Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer disease (AD), we hypothesized that C9ORF72 expansions may contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a rate of 0.76% in AD cases versus zero in controls (p=3.3E-03, 1,182 cases, 1,039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0–23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological reevaluation of identified C9ORF72 expansion carriers revealed nine clinical and/or autopsy confirmed AD and two FTD finial diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.
BackgroundNutrition-sensitive interventions supporting enhanced household food production have potential to improve child dietary quality. However, heterogeneity in market access may cause systematic differences in program effectiveness depending on household wealth and child age. Identifying these effect modifiers can help development agencies specify and target their interventions.ObjectiveThis study investigates mediating effects of household wealth and child age on links between farm production and child diets, as measured by production and intake of nutrient-dense food groups.MethodsTwo rounds (2013 and 2014) of nationally representative survey data (n = 5,978 observations) were used to measure production and children’s dietary intake, as well as a household wealth index and control variables, including breastfeeding. Novel steps used include measuring production diversity in terms of both species grown and food groups grown, as well as testing for mediating effects of family wealth and age of child.ResultsWe find significant associations between child dietary diversity and agricultural diversity in terms of diversity of food groups and of species grown, especially for older children in poorer households, and particularly for fruits and vegetables, dairy and eggs. With each additional food group produced, log-odds of meeting minimum dietary diversity score (≥4) increase by 0.25 (p = 0.01) for children aged 24–59 months. For younger children aged 18–23 months there is a similar effect size but only in the poorest two quintiles of household wealth, and for infants 6–18 months we find no correlation between production and intake in most models.ConclusionsChild dietary intake is associated with the composition of farm production, most evident among older preschool children and in poorer households. To improve the nutrition of infants, other interventions are needed; and for relatively wealthier households, own farm production may displace market purchases, which could attenuate the impact of household production on child diets.
African American (AA) individuals have a higher risk for late-onset Alzheimer’s disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome-wide association study in AAs to date confirmed that six of the AD-related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered. We performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status. Compared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences. Exploratory post-hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.
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