DESCRIPTION (provided by applicant): This proposed project uses a multimodal cognitive and neuroimaging approach to examine early changes in semantic memory in preclinical AD (pcAD; defined as cognitively normal older adults with CSF pathology indicative of AD). The project has three main goals: (1) to test cognitive models of semantic memory in pcAD, (2) to examine functional brain response to semantic memory tasks in pcAD, and (3) to reveal neurovascular function in pcAD. To achieve these goals, we systematically test semantic memory in pcAD to determine whether difficulty with person-identification knowledge [e.g., Famous Faces (FF)] results from linguistic access difficulty consistent with the Retrieval Account or a category-specific deficit consistent with the Storage Account of AD. In the process, we investigate the influence of autobiographical significance and contrast historical vs. remote vs. recent FF knowledge to examine for a temporal gradient to reveal the contribution of episodic vs. semantic memory in person-identification knowledge in pcAD. We use the innovative calibrated fMRI technique to examine for group differences in the neural correlates of person-identification vs. object-identification semantic knowledge. Since calibrated fMRI provides a measure of the cerebral metabolic rate of oxygen consumption (CMRO2), we examine the relationship between resting and functional CBF, BOLD response, CMRO2, and CVD risk in pcAD to determine whether CMRO2, is less susceptible to cerebrovascular alteration than the fMRI BOLD response, consistent with the notion that CMRO2 is a better indicator of neural function. By integrating functional and perfusion brain markers with cognitive performance we thoroughly test models of neural recruitment as a compensatory mechanism in pcAD. Examination of the possible modulating effects of cerebrovascular disease risk (e.g., stroke risk, PP, WML burden) on cognition and brain function will bring us closer to a comprehensive biomarker model of pcAD to improve diagnostic acumen and prognostic sensitivity to the earliest cognitive and brain changes associated with incipient cognitive decline. Taken together, the project aims to identify cognitive and quantitative functional neurovascular brain biomarkers of cognitive decline in presymptomatic adults with AD neuropathology.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. By 2050, 14 million Americans are expected to have AD. Close to 40% of the patients served by the VA are elderly. Since age is the greatest risk factor for AD, the increasing incidence of AD in VA Systems will significantly impact the VA's mission. The long preclinical phase of AD provides a critical opportunity for potential intervention with disease-modifying treatment, if we can elucidate the link between the AD neuropathological process and emergence of the clinical syndrome. Delaying the onset of AD by 5 years would result in a 57% reduction in number of patients and reduce projected Medicare costs of AD by 283 billion dollars with substantial reduction in VA Healthcare costs as well. We integrate multimodal neuroimaging techniques with sensitive neuropsychological test procedures to reveal the association between AD neuropathology, cognition, and functional brain variables to identify predictors of cognitive decline and improve diagnostic acumen to guide early intervention.