuroimaging findings, including regional volume loss, to try to better define characteristics that accelerate cognitive impairment as well as those that support the maintenance of cognitive health.