Alzheimer's & dementia : the journal of the Alzheimer's Association
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Current hypothetical models of Alzheimer's disease (AD) pathogenesis emphasize the role of β-amyloid (Aβ), tau deposition, and neurodegenerative changes in the mesial temporal lobe, particularly the entorhinal cortex and hippocampus. However, many individuals with clinical AD who come to autopsy also exhibit cerebrovascular disease. The relationship between AD and vascular pathology is unclear, especially whether they represent additive and independent effects on neuronal injury. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to (1) confirm whether entorhinal cortex and hippocampal volume are associated with memory among individuals with amnestic mild cognitive impairment (MCI) who are at risk for AD; and (2) determine whether regional white matter hyperintensity (WMH) volume, a radiological marker of small-vessel cerebrovascular disease, is associated with entorhinal cortex and hippocampal volume independent of putative AD biomarkers in this group. ⋯ The findings confirm the role of entorhinal cortex and hippocampus volume in influencing memory decline in amnestic MCI, and emphasize that even in this nominally AD prodromal condition, WMH may be influencing regional neurodegeneration.
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Clinical studies of β-amyloid (Aβ) immunotherapy in Alzheimer's disease (AD) patients have demonstrated reduction of central Aβ plaque by positron emission tomography (PET) imaging and the appearance of amyloid-related imaging abnormalities (ARIA). To better understand the relationship between ARIA and the pathophysiology of AD, we undertook a series of studies in PDAPP mice evaluating vascular alterations in the context of central Aβ pathology and after anti-Aβ immunotherapy. ⋯ These data suggest that vascular leakage events, such as microhemorrhage, may be related to the removal of vascular Aβ. With continued treatment, this initial susceptibility period is followed by restoration of vascular morphology and reduced vulnerability to further vascular leakage events. The data collectively suggested a vascular amyloid clearance model of ARIA, which accounts for the currently known risk factors for the incidence of ARIA in clinical studies.