Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome (“global” ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles (“local” ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors

Dementia Caregiver Experiences and Recommendations for Using the Behavioral and Environmental Sensing and Intervention System at Home: Usability and Acceptability Study

BackgroundCaregiver burden associated with dementia-related agitation is one of the most common reasons for a community-dwelling person living with dementia to transition to a care facility. The Behavioral and Environmental Sensing and Intervention (BESI) for the Dementia Caregiver Empowerment system uses sensing technology, smartwatches, tablets, and data analytics to detect and predict agitation in persons living with dementia and to provide just-in-time notifications and dyad-specific intervention recommendations to caregivers. The BESI system has shown that there is a valid relationship between dementia-related agitation and environmental factors and that caregivers prefer a home-based monitoring system. ObjectiveThe aim of this study is to obtain input from caregivers of persons living with dementia on the value, usability, and acceptability of the BESI system in the home setting and obtain their insights and recommendations for the next stage of system development. MethodsA descriptive qualitative design with thematic analysis was used to analyze 10 semistructured interviews with caregivers. The interviews comprised 16 questions, with an 80% (128/160) response rate. ResultsPostdeployment caregiver feedback about the BESI system and the overall experience were generally positive. Caregivers acknowledged the acceptability of the system by noting the ease of use and saw the system as a fit for them. Functionality issues such as timeliness in agitation notification and simplicity in the selection of agitation descriptors on the tablet interface were identified, and caregivers indicated a desire for more word options to describe agitation behaviors. Agitation intervention suggestions were well received by the caregivers, and the resulting decrease in the number and severity of agitation events helped confirm that the BESI system has good value and acceptability. Thematic analysis suggested several subjective experiences and yielded the themes of usefulness and helpfulness. ConclusionsThis study determined preferences for assessing caregiver strain and burden, explored caregiver acceptance of the technology system (in-home sensors, actigraph or smart watch technology, and tablet devices), discerned caregiver insights on the burden and stress of caring for persons living with dementia experiencing agitation in dementia, and solicited caregiver input and recommendations for system changes. The themes of usefulness and helpfulness support the use of caregiver knowledge and experience to inform further development of the technology

The Role of Vascular Endothelial Growth Factor-Induced Activation of NADPH Oxidase in Choroidal Endothelial Cells and Choroidal Neovascularization

Rac1, a subunit of NADPH oxidase, plays an important role in directed endothelial cell motility. We reported previously that Rac1 activation was necessary for choroidal endothelial cell migration across the retinal pigment epithelium, a critical step in the development of vision-threatening neovascular age-related macular degeneration. Here we explored the roles of Rac1 and NADPH oxidase activation in response to vascular endothelial growth factor treatment in vitro and in a model of laser-induced choroidal neovascularization. We found that vascular endothelial growth factor induced the activation of Rac1 and of NADPH oxidase in cultured human choroidal endothelial cells. Further, vascular endothelial growth factor led to heightened generation of reactive oxygen species from cultured human choroidal endothelial cells, which was prevented by the NADPH oxidase inhibitors, apocynin and diphenyleneiodonium, or the antioxidant, N-acetyl-l-cysteine. In a model of laser-induced injury, inhibition of NADPH oxidase with apocynin significantly reduced reactive oxygen species levels as measured by dihydroethidium fluorescence and the volume of laser-induced choroidal neovascularization. Mice lacking functional p47phox, a subunit of NADPH oxidase, had reduced dihydroethidium fluorescence and choroidal neovascularization compared with wild-type controls. Taken together, these results indicate that vascular endothelial growth factor activates Rac1 upstream from NADPH oxidase in human choroidal endothelial cells and increases generation of reactive oxygen species, contributing to choroidal neovascularization. These steps may contributed to the pathology of neovascular age-related macular degeneration