| dc.description.abstract | Alzheimer’s disease (AD) is a growing public health crisis and there are currently no disease modifying treatments, highlighting the need to reconsider traditional models of AD pathogenesis. It is well-established that vascular health interacts with AD pathology to worsen cognitive outcomes, and cerebrovascular disease exists in up to 87% of all pathologically confirmed dementia cases. However, the pathways by which these pathologies intersect are not well elucidated. Regional white matter damage may provide one intersection point, as vascular disease is the most common etiology of white matter injury and white matter damage has recently been implicated in AD. Among Vanderbilt Memory & Aging Project participants (n=335, 73±7 years, mean follow-up time 3.6±1.8 years), baseline arterial stiffening, indicating age-related vascular changes, related to a faster decline in white matter integrity assessed by diffusion tensor imaging in the temporal and occipital lobes. Blood-brain barrier permeability also related to faster decline in white matter integrity in the temporal lobe. A related to a faster decline in white matter integrity primarily in the frontal lobe, and p-tau related to a faster decline in white matter integrity primarily in the frontal and parietal lobes. Finally, non-specific neurodegeneration related to a faster decline in global white matter integrity. Arterial stiffness and non-specific neurodegeneration were the most robust predictors of future white matter damage. Temporal and frontal white matter tracts seem to be susceptible to multiple pathologies and may provide an intersection point between vascular disease and AD pathology. Importantly, we also found that integrity in the cingulum bundle and uncinate fasciculus, tracts in the temporal and frontal regions, predict decline in memory performance above and beyond other white matter tracts. Each pathology may damage the cingulum bundle or uncinate fasciculus through different mechanisms, individually leading to slower signal propagation and subsequent memory deficits. Each mechanism of damage may have an additive affect, leading to faster decline in memory. Examining the cellular mechanisms leading to injury in the cingulum bundle or uncinate fasciculus may inform new therapeutic targets aimed at slowing memory decline. | |
