Neuroimaging and postmortem histopathological studies report that up to one-third of AD patients have some degree of vascular pathology. Midlife vascular risk factors, particularly hypertension, have been associated with an increased risk of AD in later life. Similarly, reductions in BP are associated with protection against AD. Ths indicates that long-standing uncontrolled BP and other vascular factors may contribute to AD pathology, possibly through decreased cerebral blood flow (CBF) and accumulation of ?-amyloid (A?) a key pathological feature of preclinical AD. While studies show that vascular risk factors contribute to AD risk and progression, there are currently no effective interventions to prevent or slow AD progression that target these modifiable vascular factors. Although vascular risk factors have been linked to AD, the mechanism has yet to be clarified and it is unknown to what extent these measures interact with ApoE and familial history. Two mechanisms by which vascular risk factors may contribute to AD are reduced CBF and A? neuropathology. To better understand the mechanisms by which increased vascular risk and subsequent arterial dysfunction may modify CBF, A? levels and cognition, we propose a longitudinal study enrolling 80 asymptomatic, middle-aged (45-65 yrs) adults at risk for AD, due to a parental history of AD. We will make use of the University of Wisconsin Alzheimer's Disease Research Center's (ADRC) NIH-funded cohort, comprised of middle-aged participants 'at risk'for AD based on family history and created to facilitate AD prevention studies. This cohort is at high risk for AD and would likely benefit the most from an early intervention. CBF will be quantitatively ascertained via a state-of-the art neuroimaging modality developed at the UW Madison, called 3D phase contrast, vastly undersampled, isotropic voxel radial projection imaging (PC VIPR). This novel technique provides a thorough evaluation of cerebral arterial function, including flow volume, velocity, pressure gradient and shear wall stress, measures closely related to the peripheral arterial indices that we will collect in the proposed project (i.e. pulse-wave velocity and flow mediated vasodilation). CBF will be assessed in the middle and posterior cerebral arteries, bilaterally. These arteries are responsible for blood flow to the hippocampus and frontal lobes, regions impaired in AD. A? levels will be collected in CSF and cognitive tasks of particular interest will include executive function and working memory domains. The objective of the proposed study is to determine the extent to which arterial function, as ascertained by cardiac index, flow-mediated vasodilation (FMD), pulse wave velocity (PWV) and nocturnal blood pressure patterns predict: 1) cerebral blood flow (CBF) in medium and large cerebral arteries and cerebral perfusion via ASL, 2) A? levels in cerebrospinal fluid (CSF) and 3) cognition over 2 years, in participants at-risk for AD based on family history. Outcomes will then be combined to test our model described in the application and determine the primary mechanism by which arterial function may influence cognition (i.e. CBF) over time.
Without intervention, Alzheimer's disease (AD) will exert a devastating human toll. Clarifying the extent to which modifiable midlife, vascular risk factors contribute to changes in brain blood flow and AD biomarkers would contribute to prevention strategies that would, in turn, decrease the incidence of AD.