Genetic Variation in the Androgen Receptor and Measures of Plasma Testosterone Levels Suggest Androgen Dysfunction in Alzheimer’s Disease

Alzheimer’s disease (AD) prevalence varies by sex, suggesting that sex chromosomes, sex hormones and/or their signaling could potentially modulate AD risk and progression. Low testosterone levels are reported in men with AD. Further, variation in the androgen receptor (AR) gene has been associated with AD risk and cognitive impairment. We assessed measures of plasma testosterone levels as a biomarker of AD in male participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Baseline testosterone levels were significantly different between clinical diagnosis groups [cognitively normal controls, mild cognitive impairment (MCI), or AD], with the lowest testosterone levels in men with AD. Lower baseline testosterone levels were associated with higher baseline clinical severity. Change in testosterone levels between baseline and 1-year follow-up varied by diagnosis; MCI had the greatest decreases in testosterone levels between baseline and 1-year follow-up. Despite differences by clinical diagnosis, there was no association between plasma testosterone and CSF biomarkers of AD pathology. We also tested single nucleotide polymorphisms (SNPs) in AR for association with AD risk in a separate cohort from ADNI and found 26 SNPs associated with risk for AD. The top associated SNP is predicted to be an expression quantitative trait locus for AR in multiple tissues, including brain, with the AD-associated risk allele predicted to confer lower AR expression. Our findings suggest a link between the androgen pathway and AD through Aβ/tau independent pathways. These effects may be most pronounced during conversion from MCI to dementia

Susceptibility and Response of Human Blood Monocyte Subsets to Primary Dengue Virus Infection

Human blood monocytes play a central role in dengue infections and form the majority of virus infected cells in the blood. Human blood monocytes are heterogeneous and divided into CD16− and CD16+ subsets. Monocyte subsets play distinct roles during disease, but it is not currently known if monocyte subsets differentially contribute to dengue protection and pathogenesis. Here, we compared the susceptibility and response of the human CD16− and CD16+ blood monocyte subsets to primary dengue virus in vitro. We found that both monocyte subsets were equally susceptible to dengue virus (DENV2 NGC), and capable of supporting the initial production of new infective virus particles. Both monocyte subsets produced anti-viral factors, including IFN-α, CXCL10 and TRAIL. However, CD16+ monocytes were the major producers of inflammatory cytokines and chemokines in response to dengue virus, including IL-1β, TNF-α, IL-6, CCL2, 3 and 4. The susceptibility of both monocyte subsets to infection was increased after IL-4 treatment, but this increase was more profound for the CD16+ monocyte subset, particularly at early time points after virus exposure. These findings reveal the differential role that monocyte subsets might play during dengue disease

Research directions in data wrangling: Visualizations and transformations for usable and credible data

In spite of advances in technologies for working with data, analysts still spend an inordinate amount of time diagnosing data quality issues and manipulating data into a usable form. This process of ‘data wrangling’ often constitutes the most tedious and time-consuming aspect of analysis. Though data cleaning and integration arelongstanding issues in the database community, relatively little research has explored how interactive visualization can advance the state of the art. In this article, we review the challenges and opportunities associated with addressing data quality issues. We argue that analysts might more effectively wrangle data through new interactive systems that integrate data verification, transformation, and visualization. We identify a number of outstanding research questions, including how appropriate visual encodings can facilitate apprehension of missing data, discrepant values, and uncertainty; how interactive visualizations might facilitate data transform specification; and how recorded provenance and social interaction might enable wider reuse, verification, and modification of data transformations

Alzheimer Disease-associated Cortical Atrophy Does not Differ Between Chinese and Whites

PurposeTo assess whether there are differences in Alzheimer disease (AD)-associated atrophy regions in Chinese and white patients with AD versus cognitively normal older adults, and to test whether associations between clinical severity and gray matter volume are similar or different across these ethnic groups in a cross-sectional analysis.Materials and methodsChinese and white patients with AD, individuals with mild cognitive impairment, and cognitively normal controls (46 white and 48 Chinese) were clinically evaluated at an academic center within 1 year of magnetic resonance imaging acquisition. Clinical severity was assessed using the Clinical Dementia Rating Sum of Boxes and cortical atrophy was measured using voxel-based morphometry as well as Freesurfer. Chinese and white cohorts were demographically matched for age, sex, and education.ResultsClinical severity by diagnosis was similar across ethnicities. Chinese and white patient groups showed similar amounts of atrophy in the regions most affected in AD after accounting for demographic variables and head size. There was no significant difference between ethnic groups when compared by atrophy and clinical severity.ConclusionsOur study suggests that Chinese and white patients with AD, when matched demographically, are clinically and neuroanatomically similar on normalized measures of cortical atrophy and clinical severity

