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.

Delirium remains underdetected as a result of its broad constellation of symptoms and the inadequate neuropsychiatric expertise of most medical-surgical clinicians. Brief, accurate tools are needed to enhance detection. Methods:The authors extended validation of the Delirium Diagnostic Tool-Provisional (DDT-Pro), originally validated in a study of inpatients with traumatic brain injury for diagnosis of delirium by nonexpert clinicians, for 200 general medical inpatients in Colombia. The three structured, quantitatively rated items in DDT-Pro represent the three core delirium domains.Results: High interrater reliability between physician and nurse (0.873) administrators, internal consistency (.0.81), and content validity were found. Compared with independent reference standard diagnosis with DSM-5 or the Delirium Rating Scale-Revised-98, the area under the receiver operating characteristic (ROC) curve (global diagnostic accuracy) range was 93.8%296.3%. ROC analysis revealed the same cutoff score (#6) as that for the original study, with somewhat lower sensitivities of 88.0%290.0% and specificities of 85.3%281.2% (independent expert physician or nurse ratings). Even when rated by a trained expert physician, the original version of the Confusion Assessment Method algorithm (CAM-A) performed moderately, with lower sensitivities (61.8%270.0%) than the DDT-Pro (88.0%2 100%) and somewhat higher specificities (84.8%295.3% versus 67.4%286.7%), with values depending on dementia status, reference standard, and rater type. Accuracies for the DDT-Pro and CAM-A were comparable (DDT-Pro: 83.0%2 87.5% versus CAM-A: 87.5%288.5%), although lower in the dementia subgroup, especially for CAM-A. However, these tools were significantly discordant, especially in negative cases, which suggests that they do not detect diagnosis of patients in the same way. Conclusions:The DDT-Pro had high validity and reliability in provisional delirium diagnosis by physicians and nonexpert clinicians, although further validation is warranted before widespread use can be recommended.

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