Objective: The objective of this study was to define whether vascular risk factors interact with b-amyloid (Ab) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD).Methods: Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Ab was assessed using [11 C] Pittsburgh compound B-PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index.Results: Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Ab. These frontotemporal regions are also affected in individuals with Ab deposition, but the latter show additional thinning in parietal cortices. Ab and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Ab has its greatest effect. In this way, the negative effect of Ab in posterior regions is increased by the presence of vascular risk. The prevalence of b-amyloid (Ab), the hallmark of Alzheimer disease (AD), is approximately 25% among cognitively normal elderly individuals, indicating that Ab alone might not be sufficient to drive brain changes and cognitive decline, and that other factors work with Ab to promote disease onset or progression. Vascular risk factors such as hypertension, dyslipidemia, and diabetes are known risk factors for dementia in persons with clinical syndromes suggesting AD pathology. Conclusion:1 One pathway by which vascular risk increases the likelihood of dementia is by causing vascular brain injury (VBI) (e.g., white matter lesions and infarcts). 1,2In vivo studies show that increased vascular risk is related to higher Ab burden. [3][4][5][6] Other work suggests that VBI per se is not associated with elevated Ab, and that the effects of VBI and Ab on brain structure and cognition are independent. 7,8 Together, these findings suggest that vascular risk factors may have independent effects on Ab and VBI, and therefore increase AD risk through multiple pathways.Integrity of the cerebral cortex is a major determinant of cognitive function. 9 A better understanding of the interplay between vascular risk and Ab pathology in relation to cortical thickness might yield insight into the factors that drive the development of AD. In this study, we assessed how Ab and vascular risk, alone and together, affect cerebral cortex, specifically evaluating

The goal of this study was to assess the relationship between Aβ deposition and white matter pathology (i.e., white matter hyperintensities, WMH) on microstructural integrity of the white matter. Fifty-seven participants (mean age: 78±7 years) from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0–0.5) and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume >0.5% total intracranial volume) were assessed with positron emission tomography (PET) with Pittsburg compound B (PiB) and magnetic resonance and diffusion tensor imaging (DTI). Multivariate analysis of covariance were used to investigate the relationship between Aβ deposition and WMH pathology on fractional anisotropy (FA) from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix). WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate) and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi) fiber tracts. Aβ deposition (i.e., PiB positivity) was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Aβ deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE ε4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity) and in blood vessels (resulting in amyloid angiopathy and WMH pathology), and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies with a longitudinal design will be necessary to resolve this issue.

Importance: ␤-Amyloid (A␤) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI's influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD).Objective: To examine the relationship between neuroimaging measures of VBI and brain A␤ deposition and their associations with cognition. Design and Setting:A cross-sectional study in a community-and clinic-based sample recruited for elevated vascular disease risk factors. Participants: Clinically normal (mean age, 77.1 years [N = 30]), cognitively impaired (mean age, 78.0 years [N = 24]), and mildly demented (mean age, 79.8 years [N=7]) participants. Interventions: Magnetic resonance imaging, A␤ (Pittsburgh Compound B-positron emission tomographic [PiB-PET]) imaging, and cognitive testing.Main Outcome Measures: Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early A␤ deposition; PiB positivity (29 PiBpositive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory.Results: Vascular brain injury and A␤ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P Ͻ .05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI. Conclusions and Relevance:In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than A␤ in contemporaneous cognitive function and remained predictive after including the possible influence of A␤. There was no evidence that VBI increases the likelihood of A␤ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.

These findings extend our previous report of structural alterations in the hippocampi of GW veterans with suspected GB/GF exposure to volume changes in the CA2, CA3, and DG hippocampal subfields in a different cohort of GW veterans with suspected GB/GF exposure.

ApoliopoproteinE ε4 (ApoE-ε4) polymorphism is the most well known genetic risk factor for developing Alzheimers Disease. The exact mechanism through which ApoE ε4 increases AD risk is not fully known, but may be related to decreased clearance and increased oligomerization of Aβ. By making measurements of white matter integrity via diffusion MR and correlating the metrics in a voxel-based statistical analysis with ApoE-ε4 genotype (whilst controlling for vascular risk factor, gender, cognitive status and age) we are able to identify changes in white matter associated with carrying an ApoE ε4 allele. We found potentially significant regions (Puncorrected < 0.05) near the hippocampus and the posterior cingulum that were independent of voxels that correlated with age or clinical dementia rating (CDR) status suggesting that ApoE may affect cognitive decline via a pathway in dependent of normal aging and acute insults that can be measured by CDR and Framingham Coronary Risk Score (FCRS).

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