Data_Sheet_1_RETRACTED: Genetic Variation in the Androgen Receptor and Measures of Plasma Testosterone Levels Suggest Androgen Dysfunction in Alzheimer’s Disease.docx

Alzheimer’s disease (AD) prevalence varies by sex, suggesting that sex chromosomes, sex hormones and/or their signaling could potentially modulate AD risk and progression. Low testosterone levels are reported in men with AD. Further, variation in the androgen receptor (AR) gene has been associated with AD risk and cognitive impairment. We assessed measures of plasma testosterone levels as a biomarker of AD in male participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Baseline testosterone levels were significantly different between clinical diagnosis groups [cognitively normal controls, mild cognitive impairment (MCI), or AD], with the lowest testosterone levels in men with AD. Lower baseline testosterone levels were associated with higher baseline clinical severity. Change in testosterone levels between baseline and 1-year follow-up varied by diagnosis; MCI had the greatest decreases in testosterone levels between baseline and 1-year follow-up. Despite differences by clinical diagnosis, there was no association between plasma testosterone and CSF biomarkers of AD pathology. We also tested single nucleotide polymorphisms (SNPs) in AR for association with AD risk in a separate cohort from ADNI and found 26 SNPs associated with risk for AD. The top associated SNP is predicted to be an expression quantitative trait locus for AR in multiple tissues, including brain, with the AD-associated risk allele predicted to confer lower AR expression. Our findings suggest a link between the androgen pathway and AD through Aβ/tau independent pathways. These effects may be most pronounced during conversion from MCI to dementia.</p

Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples.

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), but the mechanism by which it causes cognitive decline is unclear. In knockin (KI) mice, human apoE4 causes age-dependent learning and memory impairments and degeneration of GABAergic interneurons in the hippocampal dentate gyrus. Here we report two functional apoE4-KI phenotypes involving sharp-wave ripples (SWRs), hippocampal network events critical for memory processes. Aged apoE4-KI mice had fewer SWRs than apoE3-KI mice and significantly reduced slow gamma activity during SWRs. Elimination of apoE4 in GABAergic interneurons, which prevents learning and memory impairments, rescued SWR-associated slow gamma activity but not SWR abundance in aged mice. SWR abundance was reduced similarly in young and aged apoE4-KI mice; however,&nbsp;the full SWR-associated slow gamma deficit emerged only in aged apoE4-KI mice. These results suggest that progressive decline of interneuron-enabled slow gamma activity during SWRs critically contributes to apoE4-mediated learning and memory impairments. VIDEO ABSTRACT

Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

<div><p>Background</p><p>Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations.</p><p>Methods and findings</p><p>Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case–control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999–2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer’s Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984–2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005–2007 and longitudinal cognitive data from the Alzheimer’s Disease Neuroimaging Initiative (<i>n</i> = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype <i>A*03</i>:<i>01~B*07</i>:<i>02~DRB1*15</i>:<i>01~DQA1*01</i>:<i>02~DQB1*06</i>:<i>02</i> (<i>p</i> = 9.6 x 10⁻⁴, odds ratio [OR] [95% confidence interval] = 1.21 [1.08–1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E <i>(APOE</i>) ɛ4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype <i>A*03</i>:<i>01~B*07</i>:<i>02</i> (<i>p</i> = 0.03, OR = 1.11 [1.01–1.23]) and class II haplotype <i>DRB1*15</i>:<i>01- DQA1*01</i>:<i>02- DQB1*06</i>:<i>02</i> (<i>DR15</i>) (<i>p</i> = 0.03, OR = 1.08 [1.01–1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying <i>A*03</i>:<i>01~B*07</i>:<i>02</i> was associated with higher CSF amyloid levels (<i>p</i> = 0.03, β ± standard error = 47.19 ± 21.78). We also found a dose-dependent association between the <i>DR15</i> haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer’s Disease Assessment Scale cognitive subscale [ADAS11] over time [<i>p</i> = 0.03, β ± standard error = 0.7 ± 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [<i>p</i> = 0.02, β ± standard error = −0.2 ± 0.06]). In a subset of the same cohort, dose of <i>DR15</i> was also associated with higher baseline levels of chemokine CC-4, a biomarker of inflammation (<i>p</i> = 0.005, β ± standard error = 0.08 ± 0.03). The main study limitations are that the results represent only individuals of European-ancestry and clinically diagnosed individuals, and that our study used imputed genotypes for a subset of HLA genes.</p><p>Conclusions</p><p>We provide evidence that variation in the HLA locus—including risk haplotype <i>DR15</i>—contributes to AD risk. <i>DR15</i> has also been associated with multiple sclerosis, and its component alleles have been implicated in Parkinson disease and narcolepsy. Our findings thus raise the possibility that <i>DR15</i>-associated mechanisms may contribute to pan-neuronal disease vulnerability.</p></div