Early Markers of Alzheimer's Disease: Structural and Functional Brain Changes

We are examining changes in brain structure and function as predictors of cognitive decline and impairment through longitudinal neuroimaging assessments of selected Baltimore Longitudinal Study of Aging (BLSA) participants. The hypothesis driving this study is that accelerated preclinical changes in brain structure and function in specific regions, including mesial temporal cortex, cingulate cortex, and inferior parietal cortex, will predict which individuals subsequently develop cognitive impairment and Alzheimer s disease. Since 1994, magnetic resonance imaging (MRI), positron emission tomography (PET), and neuropsychological testing have been performed for the neuroimaging participants, aged 55 and older. In the next phase of this study, we will continue longitudinal testing of older participants and will continue enrolling additional participants. We will continue MRI studies of brain structure, with enhanced measures of vascular changes, and will perform PET studies of cerebral blood flow, amyloid distribution in brain, and, in a subset of participants, cerebral glucose metabolism. We will also extend the MRI and neuropsychological evaluations to an additional 60 BLSA participants aged 20 to 54. Our initial data indicate substantial changes in brain volumes and tissue composition through the 5th evaluation, despite only minimal cognitive change in this generally healthy sample. We will continue to follow these individuals and will examine modifiers of both structural and functional brain changes and their associations with cognitive decline. Potential modulators include genetic factors, hormonal status and therapies, medications, dietary supplements, and other health-related factors. We have already observed acceleration of hippocampal volume loss in individuals at increased genetic risk for Alzheimer s disease, carriers of the apolipoprotein E epsilon 4 allele, and modulation of memory and regional cerebral blood flow activation patterns as a function of postmenopausal hormone therapy in women and endogenous testosterone concentrations in men. We will continue to examine these and other modifiers of brain-behavior associations. Early prediction of cognitive impairment and factors that alter the incidence or progression of disease will be essential as new therapies are on the horizon.