Cerebral hemodynamic impairment in symptomatic and asymptomatic Alzheimer's Disease

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Abstract Alzheimer's Disease (AD) is rapidly becoming an overwhelming economic and social burden. It is estimated that 13.8 million Americans will have AD in 2050 and the total annual payments for health, long-term, and hospice care for AD and other dementias will increase to $1.2 trillion in 2050. Despite the important role of cerebrovascular function in AD, studies on cerebrovascular impairment in the asymptomatic phase of AD are lacking. The proposed project directly addresses this important scientific area by using advanced MR imaging techniques to study biomarkers of cerebrovascular function in AD subjects both before and after the manifestation of clinical symptoms. The overarching goal of the proposed project is to study whether AD pathology directly interacts with cerebrovascular pathology in the early phases of the AD continuum, as well as the relative contributions of cerebrovascular and AD pathologies to cognitive impairments in early AD. (1) We will use an advanced MR technique for measuring cerebrovascular reactivity (CVR) as a biomarker of vascular function and study CVR in 264 subjects composed of four groups including healthy young and middle-aged subjects (HY), cognitive normal elderly without AD pathology (CN-), asymptomatic AD subjects who are cognitively normal with positive AD pathology (aAD), and prodromal AD patients who are symptomatic with mild cognitive impairment and have positive AD pathology (pAD). Longitudinal changes in CVR over two years in CN-, aAD, and pAD subjects will also be studied. (2) We will also study differences in the white matter hyperintensity volume and advanced diffusion metrics between the CN-, aAD, and pAD groups, their longitudinal changes and relationship with CVR. (3) The relative contributions of AD and vascular pathologies to cognitive performance will also be evaluated. The successful execution of the study will provide a better understanding of the interactions between AD pathology and cerebrovascular dysfunction in the early phases of AD continuum that could eventually lead to the development of effective multi-component therapeutic interventions of AD that target both AD and vascular pathologies.