Cerebrovascular Pathology Contributes to the Heterogeneity of Alzheimer's Disease

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Abstract
Heterogeneous pathology in Alzheimer's Disease (AD) is due to variability in the nature and severity of lesions, overlap with other neurodegenerative diseases such as Parkinson's disease, or the co-existence of cerebrovascular disease. In the MGH-ADRC autopsy archives, remote cerebral infarcts (CVA) were reported in 30% of the otherwise uncomplicated AD cases. To determine the potential significance of cerebrovascular lesions in relation to AD, the relative densities (CERAD grading criteria) of Bielschowsky-stained AD lesions and Ab-amyloid immunoreactive plaques were compared among cases of AD+CVA (N = 52), AD (N = 48), aged controls (NC; N = 9), and aged controls with AD lesions (ADC; N = 8). The prevalence of the ApoE e4 allele was also determined for each group. This study demonstrated: 1) higher densities of Bielschowsky-stained plaques in AD, AD+CVA, and ADC than in NC (P < 0.0001); 2) more abundant neurofibrillary tangles in AD relative to all other groups (P < 0.0005), and in AD+CVA and ADC relative to NC (P < 0.05); and 3) increased densities of Aβ-amyloid-immunoreactive plaques in AD relative to AD+CVA (P = 0.0003). In AD+CVA, cerebral vascular lesions consisting of remote microscopic cortical and subcortical white matter infarcts, ischemic lesions, and leukoaraiosis were consistently distributed in structures typically damaged by AD neurodegeneration, as well as in the basal ganglia. The ApoE ε4 allele was more prevalent in the AD+CVA (70%) than in the AD (58%) group (P = 0.05). Since the AD and AD+CVA groups had similar degrees of dementia, the results suggest that cerebral vascular lesions in regions typically destroyed by AD may contribute to the clinical manifestations of AD.

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